Anatomical and behavioral effects of 5-fluoro-2-deoxyuridine administration to rats

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Anatomical and behavioral effects of 5-fluoro-2-deoxyuridine administration to rats at different phases of central nervous system development
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Thesis--University of Florida.
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Includes bibliographical references (leaves 24-26).
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by Ted LaRue Petit.
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Vita.

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ANATOMICAL AND BEHAVIORAL EFFECTS OF 5-FLUORO-2-DEOXYURIDINE
ADMINISTRATION TO RATS AT DIFFERENT PHASES OF
CENTRAL NERVOUS SYSTEM DEVELOPMENT












By

TED LaRUE PETIT


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







UNIVERSITY OF FLORIDA


1975













DEDICATION

This dissertation is the culmination of a quarter of

a century of education; for education is but life itself.

It is dedicated to those who have taught me, and shared with

me, the power and passion of life.














ACKNOWLEDGMENTS

It is very sad, looking back, to have to thank those that

you are about to leave. Words often fall short of feelings.

I hope that each of you knows how much I have cared if I am

unable to fully express it on this page.

Foremost on my mind are those professors who gave me

guidance. Dr. Robert Thompson, who started me down this long

path.

. .. Dr. Robert Isaacson who gave me the freedom to find

my own way, and the guidance to help me along. A man who won

my admiration for his love of life, for only through a true

love of life are we able to pursue our dreams.

.. Dr. Carol Van Hartesveldt, for her support and

guidance, more as a friend than a colleague.

. Mrs. Virginia Walker, who has given more thoughtful-

ness and understanding than ever I had expected.

. .. Mrs. Lillie HemanAckah for her help in preparing the

histology and her jolly chats over morning coffee.

My fellow graduate students who have helped me along.

Especially Linda, Babs, and Jeanie, a very sincere and deep

thanks for being who you are.

And to the other members of the foursome: Dick, Lee,

and very especially Sue. They have given me love, the one

thing that makes all the rest worthwhile.


iii















TABLE OF CONTENTS

Page

ACKNOWLEDGMENTS . . .iii

ABSTRACT . . V

INTRODUCTION . ... 1

METHOD . . 3

RESULTS . . ... .. 8

DISCUSSION ... . .. 19

REFERENCES . . 24

BIOGRAPHICAL SKETCH .. 27














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

ANATOMICAL AND BEHAVIORAL EFFECTS OF 5-FLUORO-2-DEOXYURIDINE
ADMINISTRATION TO RATS AT DIFFERENT PHASES OF
CENTRAL NERVOUS SYSTEM DEVELOPMENT

By

Ted LaRue Petit

August, 1975

Chairman: Robert L. Isaacson
Major Department: Psychology

Pregnant Long Evans rats were injected subcutaneously with

either 30mg/kg 5-fluro-2-deoxyuridine or water on Days 10 and

11, Days 13 and 14, or Days 16 and 17 of gestation. All groups

were fostered to nontreated mothers at birth. During adulthood

all animals were tested on a variety of behavioral tasks.

Motor deficits were found in all three treated groups when

tested for the ability to walk on parallel bars. None of the

three treated groups were found to differ from controls in

audiogenic seizure susceptibility. Activity decreases were

seen in animals treated on Days 13 and 14 and Days 16 and 17.

Although all groups learned a spatial discrimination in a T-

maze with little difficulty, animals treated on Days 13 and 14

and Days 16 and 17 performed poorly on the position reversals,

with the animals treated on Days 13 and 14 performing more

poorly than those treated on Days 16 and 17.












INTRODUCTION

Cells of the central nervous system (CNS) are vulnerable

to any agent or environmental condition which interferes with

their proliferation, migration, or differentiation. All

parts of the CNS do not develop simultaneously. Since each

structure in the CNS has its own time table of maturation, at

a given prenatal time some cell population will be especially

vulnerable to factors which interfere with their development

or existence. Other less active populations will be less

affected. Agents interfering with cell proliferation on

different days of development of the CNS will consequently

result in cellular deficits and deformities in different re-

gions of the adult brain. It would also be expected that

different behavioral deficits arise as a consequence of inter-

vention on different days of gestation because of the dif-

ferent cell populations affected.

The present study was an attempt to investigate this

possibility by administering 5-fluoro-2-deoxyuridine (FUDR)

during three different periods of pregnancy, Days 10 and 11,

13 and 14, or 16 and 17. FUDR inhibits the activity of the

enzyme thymidine synthetase, thereby blocking DNA replication

(Bosch, Harbers & Heidelberger, 1958; Taylor, Haut, & Tung,

1962; Reyes & Heidelberger, 1965; Conrad & Ruddle, 1972), and

has been shown to inhibit cell division in the developing

nervous system (Langman, Shimada, & Rodier, 1972; Andreoli,
Rodier, & Langman, 1973; Webster, Shimada, & Langman, 1973).
1








In an attempt to find behavioral correlates of the pre-

dicted anatomical disruptions, we tested the animals using

several techniques which have been shown to be sensitive

indications of level of functioning of the CNS after terato-

logical intervention. Changes related to prenatal interven-

tion have been found in activity (Furchtgott & Echols, 1958a;

Werboff, Havlena & Sikov, 1962; Petit & Isaacson, in press),

audiogenic seizure susceptibility (Geller, 1973; Petit &

Isaacson, in press), walking on parallel bars (Werboff,

Goodman, Havlena & Sikov, 1961; Furchtgott & Echols, 1958b),

and T-maze learning and reversal learning (Haddad, Rabe,

Laquer, Spatz, & Valsamis, 1969; Furchtgott, Jones, Tacker &

Deagle, 1970). Thus, on the basis of prior research, we

selected these procedures for the study of animals born to

FUDR treated mothers.














METHOD


Timing of Pregnancy

Female Long Evans hooded rats (Rattus norvegicus) were

placed with males and vaginal smears were taken every morning.

The day on which sperm were found in the smear was considered

Day 0 of pregnancy (EO). Animals were then randomly assigned

to either three experimental groups or three control groups

and housed singly. Mating was continued until two mothers

and two corresponding foster mothers for each experimental

and control condition were obtained.



Experimental and Control Treatments

All injections were made subcutaneously. On E10 and 11,

two mothers received 30mg/kg FUDR (dissolved in distilled

water), while two mothers received distilled water injections

as a control. On E13 and 14, another two mothers received

30 mg/kg FUDR while two mothers received distilled water

injections. On E16 and 17, an additional two mothers were

given 30mg/kg FUDR and two mothers received distilled water.

Thus, each experimental and control mother received one

injection on each of two successive days of pregnancy. Fos-

ter mothers were left undisturbed throughout pregnancy.



Fostering and Postnatal Rearing

Within 12 hrs after birth, litters from all experimental
3









and control mothers were culled to 12 pups and fostered to

normal mothers which had delivered no more than 24 hrs

earlier. All offspring were then left undisturbed until

Postnatal Day 23 (PN23), when they were earmarked and

separately housed. From the two litters comprising each

experimental and control group, 16 animals were randomly

selected for testing, one half of the animals in each group

coming from each litter.



Apparatus and Testing Procedure

Beginning at PN45 the animals were handled for 5 min

daily for 3 days. On PN48, 49, and 50 the animals were

tested for locomotor activity in an automated activity arena

for 5 min each day (see Lanier & Isaacson, 1974), for details

of the apparatus.

Starting on PN51, the animals were placed on a 23-hr

water deprivation schedule. Starting on PN54, the animals

were allowed to explore a T-maze for 3 days in groups of eight.

The alleys of the apparatus were 11 cm wide and 14 cm high

with a hinged plexiglas top. The stem was 90 cm long with a

27 cm start box at the end. Each arm was 47 cm long, with a

water spout at the end protruding 1 cm into the arm. Clear

guillotine doors were located between the start box and the

stem, and in each of the arms adjacent to the choice point.

Preliminary exposure lasted 1/2 hr for each group and con-

sisted of handling, apparatus exploration, and drinking in






5


the goal compartments. During preliminary exposure, water was

available in both arms of the maze. On the fourth day, the

animals began training on a spatial discrimination in the T-

maze. The animals were trained to go to the right arm of the

maze for water reinforcement; the left arm contained a spout

from an empty water bottle. After entering the correct arm

the plexiglas guillotine door was lowered and the animal was

allowed to drink for 10 sec before being returned to the

start chamber to begin the next trial. If the animal entered

the incorrect arm, the guillotine door was lowered to prevent

a corrective response, and the animal was left for 10 sec

before being returned to the start chamber. The animals were

given 10 trials per day until a criterion of no more than two

errors in two successive days was reached. Upon reaching

criterion, each animal was begun on reversal training, during

which water was available in the left arm of the maze. During

the reversal learning the animals were given 10 trials a day

until reaching a criterion of no more than two errors in 1 day.

When the animals reached criterion on the reversal, the posi-

tion of the water was again switched to the right arm of the

maze. They were run to criterion performance again. Once

more a change in the location of the reward was made as the

animal reached criterion, for a total of three reversals.

Following reversal learning, all animals were maintained

on 23-hr water deprivation and tested for their ability to

walk on two horizontal bars 36 in long, set 1.5 in apart, and

connected to a supporting panel at both ends. One end had a









water tray placed against a dark surface and was designated

the goal. The other end, the starting point, had a light

surface. The rods were marked off in inches. The animal was

first placed at a distance of 6 in from the goal end of the

rods with front and rear feet in position and facing the water

tray. If the animal reached the water it was placed 12 in,

then 18 in, or farther from the goal end until 120 sec of time

on the bars had elapsed. Animals were never allowed to drink

more than 5 sec each time they reached the water tray during

the practice trials. Immediately following the practice

period the animal was placed in position at the starting end

with front and rear feet on the rods and pointed in the direc-

tion of the water tray. The animal was then observed until it

traversed the length of the rods. Time to traverse the rods

was recorded, as well as complete or partial falls.

The animals were then returned to ad lib. water, and 2

days later tested for audiogenic seizure susceptibility, once

that morning and once 36 hrs later (at night). The apparatus

was a modified Lehigh Valley Electronics operant chamber with

the feeding mechanisms removed. A noise level of 103-105 dB

was produced by placing a telephone bell in the space previous-

ly occupied by the feeding mechanism. The animals were placed

inside the apparatus for 15 sec, after which the sound was

presented continuously for 120 sec. For scoring purposes, the

120 sec was divided into four, 30-sec segments. Behavior was

scored during each 30-sec segment on seven counts: (1)

quiet, (2) grooming, (3) walking, (4) running, (5) hopping,

(6) clonic movements, and (7) tonic movements.









Two days following audiogenic seizure testing, all animals

were sacrificed with an overdose of ether and intracardially

perfused with physiological saline followed by 10 percent

formalin. The brains were removed, trimmed flush to the

anterior extent of the cerebral cortex and posterior extent

of the cerebellum. The brains were placed in 10 percent

formalin and allowed to harden for 3 days and weighed. The

dimensions of the brains were measured to the nearest .001

in (.0025cm) in three planes by use of a micrometer caliper.

Anterior-posterior (A-P) measurements were taken from the

most anterior tip of the isocortex to the most posterior tip

of the isocortex closest to the midline. The medial-lateral

(M-L) brain width was evaluated at the most posterior portion

of the isocortex measuring the width across the entire extent

of the brain (both hemispheres). Dorsal-ventral (D-V)

measurements were taken from the base of the brain to the top

of the isocortex at its most posterior extent. The brains

were then embedded in celloidin and cut coronally at 30 pm.

Every eighth section was mounted and stained with thionin.













RESULTS

An initial analysis of variance was run on scores of

the three control groups on all variables. No differences

were found, so their scores were combined to form a single

control group (Group C) for subsequent statistical analysis.

An analysis of variance was used to analyze all data unless

otherwise noted. When a significant F was found, a Dunnetts

post-ANOVA test was used to compare the control group with

the experimental groups (see Edwards, 1968). Only significant

differences are reported.



Anatomical Results

The anatomical results of this study are summarized

in Table 1.


Brain Weight

No differences were found between the brain weights of

Group C, the group receiving FUDR on E10-11 (Group 10-11)

or the group receiving FUDR on E13-14 (Group 13-14). The

brains of animals receiving FUDR on E16-17 (Group 16-17),

however, weighed less than the control group (p < .01).


Brain Size

No differences were found in any measurement of brain

size between Group C, Group 10-11, or Group 13-14. The Group

16-17 brains were smaller than the Group C brains in the A-P

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Histology

Histological examination of sample brains revealed no

obvious abnormality of cellular elements or structures in

any of the groups (see Figures 1, 2, 3, and 4).



Behavioral Results

The results of the various behavioral tests are summarized

in Table 2.


Activity

The females were more active than the males in all groups

(p< .01). The Group 10-11 animals were less active than the

Group C animals (p< .05), while the Group 13-14 and Group 16-

17 animals were more active than the Group C animals (p< .01).


Spatial Discrimination Learning and Reversal

Figure 5 represents the maze performance of the various

groups. No differences were found between Group C and any of

the three treated groups in the number of errors made during

original learning. There was no difference in the error

scores of Group C and Group 10-11 on any of the three reversals




The brains of experimental and control animals were ex-
amined by Jay B. Angevine, Jr., as well as the author and
Robert L. Isaacson; no one was able to find any histological
differences in any of the brains.





































Figure 1. Frontal section of the brain of an adult rat
from Group C (X-7.5: thionin).






























Figure 2.


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from Group 16-17 (X-7.5: thionin).














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Figure 5.


Mean error scores on T-maze learning and rehearsal
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On all three reversals, Group 13-14 made more errors than

Group C (p< .01). Group 16-17 made more errors only on re-

versal two (p< .01) and three (g< .05). While Group C and

Group 10-11 showed a consistent drop in the number of errors

made over the three reversals, Group 13-14 continued to make

approximately the same number of errors as original learning

throughout the three reversals. Group 16-17 showed a drop

in the mean number of errors across the three reversals, but

the drop was not as great as in Group C.

Inspection of Figure 5 indicates that Group 13-14 per-

formed more poorly on reversal learning than Group 16-17.

Group 13-14 made more errors than Group C on all three revers-

als, while the Group 16-17 error scores were higher only on

the last two reversals. During the last two reversals, Group

13-14 made more errors than Group 16-17 (p <.01, Duncan's

post-ANOVA test, Edwards, 1968).


Parallel Bar Walking

Performance on the parallel bars was measured in terms

of seconds taken to transverse the bars and number of complete

or partial falls. All three experimental groups were inferior

to Group C on both measures.


Audiogenic Seizure Susceptibility

For purposes of evaluation, all animals were divided into

two groups: those animals that had a score of 6 or 7 (clonic

or tonic movements) on either of the two test trials, and

those animals that never had a score higher than 5 (hopping).






18


Using a Chi-Square analysis, no differences were found between

the groups. In the control group, 25.5 percent of the animals

had scores above 5 while 33.3 percent of Group 10-11, 33.3

percent of Group 13-14, and 7.1 percent of Group 16-17 had

scores above 5.













DISCUSSION

The results of this study indicate that administration

of FUDR at three different points in pregnancy results in

different behavioral consequences in the offspring. Activity

decreases were seen in Group 10-11, while an increase in

activity was seen in Group 13-14 and Group 16-17. Although

all groups learned the spatial discrimination in the T-maze

with little difficulty, animals in Group 13-14 and Group 16-

17 performed poorly on the position reversals, with Group 13-

14 performing more poorly than Group 16-17. Problems in motor

performance were seen in all three experimental groups, while

no differences in audiogenic seizure susceptibility could be

detected in any of the experimental groups.

Although a significant reduction in brain size and weight

was found in Group 16-17, no anatomical anomalies could be

detected in the brains of any of the treated animals. Anatom-

ical effects frequently can not be detected in offspring

treated with teratogens, despite great behavioral differences

(Butcher, Brunner, Roth & Kimmel, 1970; Butcher, Vorhees, &

Kimmel, 1972; Hutchings, Gibbon, & Kaufman, 1973; Vorhees,

1974; Butcher, Hawver, Burbacker, & Scott, 1974; Hutchings &

Gaston, 1974). Proliferating cells can partially restitute

cell populations which are destroyed or prevented from forming

by a teratogen (Altman & Anderson, 1971; Andreoli, Rodier, &

Langman, 1973). Therefore, cells depleted by FUDR treatment

19









could have been replenished at least in part after the FUDR

treatment had been terminated. Butcher et al. (1974) have

suggested three progressive effects of increases in terato-

genic drug dosage: functional, anatomical, and lethal levels.

They postulated that at low doses there could be functional,

i.e., behavioral, effects of teratogens without producing

anatomical effects. Hutchings & Gaston (1974) have also em-

phasized the lack of correlation between teratologically pro-

duced brain damage and behavioral impairment. Noting the

similarity in behavioral, but not anatomical, impairments

found after treatments with a variety of agents, the authors

suggested a common underlying mechanism, possibly of a bio-

chemical rather than structural nature.

Activity changes in offspring subjected to teratogens

appear to be correlated with the time of prenatal inter-

vention. Treatment during early prenatal CNS formation with

hypervitaminosis A on E8, 9, and 10 (Vorhees, 1974), X-irradi-

ation on E10 (Werboff, Havlena, & Sikov, 1962), or FUDR on E10

and 11 (present study) leads to reduced activity levels in

the offspring. Intervention during the middle of the prenatal

period of CNS formation with methylazoxymethanol on E14, 15,

or 16 (Haddad, Rabe, Laquer, Spatz, & Valsamis, 1969), X-irra-

diation on E15 (Furchtgott, Tacker, & Draper, 1968; Furchtgott

& Echols, 1958a; Werboff, Havlena, & Sikov, 1962) or FUDR on

E13-14 (present study) causes hyperactivity in the offspring.

Activity differences are also found following intervention

during late prenatal CNS formation. Animals treated with









FUDR on E16-17 (present study) were found to be hyperactive.

Furchtgott & Echols (1958b) irradiated animals on E13 through

17 and tested them in tilting cages and an open field. They

found maximal activity enhancement in animals treated on E15-

16. Irradiation on E17 produced increased activity levels,

whereas neonatal irradiation produced decreased activity levels.

Petit & Isaacson (in press) tested animals treated with col-

chicine on E17, 18, and 19 in an open field on Days PN25, 26,

and 45. The animals were not found to differ from the controls

on PN25 or 45, but were hypoactive on PN26. It appears that

the hyperactivity found from intervention during mid-prenatal

CNS formation is seen after intervention during the early part

of this period. As intervention time nears birth, however,

a drop in activity level of the treated animal is seen.

Animals in Group 13-14 and Group 16-17 made more errors

during spatial reversal learning in the T-maze than the con-

trols. Previous researchers have reported that animals treated

with methylazoxymethanol (Rabe & Haddad, 1972), or X-irradiation

(Furchtgott, Jones, Tacker, & Deagle, 1970) on E15 learned a

spatial discrimination in a T-maze as quickly as controls; but

when reversal learning was required the treated animals per-

formed significantly worse than controls. However, in a WGTA

adapted for rats, a series of visual pattern discrimination

of increasing difficulty and their reversal were mastered by

the treated as well as control rats (Rabe & Haddad, 1972).

This is in contrast to the reversal learning deficits in the

T-maze shown by these same animals. These authors concluded








that the animals had a deficit in spatial reversal learning,

rather than a general cognitive impairment. The deficits

found in reversal learning in this study are consistent with

earlier findings and indicate that animals treated with FUDR

during early prenatal CNS formation, E10-11, do not show

deficits in reversal learning, while animals treated with FUDR

during late pregnancy, E16-17, although showing a spatial

reversal deficit, may not perform as poorly on this task as

animals treated during mid-prenatal CNS formation, E13-14.

Animals treated on E10-11, E13-14, or E16-17 showed an

increase in falls and time taken to traverse the parallel bars.

This is consistent with earlier reports. Similar results on

this same task were found by Werboff, Goodman, Havlena, & Sikov

(1961) in animals irradiated on E10, 15, or 20, and by Furcht-

gott & Echols (1958b) in animals irradiated on E13. Thus

deficits in motor performance can be produced in animals after

teratological intervention at several points in pregnancy.

Audiogenic seizure susceptibility was not found to be

affected by treatment with FUDR at any of the three points in

pregnancy. Geller (1973) has shown that audiogenic seizure

susceptibility was not altered in irradiated animals regard-

less of the time of administration. Butcher, Smith, Kazmaier,

& Scott (1973) were unable to find differences in this measure

in animals treated with hydroxyurea on E12. Petit & Isaacson

(in press), however, found a decrease in audiogenic seizure

susceptibility in animals treated with colchicine on E17, 18,

and 19. The results of the latter authors may be specific to









the drug colchicine. Thus, although X-irradiation and FUDR

administration during different periods of pregnancy may not

affect seizure susceptibility, results on this test may be

specific to the teratogen used.

In conclusion, this study indicates that while certain

behaviors are affected in a similar fashion after FUDR inter-

vention at any point in pregnancy (motor behaviors), some

behaviors are not affected at any point in pregnancy (audio-

genic seizure susceptibility), and other behaviors are differ-

entially affected depending on the time of intervention (activ-

ity and reversal learning). FUDR intervention during early

prenatal CNS formation (E10-11) produces hypoactivity and no

deficits in reversal learning. Intervention during mid-

prenatal CNS formation (E13-14) results in hyperactivity and

large deficits in reversal learning. Intervention later in

pregnancy (E16-17) results in a mild deficit in reversal

learning and hyperactivity.

The results of this study indicate that different be-

havioral syndromes are associated with teratological inter-

vention on different days of gestation. Additional studies

using a variety of agents administered at different gestation-

al ages are needed to fully understand the principles involved

in this area of research. If it were possible to identify the

behavioral consequences of interference with cell prolifera-

tion at different stages of gestation and postnatal life, it

might be possible to specify the etiology of some brain damage

syndromes.












REFERENCES


Altman, J., and Anderson, W. J. (1971). Irradiation of the
cerebellum in infant rats with low level X-ray: Histo-
logical and cytological effects during infancy and
adulthood. Exp. Neurol., 30: 492-509.

Andreoli, J., Rodier, P. M., and Langman, J. (1973). Influ-
ence of prenatal trauma on formation of Purkinje cells.
Am. J. Anat., 137: 87-102.

Bosch, L., Harbers, E., and Heidelberger, C. (1958). Studies
on fluorinated pyrimidines. V. Effects on nucleic
acid metabolism in vitro. Cancer Res., 18: 335-343.

Butcher, R. E., Brunner, R. L., Roth, T., and Kimmel, C. A.
(1970). A learning impairment associated with maternal
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26


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BIOGRAPHICAL SKETCH

Ted LaRue Petit was born October 20, 1949 in Bogalusa,

Louisiana. He received his Bachelor of Science degree from

Louisiana State University in 1971. In 1972 he received his

Master of Arts degree from the same university. In the

Fall of 1972 he entered the University of Florida where he

is presently a candidate for the degree of Doctor of

Philosophy.









I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly pre-
sentation and is fully adequate, in scope and quality, as a
dissertation for the degree of,Doctor of Ph losophy.




Robert L. Isaacson, Chairman
Professor of Psychology


I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly pre-
sentation and is fully adequate, in scope and quality, as a
dissertation for the degree of Doctor of Philosophy.




Frederick A. King
Professor of Neuroscie ce



I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly pre-
sentation and is fully adequate, in scope and quality, as a
dissertation for the degree of Doctor of Philosophy.


K _/<__i _
Mefle E. Meyer I
Professor and Chairman of
Psychology



I certify that I have read this study and that in my.
opinion it conforms to acceptable standards of scholarly pre-
sentation and is fully adequate, in scope and quality, as a
dissertation for the degree of Doctor of Philosophy.




Carol Van Hartesveldt
Associate Professor of Psychology









I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly pre-
sentation and is fully adequate, in scope and quality, as a
dissertation for the degree of Doctor of Philosophy.




W. Keith Berg /
Assistant Professor of Psychology



This dissertation was submitted to the Graduate Faculty of the
Department of Psychology in the College of Arts and Sciences
and to the Graduate Council, and was accepted as partial ful-
fillment of the requirements for the degree of Doctor of
Philosophy.

August, 1975


Dean, Graduate School







































UNIVERSITY OF FLORIDA
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