AN ANIMAL MODEL OF HUNTINGTON'S DISEASE: BEHAVIORAL, PHARMACOLOGICAL AND MORPHOLOGICAL CHANGES FOLLOWING INTRASTRIATAL INJECTIONS OF KAINIC ACID'

by

PAUL RONALD SANBERG

B.Sc.(Hons), York University, 1976

A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE

IN THE FACULTY OF GRADUATE STUDIES

in

THE FACULTY OF MEDICINE DEPARTMENT OF PSYCHIATRY DIVISION OF NEUROLOGICAL SCIENCES

We accept this thesis as conforming to the required standard

THE UNIVERSITY OF BRITISH COLUMBIA November, 1978

© Paul Ronald Sanberg,1978 In presenting this thesis in partial fulfilment of the requirements for

an advanced degree at the University of British Columbia, I agree that

the Library shall make it freely available for reference and study.

I further agree that permission for extensive copying of this thesis

for scholarly purposes may be granted by the Head of my Department or

by his representatives. It is understood that copying or publication

of this thesis for financial gain shall not be allowed without my

written permission.

Paul R..Sanberg

Department of Psychiatry, Division of Neurological Sciences

The University of British Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5

Date November 9, 1978 •

i ABSTRACT

Compared with saline injected controls, rats with bilateral injections of kainic acid (KA) in the dorsal striatum showed temporary aphagia and adipsia, long-lasting body weight decreases, increased locomotor response to d-amphetamine, increased spontaneous nocturnal locomotor activity, increased resistance to extinction, impaired acquisition and retention of avoidance behavior and increased latencies to leave start boxes in various mazes. The KA injections resulted in loss of local neurons in the dorsal striatum, with no appreciable damage either to dopaminergic terminals or to extrinisic myelinated axons, thus supporting both the selective neurotoxic action of KA on neuronal perikarya and the proposed similarity of KA-induced striatal lesions with those found in the caudate-putamen of patients with

Huntington's disease (HD). The present results demonstrate that KA striatal lesioned rats also show behavioral and pharmacological similari• ties with HD patients. In addition, they support the view that HD is characterized by a "subcortical syndrome". A review of HD is also presented.

Dr. H. C. Fibiger Research Supervisor iii

TABLE OF CONTENTS Page ABSTRACT ii

TABLE OF CONTENTS iii

LIST OF TABLES v

LIST OF FIGURES vi

ACKNOWLEDGEMENT vii

INTRODUCTION 1

Neuropathology 6

Neurochemical Pathology 11

Dopamine 13 Serotonin and norepinephrine 14 Acetylcholine 15 GABA 15 Angiotensin II 16 Substance P 17 Summary " 17

Therapeutic Rationale Based on Neurochemical Pathology 19

Dopamine 21 Acetylcholine 22 GABA 22 23 Neurotransmitter receptors 26 Psychopathology 31 Animal Models 33 Striatal kainic acid model 37 METHODS 37 Subjects 37 Apparatus Locomotor activity 37 Appetitive bar pressing 37 Step-down avoidance 38 Spontaneous alternation 38 Alleyway maze exploration 38 Shuttle-box avoidance 39 iv

Page

Procedures 39

Body weight, water intake and food intake 39 Locomotor activity 40 Acquisition and extinction of bar pressing 40 Step-down passive avoidance 41 Spontaneous alternation 42 Alleyway maze exploration 43 Shuttle-box avoidance 44 Histology 45 Biochemistry 46

RESULTS 47

Aphagia and Adipsia 47 Body Weight 47 Foot and Water Intake 49 Locomotor Activity 49 Appetite Bar Pressing 49 Step-down Passive Avoidance 53 Spontaneous Alternation 57 Alleyway Maze Exploration 57 Shuttle-box Avoidance 62 Histology 62 Biochemistry 68

DISCUSSION 72

Neuropathology 72 Body Weight and Regulatory Behaviors 74 Motor Behavior 78 Psychopathology 79

REFERENCES