Cocaine and food deprivation

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Cocaine and food deprivation effects on food-reinforced fixed-ratio performance in pigeons
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Hughes, Christine E., 1963-
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Cocaine   ( lcsh )
Food supply   ( lcsh )
Reinforcement (Psychology)   ( lcsh )
Pigeons -- Behavior   ( lcsh )
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theses   ( marcgt )
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Thesis:
Thesis (Ph. D.)--University of Florida, 1991.
Bibliography:
Includes bibliographical references (leaves 111-119).
Statement of Responsibility:
by Christine E. Hughes.
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Typescript.
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Vita.

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oclc - 25604939
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COCAINE AND FOOD DEPRIVATION: EFFECTS ON
FOOD-REINFORCED FIXED-RATIO PERFORMANCE IN PIGEONS





















By

CHRISTINE E. HUGHES


A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA


1991































This dissertation is dedicated to
one of the pioneers in Behavioral Pharmacology:

Dr. Burrhus Frederic Skinner
(1904 1990)













ACKNOWLEDGMENTS

This research was supported by Grant No. DA04074 from

the National Institute on Drug Abuse. Portions of these

data were presented at the 17th Annual Convention of the

Association for Behavior Analysis, Atlanta, GA, May 1991.

First, I would like to thank my Canadian and Floridian

families for all their forms of support over the past five

years, especially my parents who taught me that education

was something that should be cherished.

I thank Dr. Jeff Arbuckle, Forrest Files, and Glen

Sizemore for technical and/or conceptual input for this

experiment and especially thank Janelle Betts, Marilyn

Dalzin, Mark Reilly, and Jay Steel for assistance in the

daily running of the experiment and upkeep of the subjects

and equipment. Special thanks are extended to Dr. Steve

Dworkin for the use of his computers, software, and paper.

Drs. Jeff Farrar and Fulton Crews are thanked for

expanding the data and theoretical base from which I think

about things. I would like to thank Dr. Brian Iwata for his

support, financial and otherwise, and interest in my

training over the past five years. Dr. Ed Malagodi is

gratefully thanked for numerous radical things (including an

expanded world view), many hours of listening to my


iii







ratings, and his friendship. In addition, the above are

thanked for their committee-related behavior.

Billie O'Conner, Kevin Schama, Diana Walker, Jennifer

Zarcone, and Troy Zarcone are thanked for their vast support

both in and out of the lab. The completion of this document

is, to some degree, a function of their friendships. I

would especially like to thank Kevin for his perseverance

with respect to the computer system, for forcing me to learn

things I could have gotten away without doing, and for his

respect.

I would like to thank my advisor and chairperson of my

doctoral committee, Dr. Marc Branch, for five years of

financial support, for a non-punishing environment in which

to have my repertoires as a behavior analyst, behavior

pharmacologist, and radical behaviorist shaped, and for

understanding my need to escape. Over the years, he has

engendered in me a true fan and friend.

Finally, I would like to thank the person to whom

everything is owed: my husband Dr. Raymond Pitts. I thank

him for assistance in completing many of the initial aspects

of the present experiment (including Phase 1), the use of

his computer, financial support, and critical evaluation of

this document. I also thank him for the less tangible

things: his love, guidance, respect, and insistence that I

stand on my own two feet. Most importantly, he is thanked

for being my husband and best friend.














TABLE OF CONTENTS
page

ACKNOWLEDGMENTS............................ ............. iii

ABSTRACT................... .............................* vi

INTRODUCTION .. ........... ............. .................. 1

Pharmacological Variables............................ 2
Type of Behavior....................................... 5
Stimulus Conditions.................................. 6
Reinforcement Variables.............................. 13
Behavioral Properties................................. 18
Motivational Variables.................................. 20

METHOD..... ............................................. 28

Subjects........ ..................... .................. 28
Apparatus............................................. 28
Procedure...... ....................................... 0 30
Phase 1: Acute Drug Effects at 80% ffw.............. 31
Phase 2: Acute Drug Effects at 70% or 90% ffw...... 33
Phase 3: Chronic Drug Effects at 70% or 90% ffw.... 35
Phase 4: Chronic Drug Effects upon Return
to 80% ffw................................ 36
Phase 5: Chronic Administration of Saline
(Drug Withdrawal) ..................... 36

RESULTS. ... ....................... ...................... 37

Phases 1 and 2: Acute Drug Effects................... 37
Phase 3: Chronic Drug Effects at 70% or 90% ffw...... 54
Phase 4: Chronic Drug Effects upon Return
to 80% ffw................................ 71
Phase 5: Chronic Administration of Saline
(Drug Withdrawal).. ..................... 86

DISCUSSION..... ........ .......................... ....... 89

REFERENCES.... ........................................... 111

BIOGRAPHICAL SKETCH.................................... 120













Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy

COCAINE AND FOOD DEPRIVATION: EFFECTS ON
FOOD-REINFORCED FIXED-RATIO PERFORMANCE IN PIGEONS

By

Christine E. Hughes

December, 1991

Chairperson: Marc N. Branch, Ph.D.
Major Department: Psychology

Key pecking by six pigeons was maintained by a fixed-

ratio 30 schedule of food presentation while the pigeons

were maintained at 80% of their free-feeding body weights.

For each pigeon, acute administration of cocaine (0.3-13.0

mg/kg, i.m.) produced dose-dependent decreases in overall

response rate. Three pigeons' body weights then were

decreased to 70% of their free-feeding weight. Response-

rate decreases generally were attenuated when cocaine's

acute dose-effect curves were redetermined at this new

weight. The other three pigeons' body weights were

increased to 90% of their free-feeding weights. Response-

rate decreases generally were enhanced for these three

pigeons when cocaine's acute effects were redetermined.

During repeated daily administration of a fixed dose of

cocaine, tolerance to the rate-decreasing effects developed







for all subjects. That is, not only did tolerance develop

in all subjects, but there were no substantial differences

between groups in the nature or degree of the tolerance

observed. The rate at which responding recovered during

repeated cocaine administration was relatively quick (6

days) for subjects in the 70%-ffw group, whereas only one

subject in the 90%-ffw group started responding within 4

days of repeated exposure to cocaine. The other two

subjects did not start responding until after 34 (234) and

30 (233) days of repeated exposure to cocaine and

administrations of saline probes. When body weights then

were increased from 70% to 80% of free-feeding weight while

cocaine was still administered chronically, all of the

pigeons stopped responding. One of these pigeons started

responding 90 days later, but the degree of behavioral

tolerance was diminished. The other pigeons began to

respond after 8 to 10 days, and the degree of tolerance did

not change or increased only slightly. When body weights

were decreased from 90% to 80% of free-feeding weight while

cocaine was still administered chronically, the degree of

behavioral tolerance increased immediately for two pigeons

and remained the same for the third subject. Level of food

deprivation was not a determinant of whether tolerance

developed or the degree to which it developed under the

conditions of these experiments, but may be a partial

determinant of when behavioral tolerance is first evident.


vii













INTRODUCTION

Behavioral effects of a drug often depend upon the

administration regimen. For example, effects of a drug can

change when it is administered repeatedly (chronically).

Two types of changes are generally reported. One, the drug

may produce a bigger effect, i.e., behavioral sensitization

(reverse tolerance) occurs. Two, the drug may produce a

smaller effect, i.e., behavioral tolerance develops. These

two kinds of effects may be produced only at the chronically

administered dose, i.e., effects of other doses may remain

unchanged. If so, the behavioral tolerance or sensitization

is considered dose-specific. More commonly, however,

behavioral tolerance or sensitization is seen not only at

the chronically administered dose, but also at other doses

of the drug. In such cases, the dose-effect curve may be

shifted either to the left (sensitization), and, therefore,

smaller doses are required to produce a particular effect,

or to the right (tolerance), and, therefore, larger doses

are required to produce a particular effect.

Both sensitization and tolerance to cocaine's

behavioral effects have been demonstrated in laboratory

research. A goal of behavioral pharmacology has been to

delineate the environmental conditions under which either









will develop. To this end, several classes of variables

have been identified as determinants of the development of

sensitization and/or tolerance to cocaine's effects: (1)

pharmacological variables such as dose of cocaine,

intermittency of administrations, or prior chronic

administration of another drug; (2) type of behavior

measured; (3) the environmental context (stimulus

conditions) present while cocaine is administered; (4)

reinforcement variables: how reinforcer delivery is changed

as a function of the drug and how reinforcers are scheduled

under non-drug conditions; and (5) behavioral properties

under non-drug conditions, e.g., the force or the complexity

of the required response. These five classes of variables

are discussed in more detail in what follows.

Pharmacological Variables

A critically important variable that may determine

whether behavioral sensitization or tolerance is observed is

the dose of cocaine. Reith (1986) showed that sensitization

occurred to effects of cocaine on locomotor activity in mice

at doses smaller than 25.0 mg/kg while tolerance developed

to the same effects at larger doses. In contrast, Branch

(1990) found that after 158 days of administration of 10.0

mg/kg cocaine, sensitization developed to cocaine's rate-

decreasing effects on pigeons' keypecking maintained by

random-interval (RI) schedules. When the dose was decreased

to 7.4 mg/kg cocaine, response rates increased indicating







3

that behavioral tolerance developed. The nature of the role

that the dose of cocaine plays in the development of

behavioral tolerance or sensitization is not clear; chronic

administration of large doses produced tolerance in one

situation (Reith) and sensitization in the other (Branch).

It may be that the dose of cocaine interacts with the type

of behavior measured (respondent or operant). The results

from these two studies point to the importance of

determining effects of cocaine at multiple doses when it is

administered chronically.

The intermittency of administration of the dose of

cocaine also can play a role in the development of

behavioral sensitization and tolerance. Chronic

administration usually refers to the administration of a

dose of the drug prior to every session in which the

behavioral effects of the drug are measured. When cocaine

or d-amphetamine has been administered to rats using an

implanted pellet that delivered the drug continuously,

sensitization to locomotor activity and stereotypy have not

developed, but have developed when the drug has been

administered intermittently (Nelson & Ellison, 1978; Reith,

Benuck, & Lajtha, 1987).

In addition, it appears that drugs classified as

psychomotorr stimulants" (e.g., d-amphetamine, cocaine, and

methylphenidate) do not have to be administered prior to

every experimental session for behavioral tolerance to







4

develop. Smith and McKearney (1977) found that during acute

administrations (twice weekly) of various doses of d-

amphetamine, the initial rate-increasing effects of the drug

on pigeons' keypecking maintained by a differential

reinforcement of low-rates (DRL) schedule of food

presentation diminished. In other studies the inter-

injection intervals of methylphenidate and cocaine were

systematically varied. In one of these studies, tolerance

to the reduction of milk-drinking in rats produced by 15.0

mg/kg methylphenidate developed to the same degree when

either zero, one, or three drug-free days intervened between

each of 15 drug administrations (Emmett-Oglesby & Taylor,

1981). Preliminary data from another experiment indicate

that tolerance also developed to the rate-decreasing effects

on keypecking, maintained by a fixed-ratio (FR) 30 schedule

of food presentation, of pigeons when 3.0 mg/kg cocaine was

administered once every 8 days, and saline was administered

prior to the intervening sessions (Hughes, Stafford, &

Branch, 1991). Tolerance did not develop as completely when

5.6 mg/kg cocaine was administered once every 8 days.

Again, here the dose of cocaine seems to be a critical

factor in the development of behavioral tolerance.

A third pharmacological variable that has been shown to

play a role in the development of tolerance to cocaine's

behavioral effects is a prior history of repeated

administrations of d-amphetamine. In a study by Woolverton,









Kandel, and Schuster (1978b) different groups of rats

received repeated administrations of either d-amphetamine or

cocaine until tolerance to the drug-produced reduction of

milk-drinking had developed. When cocaine was substituted

for d-amphetamine and vice versa, cross-tolerance to the

substituted drug's behavioral effects was evident. That is,

tolerance had developed to+ the behavioral effect of cocaine

or d-amphetamine as a function of repeated administrations

of another drug with similar pharmacological actions.

Type of Behavior

When cocaine is administered repeatedly, the usual

result is sensitization to its effects on reflexive (non-

operant) behavior. For example, with repeated

administration of cocaine, levels of motor activity,

sensitivity to seizures, and stereotypic behavior, e.g.,

sniffing, head bobbing, and rearing, increase across a

variety of species (e.g., Downs & Eddy, 1932a, 1932b; Post,

Kopanda, & Black, 1976; Post & Rose, 1976; Shuster, Yu, &

Bates, 1977). There have been studies, however, in which

tolerance developed to convulsions in both cats (Castellani,

Ellinwood, & Kilbey, 1978) and monkeys (Matsuzaki,

Springler, Misra, & Mule, 1976) and to cardiorespiratory

effects in monkeys (Matsuzaki et al., 1976). Behavioral

tolerance, rather than sensitization, usually develops to

cocaine's effects on schedule-controlled behavior (i.e.,

intermittently reinforced operant behavior) across a variety









of schedules of reinforcement, behavioral measures, and

species (see Wolgin, 1989 for a review). Sensitization has

also been documented, however, in a few studies involving

similar behavioral procedures (e.g., Branch, 1990).

Therefore, the type of behavior is not a clear predictor of

the development of behavioral tolerance or sensitization to

cocaine's effects.

Stimulus Conditions

The environmental (stimulus) conditions present when

cocaine is administered can modulate the development of

behavioral sensitization and tolerance to cocaine's effects.

One important stimulus variable is the presence of the drug

while the organism's behavior is being measured.

Sensitization in locomotor activity and stereotypy was

observed in groups of rats that were injected repeatedly

with 10.0 mg/kg or 15.0 mg/kg of cocaine before experimental

sessions. Sensitization to these effects was not evident

when the same dose and number of injections were

administered to groups of rats after sessions so that they

did not experience the testing apparatus while under the

influence of the drug (e.g., Barr, Sharpless, Cooper,

Schiff, Paredes, & Bridger, 1983; Post, Lockfeld, Squillace,

& Contel, 1981).

Similarly, Woolverton, Kandel, and Schuster (1978a)

found that tolerance developed to cocaine's reduction of

milk-drinking of rats when cocaine was administered prior to









each session, but when cocaine was administered after each

session the disruptive effects increased (sensitization).

Branch and Sizemore (1988) also found that tolerance

developed to cocaine's rate- and accuracy-decreasing effects

on 2- to 5-response sequences by squirrel monkeys only when

cocaine was administered prior to sessions. These data

suggest that operant behavior must be reinforced while

cocaine is acting in order for tolerance to the initial

behavioral effects to develop.

Hinson and Poulos (1981) showed that the development of

sensitization to locomotor effects in rats was not only

dependent on the pairing of the drug effect and opportunity

to engage in the behavior, but also on environmental stimuli

(environmental context) associated with drug delivery. Rats

were injected 13 times with 30.0 to 40.0 mg/kg of cocaine in

a distinct environment (cocaine environment) and 13 times

with saline in a different environment (saline environment).

During test sessions cocaine was administered in both

environments. Sensitization to cocaine's effects on

locomotor activity had developed and was only observed

during test sessions when the rats were administered cocaine

in the cocaine environment. When cocaine was administered

to rats in the saline environment, there was no increase in

locomotor activity. Utilizing the same two-environment

procedure as described above, Poulos, Wilkinson, and Cappell

(1981) demonstrated that tolerance to amphetamine-induced









anorexia in rats was also context specific. Again, the

initial reduction in eating produced by amphetamine in rats

was attenuated with repeated exposure to the drug only in

the environment paired with amphetamine injections.

It has been proposed that a behavioral mechanism of

context-dependent sensitization and tolerance is respondent

conditioning (see Siegel, 1989 for a review). A behavioral

mechanism of drug action is an explanation of a drug's

effects in terms of known behavioral processes. In

respondent conditioning, the presentation of a stimulus (US;

unconditional stimulus) that elicits an unconditional

response (UR) is repeatedly preceded by a presentation of a

novel stimulus (CS; conditional stimulus) and the CS can

come to elicit a conditional response (CR). The CR is

usually the same form and quantitatively similar to the UR;

however, in some cases the CR is opposite to that of the UR.

For example, when an audible tone (CS) was presented

repeatedly prior to an electric shock (US) to humans, the CS

came to elicit a decrease in heart rate which was opposite

to the UR, an increase in heart rate (Notterman, Schoenfeld,

& Bersh, 1952). The respondent model of behavioral

tolerance and sensitization considers the effects produced

by a drug as the UR. When a drug is administered

repeatedly, the drug-injection stimuli, e.g., time of day,

injection room, needle insertion, etc., precede the US (the

drug). These CSs are thought to elicit a CR that, in the









case of sensitization, is similar to the UR (the drug

effect) and in the case of tolerance, is opposite to the UR.

In both cases the CR and UR are thought to be algebraically

additive. For example, in the case of behavioral tolerance

the CR is opposite to the UR and when these responses are

added the measured response is smaller than the original

effect. When injections of cocaine occur in a novel

environment, the contextual cues of the novel environment do

not elicit a compensatory CR, and the effect of the drug

(UR) is similar to that of an initial injection. Therefore,

tolerance is not evident. When saline injections occur in

the environment previously paired with cocaine, the

contextual cues elicit the compensatory CR, and the overall

effect of the saline administration is opposite to the

initial effect of the drug.

Manipulations of relationships between the drug US and

environmental stimuli often produce results consistent with

results of the same sorts of manipulations with non-drug

stimuli, thus supporting respondent conditioning as a

behavioral mechanism of context-specific sensitization and

tolerance. For example, when an animal is exposed to the CS

but not administered the drug, i.e., when an extinction

procedure is implemented, tolerance or sensitization

diminishes presumably because the CR is no longer elicited

(Siegel, 1989). Also, if the drug environment and the drug

are presented independently, i.e., according to the "truly









random" control procedure for respondent conditioning

(Rescorla, 1968), tolerance is not evident (Siegel, 1989).

There are some data, however, that conflict with a

respondent-conditioning model of context-specific

sensitization and tolerance. Sensitization to cocaine's

effects on rotational behavior in rats has been evident

after only one injection (Lin-Chu, Robinson, & Becker,

1985). Generally, multiple pairings of the CS and the US

must occur before the CS elicits a CR, however, a

conditioned taste aversion can develop after only one

pairing of food (CS) and noxious stimuli (US). Also, in

some studies a CR has not been observed under specific

conditions expected to produce one (Shuster et al, 1977;

Post & Rose, 1976). In these studies, after sensitization

developed to cocaine's increase in locomotor activity and

stereotypy in rodents, during test sessions saline was

administered in the environment where the drug had been

administered. According to the respondent-conditioning

interpretation, the stimuli associated with cocaine

injections (CS) should elicit the CR, which in the case of

sensitization is similar to the drug effect, i.e., an

increase in locomotor activity. In these studies, however,

locomotor activity did not increase relative to non-

injection levels.

In addition to these experimental data, the fact that

the CR elicited by the drug-context stimuli can be either









opposite or similar to the UR produced by the drug

compromises the predictive utility of the respondent-

conditioning model of drug sensitization or tolerance.

Further research is required to delineate the conditions

under which either will occur and to quantify the nature of

the CR.

Behavioral tolerance to cocaine's effects on schedule-

controlled behavior also has been shown to be context-

specific (Smith, 1990). Rats were exposed daily to three

different sets of contingencies in distinctly different

environments with sessions separated by 3 to 4 hours. In

one chamber nose poking (through a hole to break a photo

beam) was maintained by a free-operant avoidance schedule:

a brief shock was delivered every 5 s in the absence of

responses and each response postponed the delivery of shock

for 30 s. In two other distinct chambers nose-key pressing

was maintained by either a fixed-interval (FI) 5 min or an

FR 30 schedule of food presentation. When 13.0 mg/kg

cocaine was administered repeatedly at the end of the third

session (the FR session), tolerance did not develop in any

condition. This outcome is similar to the findings of

Woolverton et al. (1978a) and Branch and Sizemore (1988) in

that daily post-session drug administration produced little

change in the drug's effects. Cocaine then was administered

prior to the third session (FR schedule) each day for four

weeks, then prior to only the second session (FI schedule)







12

for four weeks, and, finally, before only the first session

(avoidance procedure) for four weeks. Tolerance developed

to the rate-decreasing effects of cocaine during the FR- and

FI-sessions only when cocaine was administered prior to

these sessions. Thus the development of behavioral

tolerance did not transfer across schedules of reinforcement

or environments. It is not apparent, however, which

aspects) of the scheduling contingencies or environments,

as there were several concurrent manipulations, was(were)

responsible for the lack of transfer. Cocaine initially

increased response rates and did not affect reinforcement

rate during the avoidance schedule; tolerance did not

develop to these effects. (See Reinforcement Variables)

In a similar experiment, Emmett-Oglesby, Spencer, Wood,

and Lal (1984) found that the development of tolerance to d-

amphetamine's effects was behaviorally specific. Rats'

lever pressing was maintained by a DRL schedule of food

presentation on one day and milk drinking was measured (ml)

during a 20-min session on the next day. The types of

sessions alternated daily. d-Amphetamine was administered

prior to either the DRL session or the milk-drinking session

for different groups of rats, and saline was administered

prior to the other session. Initial administrations of d-

amphetamine increased response rates during the DRL

sessions, thus decreasing the number of reinforcers obtained

per session, and decreased milk consumption in the other









type of session. Tolerance developed to d-amphetamine's

effects on the behavior prior to which the drug was

administered. When d-amphetamine was administered prior to

the other type of session no tolerance was evident.

Therefore, behavioral tolerance did not transfer across two

different classes of behaviors.

Reinforcement Variables

In the experiment by Smith (1990), tolerance did not

develop to the rate-increasing effects of cocaine on

avoidance responding in which shock rate (negative

reinforcement rate) was not affected by acute

administrations of cocaine. This result suggests that a

drug-produced initial decrease in reinforcement frequency

may be a factor important to the development of tolerance to

cocaine's effects on schedule-controlled behavior. For many

behaviorally active drugs, including cocaine, development of

tolerance to behavioral effects can depend on the initial

effect of reducing reinforcement frequency (see Corfield-

Summer & Stolerman, 1978; Goudie & Demellweek, 1986 for

reviews). In one study, for example, rats' lever pressing

was maintained by either an FI or a DRL schedule of food

presentation within the context of a multiple schedule

(Schuster, Dockens, & Woods, 1966). The multiple schedule

allowed determination of a drug's effects on behavior under

two different reinforcement schedules within an individual

organism at the same time by arranging two distinct









discriminative stimuli associated with each schedule of

reinforcement. Acute administrations of d-amphetamine

increased response rates maintained by both schedules which

produced a decrease in reinforcement rate in the DRL

component only. Tolerance to these rate-increasing and

reinforcement-decreasing effects developed in the DRL

component; tolerance to the rate-increasing effects on the

FI performance did not develop. Such findings have led to

the formulation of the "reinforcement-density" or

"reinforcement-loss" hypothesis which states that, other

things being equal, tolerance will be more likely to

develop, develop more completely, or develop more rapidly,

to a drug's behavioral effects if those effects include a

reduction in reinforcement frequency.

An extension of the "reinforcement-loss" hypothesis was

offered by Smith (1986). Pigeons' keypecking was maintained

by a multiple random-ratio (RR) DRL schedule of food

presentation. d-Amphetamine initially decreased response

rates maintained by the RR schedule and increased response

rates maintained by the DRL schedule; as a result, there was

reinforcement loss under both conditions. Behavioral

tolerance developed to the rate-decreasing effects in the RR

component, but did not develop to the rate-increasing

effects seen in the DRL component. When the RR component

was removed from the schedule, and only the DRL contingency

was in effect, tolerance developed to the rate-increasing









effects. Subsequently when the RR component was

reintroduced, the recently developed behavioral tolerance in

the DRL component diminished, while tolerance remained

evident in the RR component. Smith suggested that tolerance

developed to the rate-decreasing effects of d-amphetamine

during the RR component because the initial loss of

reinforcement during this component was relatively large

compared to the loss during the DRL component. When the RR

component was removed and all the reinforcers were obtained

via the DRL contingencies, tolerance developed to the rate-

increasing effects of d-amphetamine. Therefore, Smith

concluded that the development of behavioral tolerance was

influenced by the "global" density of reinforcement, that

is, tolerance developed in the situation in which there was

an initial proportionally greater loss of reinforcement.

Contrary to the above findings, behavioral tolerance

has developed under conditions in which cocaine initially

increased response rates and had no effect on the

reinforcement rate of lever-pressing by squirrel monkeys

maintained by FI schedules of food presentation (Branch,

1979; Howell & Morse, 1989; Schama & Branch, 1990) and

stimulus-shock termination (Branch, 1979). These data imply

that an initial decrease in reinforcement rate is not a

necessary condition for the development of tolerance. These

effects may be a function of the interaction of the dose of

cocaine and the development of tolerance. Usually in the









above situations small doses of cocaine increase response

rates, whereas larger doses decrease response and

reinforcement rates.

The schedule of reinforcement maintaining responding

also has been shown to modulate the development of tolerance

to the behavioral effects of cocaine. In a study by

Hoffman, Branch, and Sizemore (1987), pigeons' keypecking

was maintained by a three-component multiple FR schedule of

food presentation in which components differed with respect

to the size of the ratio ("small," "medium," or "large").

When administered acutely, cocaine decreased response rates

in each of the components. After daily administration of

5.6 mg/kg cocaine, tolerance to these rate-decreasing

effects generally was observed under the "small" and

"medium" ratios, but not at all or to a lesser degree under

the "large" ratio. Comparable results were found with

squirrel monkeys when their lever pressing was maintained by

a similar schedule of food presentation (Hughes & Branch,

1991) and with pigeons when keypecking was maintained by a

multiple schedule comprised of three different values of RR

schedules (Branch, 1990). In addition, tolerance was

observed to a greater degree earlier in the session in

components consisting of the smaller of two ratios in a

multiple schedule (e.g., Mult. FR 45 FR 90). The same

degree of tolerance was not observed when this same "small"

ratio was the "large" ratio in another multiple schedule









(e.g., Mult. FR 10 FR 45) for a different pigeon (Files,

1991). Thus, not only is behavioral tolerance development a

function of the absolute ratio size, but relative ratio size

also is important. In the above studies, reinforcement

frequency was initially decreased by cocaine under each of

the ratio contingencies, yet tolerance did not develop in

the larger-ratio components. Therefore, these are

additional data indicating that reinforcement loss is not a

sufficient condition for the development of tolerance to

cocaine's effects on schedule-controlled behavior.

In the studies that investigated reinforcement-schedule

parameter as a determinant of behavioral tolerance,

differences in response requirements across ratios were

confounded with differences in baseline reinforcement rates,

which varied across ratio values. In order to investigate

directly the role of baseline reinforcement rates on the

development of tolerance to the rate-decreasing effects of

cocaine, Schama and Branch (1989) employed FI schedules of

different parameters. Fixed-interval schedules require only

one response per reinforcer, independent of the interval

value, and reinforcement rates depend largely on the

interval value; that is, response rates may vary widely yet

have little effect on reinforcement rate. The FI values

were selected to produce baseline reinforcement rates

comparable to those obtained in the Hoffman et al. (1987)

study. Keypecking by pigeons was maintained by a three-









component multiple FI schedule of food presentation (FI 5s,

FI 30s, and FI 120s). Tolerance was observed under each FI

schedule. That is, the baseline rate of reinforcement did

not modulate how or whether tolerance developed. Similar

results were found when pigeons' keypecking was maintained

by RI schedules (Branch, 1990). These results suggest that

the response requirement per reinforcer was crucial in the

differential development of tolerance observed under FR

schedules (Branch, 1990; Files, 1991; Hoffman et al., 1987;

Hughes & Branch, 1991) and that baseline reinforcement rates

were less important.

Behavioral Properties

Hoffman et al. (1987) pointed to the ratio of responses

per reinforcer as a modulator in the development of

behavioral tolerance to cocaine and proposed that increasing

the number of responses was analogous to increasing the

amount of required effort. In an extension of the Hoffman

et al. study, Schama and Branch (1991) examined effects of

repeated exposure to cocaine on monkeys' lever pressing on

two levers, each requiring different amounts of force in a

context of a multiple schedule of food presentation.

Sensitization, and not tolerance, developed to cocaine's

rate-decreasing effects in both components, and the degree

of sensitization was slightly greater in the component

requiring the greater force. These data indicate that

number of required responses is not comparable to force







19

requirement as a determinant of tolerance to cocaine's rate-

decreasing effects. In the above study, rates remained

suppressed even when saline was administered during the

chronic regimen and at the end of the experiment when saline

was administered chronically. These residual suppressive

effects are consistent with effects seen with squirrel

monkeys during the large-ratio components in the study by

Hughes and Branch (1991) in which there was differential

development of behavioral tolerance, so, with regard to

residual effects, ratio size and force requirement seem

similar.

A second behavioral property that has been suggested to

be important in the development of tolerance to cocaine's

effects is the degree of stimulus control under which

behavior is maintained. Thompson (1977) arranged two

conditions in which four-response sequences emitted by

pigeons were reinforced either in a "learning" condition (a

different sequence was established each session) or in a

"performance" condition (the same sequence was repeated

across sessions). Tolerance to the rate- and accuracy-

decreasing effects of cocaine developed less completely, and

more slowly, during the "learning" condition. He cited the

lower degree of stimulus control over the response sequences

during the condition in which a new response sequence was

required each session as a determinant of the rate and

extent of tolerance development. Thompson also reported







20

that changes in responding during timeouts during the inter-

trial interval, where there were no contingencies arranged

for keypecking, did not show any evidence of tolerance.

This finding is in accord with a reinforcement-loss view as

there was not a possibility of a loss of reinforcement with

changes in responding.

In another experiment, pigeons' keypecking was

maintained in a delayed matching-to-sample procedure (Branch

& Dearing, 1982). A sample stimulus was presented and

contingent on key pecks was turned off. Two comparison

stimuli were presented after a delay that was systematically

varied. Responses to the comparison stimulus that matched

the sample stimulus were reinforced. As the delay

increased, percentage of correct responses, or accuracy,

decreased. Acute administrations of cocaine decreased rate

and accuracy of responding. Tolerance to the latter effect

developed relatively slowly at the longest-delay condition.

Performance at the longest delay was not as well controlled

by the presentation of the sample stimulus as that at

shorter delays (poorer stimulus control). Therefore, these

data are consistent with Thompson's (1977) view.

Motivational Variables

One class of variables that has not been investigated

as a factor in the development of behavioral tolerance or

sensitization to cocaine's effects includes what

traditionally have been called "motivational" variables,









e.g. level of deprivation, amount of reinforcement,

presentation of aversive stimuli. In one study, level of

food deprivation was investigated as it pertained to the

development of tolerance to d-amphetamine's reduction in

milk consumption of rats (Demellweek & Goudie, 1983).

Groups of rats were fed 6, 12, or 18 g of lab chow and

injected with 1.0 mg/kg d-amphetamine prior to sessions in

which they had 30-min access to condensed milk. Milk

consumption initially was decreased similarly by d-

amphetamine in each of the food-deprived groups compared to

a group that was fed 12 g of lab chow and injected with

saline prior to sessions. Tolerance to these decreases in

milk consumption developed in each group at the same rate,

but not to the same degree. At the end of 21 days of

chronic d-amphetamine administration, the rats that were

pre-fed 6 g of lab chow (most food deprived) were consuming

as much milk during sessions as the rats that received only

saline, i.e., complete behavioral tolerance had developed.

The groups of rats that were pre-fed 12 and 18 g of lab chow

were consuming equivalent amounts of milk, but less than the

group pre-fed 6 g of lab chow, at the end of the chronic

regimen.

Although level of food deprivation has not been

investigated as a determinant of behavioral tolerance or

sensitization to cocaine's effects on schedule-controlled

behavior, it has been manipulated in investigations of acute









effects of drugs other than cocaine. Generally, acute

effects of drugs classified as psychomotorr stimulants"

decrease when the level of deprivation is increased.

Specifically, d-amphetamine decreased averaged response

rates of lever pressing, maintained by an FR 8 schedule of

sucrose presentation, of a group of rats maintained at 100%

of their free-feeding body weights (ffw). Response rates

were decreased by approximately 20% to 40% of control rates

at 0.1 mg/kg and 0.25 mg/kg d-amphetamine and by 80% at 0.5

mg/kg d-amphetamine. In contrast, response rates were

increased and/or only slightly decreased (by 5% to 10%) at

all doses in a second group of rats maintained at 80% ffw.

(Samson, 1986). In another study, three groups of rats were

maintained at 60%, 80%, and 100% ffw, and lever pressing was

established under an FR 50 schedule of milk presentation.

The rate-decreasing effects of d-amphetamine were largest

for the group maintained at 100% ffw and were less, but

equivalent, for the two groups maintained at 60% and 80% ffw

(Gollub & Mann, 1969). The lack of a difference between the

latter two groups may reflect an interaction between ratio

size and level of deprivation as determinants of the acute

effects of a drug. As noted above, within the context of a

multiple schedule, responding maintained by large FRs has

been more sensitive to cocaine's rate-decreasing effects

than has behavior under small FRs (Hoffman et al., 1987;

Hughes & Branch, 1991). In the Gollub and Mann study, lever









pressing was maintained by an FR 50 schedule of milk

presentation. Perhaps if the ratio size had been smaller as

in the Samson study, a greater degree of attenuation of d-

amphetamine's effects would have been observed at the lower

body weight (60% ffw).

In another study (Owen & Campbell, 1974),

methamphetamine's rate-decreasing effects on rats' lever

pressing maintained by sweetened-condensed milk presentation

were smaller for a group maintained at 80% ffw compared to a

group maintained at 100% ffw. The differences in

methamphetamine's effects between the two groups increased

as FR value was increased (1, 4, 8, 16, 32). Therefore, it

seems less likely that the lack of a difference in d-

amphetamine's effects between the groups maintained at 60%

and 80% ffw in the Gollub and Mann study (1969) was a

function of the size of the ratio schedule maintaining

responding.

After methamphetamine's effects were determined in the

Owen and Campbell (1974) study once, the body weights of the

individual subjects in each group were reversed. That is,

the 80%-ffw group's weight was increased to 100% ffw and the

100%-ffw group's weight was decreased to 80% ffw.

Methamphetamine's rate-decreasing effects were attenuated

when body weights were decreased (100% to 80% ffw), but were

not affected when body weights were increased (80% to 100%

ffw).









Attenuation of a drug's effects as a function of

increasing the level of deprivation has been demonstrated

across a variety of drugs, e.g., methadone (Kelly &

Thompson, 1988), imipramine (Gundersen & Berntzen, 1983),

and delta-9 tetrahydrocannabinol (Musty & Sands, 1978);

species, e.g., rats (e.g., Owen & Campbell, 1974) and

pigeons (e.g., Kelly & Thompson, 1988); and behavioral

measures: locomotor activity, amount of food eaten, and

food-dish contact (Cole, 1979).

Nevin (1974, 1979) has proposed that a measure of

response strength is the extent to which responding is

disrupted as a function of changes in the organism's

environment. Generally, responding maintained by a higher

rate of reinforcement, a smaller delay to reinforcement, or

a larger magnitude of reinforcement will be less disrupted

by the presentation of response-independent food or the

presentation of a period of extinction (Nevin, 1974).

Responding is considered "stronger" when it is more

resistant to change in the face of manipulations expected to

produce changes. It appears that deprivation level also may

be viewed within the context of this framework. For

example, responding by rats maintained at a more extreme

deprivation level (e.g., 20 hr without food) is more

resistant to change, i.e., a greater number of responses are

made during extinction, than is responding by rats

maintained at a less extreme deprivation level (e.g., 5 hr







25

without food) (Crocetti, 1962). The attenuation of a drug's

effects when the deprivation level is increased may be a

function of the strength of responding under non-drug

conditions. That is, responding maintained at a more severe

level of deprivation may be said to be "stronger" because it

was less disrupted by the acute administrations of drugs.

When d-amphetamine, pentobarbital, haloperidol, and

cholecystokinin-octa-peptide were examined as "response

disruptors," however, effects similar to those of more

conventional disruptors (e.g., extinction, response-

independent food presentations) were not obtained (Cohen,

1986).

In the present experiment, pigeons' keypecking was

maintained by an FR 30 schedule of food presentation. Acute

effects of cocaine were assessed when all of the pigeons

were maintained at 80% ffw. Body weights of half of the

pigeons then were increased to 90% ffw and those of the

other half were decreased to 70% ffw. Cocaine's acute

effects were determined again, and then a fixed dose was

given before each session. Cocaine and amphetamine, when

administered acutely, typically produce similar overall

decreases in response rates maintained by FR schedules of

food presentation in pigeons (e.g., Dews & Wenger, 1977;

Thompson & Moerschbaecher, 1980). Therefore, it was

predicted that the attenuation of amphetamine's effects on

responding when the level of deprivation was increased









(e.g., Samson, 1986) would also be seen in the present

experiment with cocaine. In addition, it was predicted that

the keypecking of pigeons maintained at 90% ffw would be

more sensitive to cocaine's acute effects.

The strength of responding under non-drug conditions

also may be a determinant of the development of behavioral

tolerance to cocaine's effects. Tolerance to cocaine's

rate-decreasing effects has developed differentially in

situations in which responding was maintained by small

ratios and has not developed, or developed to a smaller

degree, in situations in which responding was maintained by

large ratios (e.g., Hoffman et al., 1987; Hughes & Branch,

1991). In these studies, acute administrations of cocaine

decreased response rates of responding maintained by smaller

ratios to a smaller extent (disrupted responding less) than

responding maintained by the larger ratios. These effects

may be evidence that responding maintained by the smaller

ratios was "stronger." The differential tolerance

development observed under the smaller ratios then may be a

function of the "stronger" non-drug responding. In the

present experiment, it was predicted that tolerance should

develop more rapidly and/or to a greater extent in the group

of pigeons maintained at 70% ffw as their responding should

be of greater strength.

Additionally, if the effect of a given dose increases

as the degree of deprivation decreases, the dose could be









said to be functionally larger with respect to its

behavioral effect. It has been discussed above that the

dose of the drug can be a determinant of the development of

behavioral tolerance to cocaine (Branch, 1990; Reith, 1986).

Thus, if the effect of an acute administration of a dose of

cocaine changes as a function of the level of food

deprivation, i.e., the dose changes in functional magnitude,

then the development or degree of behavioral tolerance would

be expected to be a function of the level of deprivation

because deprivation level is a determinant of functional

dose magnitude.













METHOD

Subjects

Six experimentally naive, adult, male White Carneau

pigeons (Columba livia) served. All birds were initially

maintained at 80% ffw through post-session feedings of

Purina Pigeon Chow and Checkers. If a subject was below its

running weight, it was fed the difference (g) between its

post-session weight and its running weight. If a subject

was above its running weight, it was fed only one or two

grains of seed. Table 1 shows the nominal body-weight

levels and means and ranges of the obtained body weights

across all sessions of each phase of the experiment for each

pigeon. Each bird was housed individually in a colony room

(16 hrs light/8 hrs dark) with free access to vitamin-

enriched water and health grit.

Apparatus

Experimental sessions were conducted in an operant-

conditioning chamber for pigeons (Model #132-02, Lehigh

Valley Electronics, Fogelsville, PA) with a work space

measuring 35.0 cm deep by 30.5 cm wide by 35.5 cm high.

Three response keys, 2.5 cm in diameter, were located in a

horizontal row on the front wall, 5.6 cm from each other










TABLE 1
BODY WEIGHTS (g) ACROSS EXPERIMENTAL PHASES


PHASES SUBJECTS
(chronic dose in mg/kg)

70%-ffw group 90%-ffw group
1225 1221 1457 7404 234 233
(10.0) (10.0) (5.6) (3.0) (3.0) (10.0)
80% ffw

Nominal 446 479 532 437 539 438

Acute
Mean 433 472 520 428 523 429
Maximum 455 522 550 450 539 440
Minimum 412 459 492 407 500 418

70/90% ffw

Nominal 390 419 466 492 606 494

Acute
Mean 380 411 459 479 588 481
Maximum 397 425 492 501 607 497
Minimum 362 401 430 459 572 459

Chronic
Mean 379 410 448 480 583 479
Maximum 399 434 488 498 603 495
Minimum 364 393 407 462 560 466

80% ffw

Chronic
Mean 430 465 512 429 522 431
Maximum 450 481 530 440 530 443
Minimum 405 450 425 420 500 420

End of experiment
541 641 701 512 637 570

Percentage of original weight
97 114 105 94 94 104







30

(center to center), and each side key was 8.0 cm from a side

wall. Only the middle key was operative, and it could be

transilluminated by a white light. A 1.2-W white houselight

was located 5.5 cm above the center response key. Static

forces in excess of .18N (18g) on the key operated a

microswitch, produced a 30-ms tone from a Sonalert (Model

#Sc628) located behind the front wall 2.0 cm from the floor,

and were counted as responses. A 5.7- by 5.2-cm opening,

through which mixed grain could be presented, was centered

on the front wall, 9.0 cm below the response key. Whenever

grain was presented the houselight and keylight were turned

off and the hopper was illuminated.

The chamber was located in a room with white noise

continuously present. Contingencies were programmed and

data were collected by a computer system (Walter & Palya,

1984) located in a metal enclosure on top of the chamber. It

was interfaced with an IBM-compatible personal computer in

an adjacent room and operated under the ECBasic control

system (Palya & Hunter, 1987). A Gerbrands model C-3

cumulative response recorder also was used to monitor

responding.

Procedure

Each pigeon was placed in the chamber for at least two

30-min adaptation sessions in which the houselight was on

and no behavioral contingencies were programmed. Once the

pigeon was moving around the chamber, magazine training









(training the pigeon to eat from the food magazine) began.

Initially, the hopper was raised and filled with extra

grain. Once the pigeon ate from the hopper for 10-15 s the

hopper was lowered and raised quickly. The hopper-

presentation duration was gradually shortened to 4 s, and

the inter-food interval was lengthened to an average of 1

min. This training continued until the pigeon would

reliably, and with short latencies, approach and eat from

the hopper from anywhere in the chamber. Keypecking then

was shaped through differential reinforcement (4-s access to

mixed grain) of successive approximations. The response

requirement was increased gradually, across sessions, until

keypecking was maintained by an FR 30 schedule. Sessions

began with a 5-min timeout, during which the lights were out

and the response key was inoperative, and ended after 40

food presentations or 30 min, whichever occurred first. The

first response of a session produced food, but was not

included in calculations of response rates. The latency (s)

to the first peck, however, was recorded.

Phase 1: Acute Drug Effects at 80% ffw

Drug experiments began after rates of keypecking had

become stable from session to session. Performance was

considered stable after 10 consecutive sessions evidencing

minimal variability and no consistent trends in response

rates as determined by visual examination of the daily plots

of response rates. Table 2 shows the number of sessions per










TABLE 2
NUMBER OF SESSIONS FOR EACH EXPERIMENTAL PHASE


SUBJECTS
(chronic dose in mg/kg)


70%-ffw group
1225 1221 1457
(10.0) (10.0) (5.6)


Baseline

80% ffw
Acute

70/90% ffw
Acute


Chronic


80% ffw
Chronic
Cocaine


18


191


124

100


46


134


123

127


169


7404
(3.0)


10


160


155

181


112


90%-ffw group


234 233
(3.0) (10.0)


13 19


120


113

179


151


189

173


79 77


192


290

145


103


36 17 10


PHASES


Saline 11


17 10









experimental phase for each pigeon. Cocaine hydrochloride

(Sigma) was dissolved in 0.9% sodium chloride (saline)

solution. Dosages were determined in terms of the salt.

Injections, in a volume of 1.0 ml/kg, determined by the 80%

ffw (i.e., pigeons received the same volume every injection)

were made in the left or right pectoral muscle (site

alternated from injection to injection) immediately prior to

selected sessions. Dosages were administered in at least

two descending series: saline, 13.0 mg/kg (for some

subjects), 10.0 mg/kg, 5.6 mg/kg, 3.0 mg/kg, 1.0 mg/kg, and

0.3 mg/kg (for some subjects). Table 3 shows number of

injections of each dosage across experimental phases of the

experiment for each subject. If a dose of cocaine decreased

response rates outside of the range of rates obtained when

no drug was administered (control), the next dose was

administered at least seven days later; if a dose did not

decrease response rates outside of the range of control

rates, the next dose was administered at least four days

later.

Phase 2: Acute Drug Effects at 70% or 90% ffw

Once acute effects of cocaine were determined when the

pigeons were maintained at 80% ffw, three pigeons' body

weights were decreased to 70% ffw by not providing post-

session feedings, and three pigeons body weights were

increased to 90% ffw by giving an extra 5 g of food post-

session until the new target weight was reached.










TABLE 3
NUMBER OF DETERMINATIONS OF EACH DOSAGE
ACROSS EXPERIMENTAL PHASES


SUBJECTS
(chronic dose in mg/kg)


80% ffw
Acute
Saline
0.3
1.0
3.0
5.6
10.0
13.0

70/90% ffw
Acute
Saline
0.3
1.0
3.0
5.6
10.0
13.0

Chronic
Saline
0.3
1.0
3.0
5.6
10.0
13.0

80% ffw
Chronic
Saline
0.3
1.0
3.0
5.6
10.0
13.0


70%-ffw group
1225 1221 1457
(10.0) (10.0) (5.6)


7404
(3.0)


90%-ffw grou
234
(3.0)


p


233
(10.0)


2
0
2
3
3
4
5


Acutel/Acute2
* 2/2
* 0/2
2/2
2/2
2/5
2/4
S 2/2


3
0
2
2
2
13
4



2
0
2
2
2
10
2


PHASES









Determination of which pigeons' weights were decreased or

increased was semi-random; the only specification was that

each pigeon of one group was matched as closely as possible

to a pigeon of the other group with respect to control rates

of responding (response rates under nondrug conditions).

After at least 10 sessions of stable responding (See Table

2), cocaine was administered in a volume of 1.0 ml/kg,

determined by the original 80% ffw, according to the

procedure described above. Thus, the absolute amount of

drug at a given dosage remained the same as it had been

during the initial determination of acute effects.

Phase 3: Chronic Drug Effects at 70% or 90% ffw

After the assessment of the acute drug effects at 70% or

90% ffw and at least 10 consecutive days of stable

responding (See Table 2), subjects were given at least seven

daily, pre-session injections of saline. The smallest dose

of cocaine that reliably suppressed response rates then was

administered prior to every session. The chronic dose was

10.0 mg/kg for 1225, 1221, and 233, 5.6 mg/kg for 1457, and

3.0 mg/kg for 7404 and 234. Injection location alternated,

from session to session, between the left and right pectoral

muscle to prevent bruising.

After at least 20 days of administration of the chronic

dose of cocaine, other dosages occasionally were substituted

for the daily dosage and were administered in two descending

series identical to that used in the other phases. The









injection regimen of these "probe" dosages was the same as

described in Phase 1, i.e., if a dose decreased response

rates outside of the non-drug control range of Phase 2, the

next dose was administered at least seven days later, and if

the dose did not decrease response rates outside of the non-

drug control range, the next dose was administered at least

four days later. Intervening sessions were still preceded

by injections of the chronic dose.

Phase 4: Chronic Drug Effects upon Return to 80% ffw

After the assessment of chronic effects of cocaine, each

pigeon's weight was returned to 80% of the original free-

feeding weight by not feeding the 90%-ffw pigeons after

sessions and feeding the 70% ffw pigeons an extra 5 g after

sessions until the 80%-ffw was reached. Administrations of

the chronic dose of cocaine prior to sessions continued, and

after at least 20 consecutive days at the new weight "probe"

dosages were substituted according to the procedure

described in Phase 3.

Phase 5: Chronic Administration of Saline (Drug Withdrawal)

Following Phase 4, saline was administered prior to

every session (see Table 2). Pigeon 7404 then was exposed to

the FR schedule for an additional 7 sessions without

injections prior to sessions. After this, each pigeon was

given free access to food in its home cage until its weight

stabilized and a new free-feeding weight was determined.













RESULTS

Phases 1 and 2: Acute Drug Effects

When body weights were maintained at 80% ffw, cocaine

produced dose-dependent decreases in overall response rates

for each of the pigeons (see Figures 1 and 2, open circles).

Similar decreases were produced in run rates (response rate

excluding the post-reinforcement pause) and reinforcement

rate (see Tables 4 and 5). For three of the pigeons, 1225,

1457, and 234, response rates were almost completely or

completely suppressed by 3.0 mg/kg and larger doses of

cocaine, whereas, 5.6 (7404 and 233) and 10.0 mg/kg cocaine

(1221) were required to suppress response rates of the other

pigeons completely.

In Figures 1 and 2, filled circles represent overall

response rates as a function of cocaine when body weights

were shifted to 70% ffw (Figure 1) or 90% ffw (Figure 2).

The dosages labels on the x-axis represent the dosage

administered during Phase 1. Recall that the dosages during

all Phases were determined in terms of the 80% ffw of the

pigeons; the absolute amount of cocaine at each dosage

remained the same throughout the experiment. When body

weight was decreased, average control rates (rates during

nondrug conditions) increased only slightly (ranges overlap)







38

for 1225 and remained about the same for 1221 and 1457. For

all pigeons in the 70%-ffw group, response rates were less

sensitive to cocaine's rate-decreasing effects; the dose-

effect curves were shifted to the right. For example, when

1225's weight was lowered, 1.0 mg/kg cocaine no longer

decreased response rates, and 3.0 mg/kg and 5.6 mg/kg

cocaine produced much smaller decreases in rates compared to

the complete suppression at 80% ffw (although the range of

rates at 5.6 mg/kg cocaine was large 1.4 to 111.8 R/min).

When 10.0 mg/kg cocaine was administered, response rates

were increased 100 times relative to the complete

suppression at 80% ffw. For the other two pigeons, the

degree of the shift of the dose-effect curve to the right

was not as great; response rates were no longer completely

suppressed at 10.0 mg/kg and 3.0 mg/kg cocaine, for 1221 and

1457, respectively. Run rates increased in a similar

fashion for each subject (see Table 4).

When the weights of 7404, 234, and 233 were increased to

90% ffw (filled circles in Figure 2), average control

response rates remained approximately the same for 7404,

decreased slightly (ranges overlap) for 234, and remained

about the same for 233. Overall response rates for all of

the pigeons were more sensitive to cocaine's rate-decreasing

effects at some doses at this new weight. For each subject,

3.0 mg/kg cocaine now almost completely or completely

suppressed responding (2.7, 0.8, and 0.0 R/min for 7404,









234, and 233, respectively). For 7404 and 234, 1.0 mg/kg

cocaine now decreased response rates an additional 20% of

saline rates. Run rates for these pigeons decreased in a

similar fashion (see Table 4). During one of the two

sessions in which 10.0 mg/kg cocaine was administered, 7404

responded at the beginning of the session and then stopped.

The overall response rate for that session was 13.9 R/min

(13 ratios completed); however, the effect of 10.0 mg/kg is

better characterized by a cessation of responding.

After completion of the acute dose-effect curve for 233

at 90% ffw (Acutel), 3.0 mg/kg cocaine was administered

chronically. On the first day of Phase 3, however, 3.0

mg/kg cocaine did not completely suppress response rates.

Therefore, Phase 3 was suspended, and, after responding in

the absence of the drug had stabilized, cocaine's dose-

effect curve at 90% ffw was redetermined (Acute2). Open

squares in Figure 2 represent data from that second acute

dose-effect curve and show that overall response rates were

less sensitive to 5.6 mg/kg cocaine's rate-decreasing

effects. During the Acute2 determination, cocaine's dose-

effect curve was shifted to the right compared to the Acutel

curve.

In the present experiment, typical fixed-ratio

responding was maintained by the presentation of grain.

That is, a period of no responding after grain delivery

(post-reinforcement pause, PRP) was followed by a constant







40

rate of responding until the next grain delivery. The first

response of each session produced food, and the time from

the start of the session until this first response was

recorded as a latency (in s). A PRP was defined as the time

(in s) from the lowering of the food hopper until the first

response of the ratio; time during which a pigeon did not

ever respond after a grain presentation was not included in

the total PRP time. If a pigeon did not respond during the

session, the PRP and latency were recorded as 1800 s, i.e.,

the session time-limit. If a pigeon made only one response

(the first response of the session) then the latency was

recorded and the PRP was recorded as 1800 s minus the

latency for that session.

When body weights were decreased to 70% ffw, the

diminished sensitivity to cocaine's rate-decreasing effects

observed with 1225 and 1221 was characterized by a decrease

in the average PRP and the latency to make the first

response of the session (see Figure 3). For 1457, there was

only a very small change in the PRP and latency when 3.0

mg/kg cocaine was administered. For the pigeons whose

weights were increased to 90% ffw, there were not consistent

changes in the PRP and latency (see Figure 4). For 7404,

the PRP at 3.0 mg/kg cocaine increased, and decreased along

with latency at 10.0 mg/kg cocaine. This decrease was a

function of the one session before which 10.0 mg/kg cocaine

was administered in which 7404 responded. During this









session, 7404 responded 29.4 s into the session and the

average PRP for the 14 ratios in which there was a PRP was

60.2 s. Overall response rates for 234 decreased during the

two sessions before which 5.6 mg/kg cocaine was administered

(from 10.1 to 0.2 R/min), although the average PRP and

latency decreased. These mean decreases are a result of the

1 and 11 responses made by this pigeon at the beginning of

the two sessions whose data go into these points.

Therefore, the latency and the long PRP for each session

were on average lower than those seen during Phase 1.

During the Acutel portion of Phase 2 (filled symbols), the

PRP and latency increased at doses of cocaine that produced

a complete cessation of responding, i.e., the dose-effect

curve shifted to the left. The shift back to the right of

the dose-effect curve for 233 during the Acute2 portion of

Phase 2 was characterized by a decrease in the PRP (open

squares) and latency (open diamonds), and the PRP only, at

3.0 mg/kg and 5.6 mg/kg cocaine, respectively.

In summary, during Phase 1 when body weights were

maintained at 80% ffw, cocaine produced dose-dependent

decreases in overall response rate that were characterized

by increases in the PRP and decreases in the run rate.

Latency to begin responding during a session also increased

in a dose-dependent manner. When the level of deprivation

was increased (body weights decreased to 70% ffw) during

Phase 2, measures of keypecking were less sensitive to these

























Figure 1. Mean overall response rates as a function of the
dose of cocaine for 1225 (top), 1221 (middle), and 1457
(bottom) when body weights were maintained at 80% ffw (open
circles) and 70% ffw (closed circles). Dosage on x-axes is
in terms of the 80% ffw. Points above C are means from
sessions immediately preceding injections of a dose of
cocaine or saline. Points above S are means from sessions
when saline was administered. The rightmost points on the
curves in the bottom graph are means from sessions when 13.0
mg/kg cocaine was administered. All points, except those
above C, are means of at least two determinations. Bars on
points above C are ranges of the mean. When bars are not
visible they are subsumed by the size of the point.
Response rates equal to zero were recorded as 0.03 R/min
which was the record floor: the inverse of the maximum
session length (30 min). Note that points are slightly
displaced left and right for clarity.
























7,
1 --
DOK.


zzz:2zz..


I A -


C S .3 3; 5. 13C


kg


'I

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?ioi r~ : i1 _;






























Figure 2. Mean overall response rates as a function of the
dose of cocaine for 7404 (top), 234 (middle), and 233
(bottom) when body weights were maintained at 80% ffw (open
circles) and 90% ffw (closed circles). Plotting conventions
are the same as Figure 1. Open squares in the bottom graph
represent data from the second determination of the dose-
effect curve when weights were maintained at 90% ffw.













-N -'



-r -


0

:D-~


I1


2


3.0 5.6 1C.0


z\


90% ffw
* Acutely
E Acute2|


SS 1.0 3.0 5.6 1

COCAlNE (mg/kg)


(


0.0


t- t -


---9^
AD1


;sJ'S


r


1 '"


i O" -































Figure 3. Mean PRP (circles) and latency (triangles) as a
function of the dose of cocaine for 1225 (top), 1221
(middle), and 1457 (bottom) when body weights were
maintained at 80% ffw (open symbols) and 70% ffw (closed
symbols). Plotting conventions are the same as Figure 1.











A.
A7L


I
C~
13;3~ i


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A A. -A A A--- -


.Y


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ZAIA A----7A


SS 0.3


>0 "6 ~A


K


AAc


1221


1Q


j


,
3 r) i 1, i


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function of the dose of cocaine for 7404 (top), 234
(middle), and 233 (bottom) when body weights were maintained
at 80% ffw (open symbols) and 90% ffw (closed symbols).
Plotting conventions are the same as Figure 1. Open squares
and diamonds in the bottom graph represent average PRP and
latency, respectively, from the second determination of the
dose-effect curve when weights were maintained at 90% ffw.






Acute
80% ffw
0 PRP
A Latency
90% ffw
PRP
A Latency

C"


1000 -

100 -

10 -

1 -

0.1 -


C s


3.0 5.6 10.0


LZAAA A------


234


3.0 5.6 10.0


90% ffw
Acutel
PRP
A Latency
Acute2
E] PRP
0 Latency


3.0 5.6 10.0


COCA' E (m


7404


1000 -


in





7
0
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54

run-rate-decreasing and PRP-increasing effects of cocaine in

each of the three pigeons. When the level of deprivation

was decreased (body weights increased to 90% ffw), measures

of keypecking generally were more sensitive to the rate-

decreasing effects of cocaine in all of the pigeons. For

one subject, however, a complete redetermination of the

acute dose-effect curve revealed that the initial shift to

the left in the curve when weights were maintained at 90%

ffw did not persist.

Phase 3: Chronic Drug Effects at 70% or 90% ffw

For all pigeons maintained at 70% ffw, some degree of

tolerance to cocaine's rate-decreasing effects was observed

following daily administration of a rate-decreasing dose:

the dose-effect curves shifted to the right. Figure 5 shows

the effects of daily administration of 10.0 mg/kg cocaine

for 1225 and 1221, and 5.6 mg/kg cocaine for 1457, averaged

across two-session blocks at the beginning of the chronic

regimen. For 1225, response rates increased to

approximately 75% of saline rates within six days of chronic

administration of 10.0 mg/kg cocaine and remained at this

level on average over the 100 days of this chronic phase.

For 1221, response rates increased to the average response

rate of the Phase within six days of chronic administration

of 10.0 mg/kg cocaine. There was a great deal of

variability in overall response rates across the 127 days of

this phase (range 0.0 88.2 R/min). Pigeon 1457 started









responding by the sixth day of repeated administration of

5.6 mg/kg cocaine. Response rates increased from 0.0 to

about 10.0 R/min on average with occasional sessions of

complete suppression.

In Figure 6 overall response rates are presented as a

function of cocaine when doses were administered acutely

(filled circles) and were substituted for the chronic dose

(open diamonds). The chronically administered dose for each

pigeon is indicated by the box on the x-axis. Probes with

other doses with 1225 revealed that response rates returned

to within 84% to 92% of saline rates when 3.0 mg/kg and 5.6

mg/kg cocaine were administered. For 1221, tolerance to

cocaine's rate-decreasing effects was evident clearly at

10.0 mg/kg cocaine only; average response rate increased

from 2.2 to 17.5 R/min. On average these rates were still

suppressed, however, to approximately 15% of rates seen

following saline administration. For 1457, behavioral

tolerance was also evident when 3.0 mg/kg was substituted

for 5.6 mg/kg cocaine.

Figure 7 shows the effects of daily administration of

3.0 mg/kg and 10.0 mg/kg cocaine for 7404 and 234, and 233,

respectively, averaged across two-session blocks at the

beginning of the chronic regimen. For 7404, response rates

increased to approximately 50% of rates following the

administration of saline within the first four days of

repeated administration of 3.0 mg/kg cocaine. Over the rest









of the phase, the average response rate following repeated

administration of 3.0 mg/kg cocaine was within the acute

dose-effect curve's control (non-drug) range.

Behavioral tolerance developed quite slowly for 234 and

233. For 234 response rates remained completely suppressed

throughout the first 29 days of repeated administration of

3.0 mg/kg cocaine (see Figure 7). When saline was

administered on day 30, response rates were similar to rates

when saline was administered prior to the beginning of the

chronic regimen. Pigeon 234 responded during the following

session (preceded by an administration of 3.0 mg/kg

cocaine). Similar rates were observed throughout the

remainder of the phase; these rates still were suppressed

approximately to 85% of saline rates.

Response rates remained completed suppressed during the

first 27 days of repeated administration of 10.0 mg/kg

cocaine for 233 (see Figure 7). Response rates increased

slightly over the four sessions following an injection of

saline on the 28th day and then decreased. Response rates

remained quite variable after a second injection of saline

on the 36th day of the phase. After a third saline

injection, the average response rate was 30.4 R/min and

remained at about that level throughout the rest of the

phase.

Following the development of steady-state performance

during daily drugging, the acute dose-effect curves shifted









to the right for each of the pigeons in the 90%-ffw group.

(see Figure 8; the chronic dose for each pigeon is indicated

by a box on the x-axis). For 7404, behavioral tolerance was

also evident when 5.6 mg/kg was substituted for 3.0 mg/kg

cocaine (rates increased from 0.0 to 8.3 R/min). Effects of

10.0 mg/kg when substituted for 3.0 mg/kg cocaine could be

viewed as evidence of tolerance. Recall that the average

rate when 10.0 mg/kg cocaine was administered acutely is a

result of 7404 making some responses at the beginning of one

of two sessions and then stopping. If the effects of 10.0

mg/kg cocaine administered acutely are characterized as a

cessation of responding, then effects of 10.0 mg/kg cocaine

off the chronic baseline could be viewed as tolerance.

For 234, tolerance was evident conclusively only at the

chronic dose, although response rates were slightly elevated

(0.2 to 0.8 R/min) when 5.6 mg/kg was substituted for 3.0

mg/kg cocaine. For 233 behavioral tolerance was clearly

evident at the chronic dose (10.0 mg/kg) as well as when 5.6

mg/kg and 13.0 mg/kg cocaine were administered, although the

latter dose still completely suppressed responding on some

occasions.

Figures 9 and 10 show average PRP and latency to the

first response for 1225, 1221, and 1457, and 7404, 234, and

233, respectively, when cocaine was administered acutely

(filled symbols) and chronically (PRP-open squares; latency-

open diamonds) when the pigeons were maintained at either









70% or 90% ffw. In general, tolerance to cocaine's rate-

decreasing effects was manifested as a combination of both a

decrease in the PRP and/or latency to the first peck and/or

an increase in the running rate of responding (see Table 4).

For example, note the PRP and latency measures for 1225 at

5.6 mg/kg and 10.0 mg/kg cocaine, and for 7404 at 3.0 and

5.6 mg/kg cocaine. Interestingly, for 1221 and 234 both PRP

and latency increased when the chronically given dose (10.0

mg/kg or 3.0 mg/kg cocaine, respectively) was administered.

Thus, the behavioral tolerance evident at the chronic doses

for these two birds (See Figures 6 and 8) was in large part

a function of increased run rates (See Table 4).

In summary, tolerance developed to the overall rate-

decreasing effects of cocaine for each subject. For four of

the six subjects the behavioral tolerance was characterized

by an increase in the running rate and a decrease in the PRP

and latency to respond in a session. For one of the

subjects in each group (1221 and 234), behavioral tolerance

was a function of increased run rates. Response rates for

the subjects in the 70%-ffw group tended to recover more

quickly during the chronic administration of cocaine than

two of the subjects in the 90%-ffw group (with the exception

of 7404 who started responding by the fourth day).































Figure 5. Mean overall response rates averaged across two-
session blocks for 1225 (top), 1221 (middle), and 1457
(bottom) when saline (open circles) or the chronic dose
(closed circles) was administered. Asterisks on the x-axis
denote one-session means prior to which the chronic-dose of
cocaine was administered. The open circles above sessions
374, 344, and 362 for 1225, 1221, and 1457 are data from one
session.








70% ffw




0 Saline
* 10.0 mg/kg


1225


II I I I I I I I I I I5 3 5I
345 355 365 375


I I I I III I II


100 -0000


0 Saline
* 10.0 mg/kg


1221


305 315 325 335 345


0000


0


m. -.._


I I I I I lwl I I I I I I II I I i
327 337 347 357 366


SESSIONS


O Saline
* 5.6 mg/kg






1457


10oo0o


10 -


1-


0.1 -


I35
335


z/



on

(9
wL
0.


100 -


10 -


1-


0.1


I I I l i I I I i I I





























Figure 6. Mean overall response rates as a function of the
dose of cocaine for 1225 (top), 1221 (middle), and 1457
(bottom) when weights were maintained at 70% ffw. Plotting
conventions are the same as Figure 1. All points are means
of at least two determinations. Those above C are means
from sessions immediately preceding injections of a dose of
cocaine or saline during Phase 2. Open diamonds above the
chronic dose, enclosed in a box, are means from all sessions
that immediately preceded "probes" during assessment of
effects during daily administration of the chronic dose.







0 --0


70% ffw
0 Acute 0
O Chronic


100 -


10



01

0.1


C S 0.3


3.0 5.6 10.0


* >







1221


3.0 5.6 10.0


C S


100


10


1


0.1


C S 0.3 1.0


COCAINE (m


3.0 5.6

g/kg


1225


z



CL


LLJ
D_


100


10 -


10


0.1 -


10.0

)






























Figure 7. Mean overall response rates averaged across two-
session blocks for 7404 (top), 234 (middle), and 233
(bottom) when saline (open circles) or the chronic dose of
cocaine (closed circles) was administered. Plotting
conventions are the same as Figure 5. Open circles above
sessions 280 for 7404, 397 for 234, and 539, 547, and 563
for 233 are data from one session.












o C s 0.,,



jI..0 0


100 -


10 -


1


0.1


248


904 ffw


0 Saline
* 3.0 mg/kg


7404


58 68 78


I I I I


100 Hcco


**


O Saline
* 3.0 mg/kg


234


371 381 391 401


100


000C


10 0 Saline
S 0 10.0 mg/kg


233


505 15 25 35


55 65


SESSIONS


III
0
C..


10 -


1


0.1


361


Mmmmmm -~-


I II I


I I I I I l I I I I l
































Figure 8. Mean overall response rates as a function of the
dose of cocaine for 7404 (top), 234 (middle), and 233
(bottom) when weights were maintained at 90% ffw. Plotting
conventions are the same as Figure 6.










10 900" ffw
0 Acute
<0 Chronic


7404


C S 1.0 3.0 5.6 10.0


z





U
n
0

CL


100 -

10 -

1-


0.1


C S 1.0

COCAINE (m


3.0 5.6 10.0


g/


kg


_ _


1.


233
































Figure 9. Mean PRP (circles and squares) and latency
(triangles and diamonds) as a function of the dose of
cocaine for 1225 (top), 1221 (middle), and 1457 (bottom)
when body weights were maintained at 70% ffw. Plotting
conventions are the same as Figure 6.







70% ffw
Acute
0 PRP


1000 -

100 -

10 -

1-

0.1-


C S 0.3


3.0 5.6 10.0


1221


1.0


3.0 5.6 10.0


1457


C S 0.3


COCAINE


3.0 5.6 10.0

mg/kg)


A Latency
Chronic
[ PRP
O Latency





1----225
12235


1000 -


w~
a1

z3
0)
U
w3


100 -

10 -

1

0.1


C S


1000 -

100 -

10 -

1 -

0.1































Figure 10. Mean PRP (circles and squares) and latency
(triangles and diamonds) as a function of the dose of
cocaine for 7404 (top), 234 (middle), and 233 (bottom) when
body weights were maintained at 90% ffw. Plotting
conventions are the same as Figure 6.







9C-: ffw
Acute
0 PRP
A Latency
Chronic
[L PRP
0 Latency
* e


//


740

7404


3.0 5.6 10.0


el>

*0

AA


234


C S 0.3


3.0 5.6 10.0


233


1.0


3.0 5.6


mg/


10.0


kg)


100

10 -

1-

0.1 -


C s


1000 -


CO



(l
(-J
i O


100

10 -

1-

0.1


1000 -

100 -

10 -

1-

0.1


A A


C s


COCA NE









Phase 4: Chronic Drug Effects upon Return to 80% ffw

Figure 11 shows the effects of daily administration of

10.0 mg/kg cocaine for 1225 and 1221, and 5.6 mg/kg for

1457, averaged across four- (1225) and two-session blocks

(1221 and 1457) at the beginning of Phase 4 when body

weights were returned to 80% ffw. Subject 1225 stopped

responding for 90, 1221 for 8, and 1457 for 10 days when

their weights reached 80%, 77%, and 72.5% ffw, respectively.

For 1225, saline and other doses of cocaine were substituted

for 10.0 mg/kg cocaine after 18 days of no responding.

Response rates remained completely suppressed until session

number 495 prior to which saline was administered. Average

response rates increased to levels observed when 1225's

weight was maintained at 70% ffw during sessions 500 and 505

prior to which saline was administered. Response rates

remained completely suppressed, however, when 10.0 mg/kg

cocaine was administered prior to sessions. Response rates

did not recover to prior levels until after one additional

administration of saline, 3.0 mg/kg and 5.6 mg/kg cocaine.

For subjects 1221 and 1457, the complete suppression of

response rates as weight was returned to 80% ffw was

temporary as each of these pigeons' response rates increased

to levels seen when weights were maintained at 70% ffw after

the 8 and 10 days of no responding.

Figure 12 shows overall response rate as a function of

dose of cocaine during Phase 3 when weights were maintained







72

at 70% ffw (closed circles) and during Phase 4 when weights

were returned to 80% ffw (open circles). For 1225, the data

from the first determination of the dose-effect curve off

the chronic baseline in which response rates remained

completely suppressed were not included in the dose-effect

curve presented in Figure 12. Generally, the shape of the

dose-effect curve remained the same, i.e., behavioral

tolerance was still evident, however, the degree of

tolerance observed when 3.0 mg/kg and 5.6 mg/kg cocaine were

substituted for 10.0 mg/kg cocaine was slightly smaller.

Similarly, there was essentially no change in the dose-

effect curve for 1221 and a small increase in average

response rate when 3.0 mg/kg and 5.6 mg/kg cocaine were

administered and a larger increase when 10.0 mg/kg cocaine

was administered for 1457 (see Figure 12).

Figure 13 shows response rates averaged across two-

session blocks when the weights of the 90%-ffw group were

decreased to 80% ffw while administrations of 3.0 mg/kg and

10.0 mg/kg cocaine continued for 7404 and 234, and 233,

respectively. For 7404 response rates remained essentially

the same when weights were decreased. For 234 and 233,

response rates increased as their weights reached 82.5% ffw

and 87% ffw, respectively.

Behavioral tolerance was still evident for each of the

pigeons in the 90%-ffw group when their weights were

returned to 80% ffw. For 7404, there was no change in the







73

effects of other doses of cocaine or saline when substituted

for 3.0 mg/kg cocaine (see Figure 14). For 234, the dose-

effect curve was shifted to the right. Response rates were

elevated when all doses of cocaine were administered. For

233, response rates also increased across all doses.

Figures 15 and 16 show average PRP and latency for 1225,

1221, and 1457 and 7404, 234, and 233, respectively, as a

function of dose of cocaine during Phase 3 (closed symbols)

and Phase 4 (open symbols). The slight decrease in response

rates when 1225's weights were increased to 80% ffw was a

function of both a decrease in the run rate (see Table 4)

and increases in the PRP and latency to the first response

of the session. The small increases in response rates

observed with 1457, when its weight was increased to 80%

from 70% ffw, and the larger increases observed with 234 and

233, when their weights were decreased to 80% from 90% ffw,

were combinations of increased run rate (see Table 4) and a

decrease in the average PRP and latency.

In summary, the three subjects in the 70%-ffw group

ceased responding when weights were increased to 80% ffw.

All subjects started responding again under chronic

administration of cocaine. For one of these subjects (1225)

the degree of tolerance, compare to that seen when weights

were maintained at 70% ffw, was diminished; for the other

two subjects (1221 and 1457) there was virtually no change

in the dose-effect curves (except when 10.0 mg/kg cocaine




























Figure 11. Mean overall response rates averaged across
four-session blocks for 1225 (top) and across two-session
blocks for 1221 (middle) and 1457 (bottom) when saline (open
circles) and the chronic dose of cocaine (filled circles)
was administered when body weights were shifted from 70% to
80% ffw. Body weight is marked on the plot. Open squares
and open triangles represent overall means from sessions in
which 3.0 mg/kg and 5.6 mg/kg cocaine was administered,
respectively. Asterisks below 1225's x-axis denote two-
session means; asterisks below the other two pigeons' x-axis
denote one-session means. Open circles, squares, and
triangles are data from one session.









100 OO O
100 Si 00 0Cle
S O Saline S*
O 3.0 mg/kg
10 5.6 mg/kg
10.0 mg/kg

1 1225 o


0.1

430 50 70 90 510 30


100 0


10 -
(f 0 Saline
0 10.0 mg/kg
1

W o 1221
0.1

425 435 445


100 O 0


10
0 Saline
0 5.6 mg/kg
1


0.1 145
-*--*****-I 1 **------
491 501 511 521 531


SESS ONS


r





























Figure 12. Mean overall response rates as a function of the
dose of cocaine for 1225 (top), 1221 (middle), and 1457
(bottom) when weights were maintained at 80% ffw (open
circles) and 70% ffw (filled circles). Plotting conventions
are the same as Figure 1. All points are means of at least
two determinations. Points above the chronic dose, enclosed
in a box, are means from all sessions that immediately
preceded "probes" during assessment of effects during daily
administration of the chronic dose.

















1225


3.0 5.6 10.0


1221


1.0


3.0 5.6 10.0


S 0.3 1.0 3.0 F561 10.0

COCA NE (mg/kg)


10



0.1-

0.1 -


S 0.3


U

u


100 -


10





0.1 -


100


10


1


0.1


!il4w
- --------------------































Figure 13. Mean overall response rates averaged across two-
session blocks for 7404 (top), 234 (middle), and 233
(bottom) when saline (open circles) or the chronic dose of
cocaine (closed circles) was administered as body weights
were shifted from 90% to 80% ffw. Plotting conventions are
the same as Figure 5.










100 -


10


1-


0.1


I I I I I I i


437


ln
M 0
appcOoe


0 Saline
* 3.0 mg/kg


234


S45
545 *


o r-N O




O Saline
10.0 mg/kg


233


640


650 660
650 660


SESS0 NS


S0 in r, 0
(n co 00a
o--0


0 Saline
* 3 0 mg/kg


7404


418


428


zn



on
Lii
Ul


100 -


10 -


S-


0.1 -


525


535


100


10


1-


0.1 -


630


I ( I I 1 I 1 I / I j I I 1 I j I


I I / / 1 I / r / / ( I I r


i i ; i i I i































Figure 14. Mean overall response rates as a function of the
dose of cocaine for 7404 (top), 234 (middle), and 233
(bottom) when weights were maintained at 80% ffw (open
circles) and 90% ffw (filled circles). Plotting conventions
are the same as Figure 12.






100 81


10 Chronic
0 80% ffw
90% ffw

7404
0.1

S 1.0 .0] 5.6 10.0

100 -





10

L0 01- 234
IL

S 0.3 1.0 .0 5.6 10.0

100 -


10 -




0.1 233

S 1.0 3.0 5.6 1

COCA NE (mg/kg)































Figure 15. Mean PRP (circles) and latency (triangles) as a
function of the dose of cocaine for 1225 (top), 1221
(middle), and 1457 (bottom) when body weights were
maintained at 80% ffw (open symbols) and 70% ffw (closed
symbols). Plotting conventions are the same as Figure 12.







Chronic
80C ffw
O PRP

* PRP
A Latency
A
o


1000 -

100

10 -

10

0.1


S 0.3


3.0 5.6 10.0


1221


3.0 5.6 10.0


A
AA -A


1457


1.0 3.0 5.6 10.0

!HE (mg/kg)


1225


1000


CO'
Q


0

Lw
C I
0'


100 -

10 -

1

0.1 -


1000

100 -

10 -

1

0.1


C OCA































Figure 16. Mean PRP (circles) and latency (triangles) as a
function of the dose of cocaine for 7404 (top), 234
(middle), and 233 (bottom) when body weights were maintained
at 80% ffw (open symbols) and 90% ffw (closed symbols).
Plotting conventions are the same as Figure 12.







Chronic
80% ffw
O PRP
A Latency
90% ffw
* PRP
A Latency


1000

100

10 -

1

0.1


7404


1.0


3.0 5.6 10.0


234


3.0 5.6 10.0


233


3.0 5.6 10.0


COci


NE (


A--,- A


1000

100 -

10 -

1-

0.1


0
C)
m
07
O


S 0.3


1.0


1000 -

100 -

10 -

1-

0.1


1.0


mg/


kg)







86

was administered to 1457). When weights were decreased from

90% to 80% ffw, the degree of tolerance increased for two of

the three subjects immediately and remained the same for the

third subject.

Phase 5: Chronic Administration of Saline (Drug Withdrawal)

Figure 17 shows average overall response rates when

saline was administered acutely (Phase 1) and chronically

(Phase 5) when the pigeons weights were maintained at 80%

ffw. For each subject, overall response rates returned to

within the range of rates observed when saline was

administered acutely during Phase 1. For 7404, run rates

did not return to run rates observed when saline was

administered during Phase 1 (see Table 4) and, therefore,

saline administrations were discontinued and he was run for

an additional 7 sessions. Run rates remained decreased

across this phase.































Figure 17. Mean overall response rates for, from left to
right, 1225, 1221, 1457, 7404, 234, and 233, as a function
of acutely- (open bars) and chronically-administered
(hatched bars) saline when body weights were maintained at
80% ffw. Bars represent means of all injections of saline
under each condition.



































1225 1221 1457 7404 234


80% ffw
= Acute
=Phase 5


233


SUBJECT


160 -

140 -

120 -

100 -

80 -

60 -

40 -


c/

U
-..<





LJ
III
nI













DISCUSSION

Acute administrations of cocaine decreased response

rates, and therefore reinforcement rates, of keypecking,

maintained by an FR 30 schedule of food presentation in six

pigeons maintained at 80% ffw. These rate-decreasing

effects were attenuated, i.e., the dose-effect curve was

shifted to the right when body weight was maintained at 70%

ffw for three of the six pigeons, and were enhanced, i.e.,

the dose-effect curve was shifted to the left, when body

weights were maintained at 90% ffw for the other three

pigeons. Despite differences in body weight, following

repeated administration of a rate-decreasing dose, tolerance

to these rate-decreasing effects developed for all subjects:

for all subjects the dose-effect curves were shifted to the

right. That is, not only did tolerance develop in all

subjects, but there were no substantial differences between

groups in the nature or degree of the tolerance observed.

Whether tolerance developed and the degree to which it

developed, therefore, was not a function of the level of

deprivation under the conditions of these experiments. The

rate at which responding recovered during repeated cocaine

administration was relatively quick (6 days) for subjects in

the 70%-ffw group, whereas, only one subject in the 90%-ffw







90

group started responding within 4 days of repeated exposure

to cocaine. The other two subjects did not start responding

until after 34 (234) and 30 (233) days of repeated exposure

to cocaine and administrations of saline probes. Thus it

appears that level of deprivation may be a partial

determinant of when behavioral tolerance is first evident,

but not the degree to which it develops. The former

conclusion, however, is tentative at best given that one

subject in the 90%-ffw group showed rapid development of

tolerance. Further research is necessary to determine how

consistently food-deprivation level modulates the rate at

which behavioral tolerance develops.

That the level of food deprivation was not a determinant

of whether tolerance developed or the degree to which it

developed to cocaine's rate-decreasing effects in the

present experiment was surprising. Manipulations of

deprivation levels within the range studied in this

experiment consistently produce a variety of behavioral

effects across a variety of species. As deprivation level

increases: 1) response rates maintained by different

schedules of food presentation increase (Ferster & Skinner,

1957; Sidman & Stebbins, 1967); 2) the largest ratio

produced under progressive ratio schedules before the

subject stops responding increases (Hodos, 1961); 3) the

amount of suppression of response rates as a function of

response-produced electric shock decreases (Azrin 1959;







91

Azrin, Holz, & Hake, 1963); 4) the number of errors made in

a simple two-choice discrimination decrease (Broadhurst,

1957); and 5) levels of schedule-induced polydipsia and

attack increase (Dove, 1976; Falk 1969). Therefore, the

deprivation levels chosen as one of the independent

variables in the current experiment are behaviorally

significant. It could be argued, however, that the range

employed (70%, 80%, 90% ffw) was not large enough and/or

that the extended period of time that the pigeons were

maintained at a particular deprivation level altered the

"actual" deprivation level. It is important to note,

however, that at the end of the experiment all pigeons were

free-fed and their 100% ffw was redetermined. With the

exception of 1221, the pigeons' weights at the end of the

experiment were not more than 6% below their original

weights. Thus, at the end of Phase 5, the pigeons were

still deprived. Additionally, manipulations of body weight

outside of the range examined in this study were not

practical. Maintaining pigeons' weights for a prolonged

period of time, such as in this experiment, below 70% ffw

could threaten the pigeons' health. Response rates are not

very well maintained under the conditions of the present

experiment when pigeons' weights are maintained above 90%

ffw.

Hoffman et al. (1987) found that the degree of tolerance

to cocaine's rate-decreasing effects was dependent on the









response requirement; tolerance was less likely to develop

or develop to a smaller degree in situations in which

responding was maintained by larger ratios. They suggested

that their results could be accounted for based on the

concept of response strength. That is, responding

maintained by small ratios was more resistant to disruption

by acute administration of cocaine than responding

maintained by larger ratios. According to Nevin (1974,

1979) such behavior is "stronger" as it is more resistant to

disruption in the face of environmental change. Given that

responding maintained by small ratios was "stronger" and

that behavioral tolerance was evident under these

contingencies, Hoffman et al. suggested that response

strength could be a determinant of behavioral tolerance.

Following from this conceptualization, other independent-

variable manipulations such as reinforcement frequency and

level of deprivation, that are used conventionally to alter

response strength, should be determinants of behavioral

tolerance. Schama and Branch (1989) showed that tolerance

to the rate-decreasing effects of cocaine developed under

three different FI schedules. That is, baseline rate of

reinforcement did not modulate how or whether tolerance

developed. In the present experiment, the level of

deprivation also was not a determinant of whether or to what

degree behavioral tolerance developed. Given that

reinforcement frequency or the level of deprivation did not









predict tolerance, the notion of "response strength" in

general as a predictor of behavioral tolerance is less

credible. More research is required in which other

"standard" modulators of response strength are manipulated,

such as amount of reinforcement, delay to reinforcement, or

progressive ratio schedules, to determine the utility of

"response strength" as a determinant of behavioral

tolerance.

It appears that the differential tolerance observed in

the Hoffman et al. (1987) study was a function of some

property other than strength of responding (i.e., general

resistance to disruption). Hoffman et al. point to the

small ratio of responses to reinforcer as a possible

determinant of behavioral tolerance development to cocaine's

effects. Small-ratio schedules possess this property as can

interval schedules. If response rates maintained by small-

ratios or interval schedules are suppressed because of

administration of a drug, a few responses can produce

reinforcement. This characteristic is believed to initiate

and further the development of behavioral tolerance.

This view could be examined by studying responding

maintained by an Alternative FR FI schedule of reinforcement

which arranges the contingency that completion of either

schedule produces reinforcement. If an Alternative schedule

consisting of "small," "medium," and "large" FRs and FIs

(e.g., Alternative FR 5 FI 10 s, Alternative FR 25, FI 30 s,