AN ASSESSMENT OF THE EFFECTS OF PSYCHOACTIVE DRUGS AND ELECTRICAL STIMULATION OF THE VENTRAL TEGMENTAL AREA ON THE STIMULUS PROPERTIES OF AMPHETAMINE By JONATHAN PETER DRUHAN B.Sc, McGill University, 1983 M.A., The University of British Columbia, 1985 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Psychology) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA January 1989 (c) Jonathan Peter Druhan , 1989 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 or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of PSYCHOLOGY The University of British Columbia Vancouver, Canada Date JANUARY 20, 1989 DE-6 (2/88) ABSTRACT The discriminative stimulus properties of amphetamine are thought to result from the facilitatory actions of this drug on dopamine neurotransmission within the nucleus accumbens. As such actions within the nucleus accumbens also are hypothesized to be responsible for amphetamine's rewarding effects, the stimulus properties of amphetamine may be related to the hedonic effects of the drug. If these conclusions are correct, then tests for generalization with the stimulus properties of amphetamine might be useful either to determine the dopaminergic actions of drugs, or to screen newly developed compounds for their abuse potential. In the present thesis rats were trained to discriminate 1.0 mg/kg amphetamine from saline, and then tested for stimulus generalization to a range of amphetamine doses (0.0, 0.25, 0.50 and 1.0 mg/kg) injected either alone or in combination with either cocaine, apomorphine, haloperidol, nicotine, morphine, midazolam, ethanol or electrical stimulation of the ventral tegmental area (VTA). Comparisons were then made between the amphetamine stimulus generalization functions obtained in the presence and absence of the test stimuli, to determine whether the functions were altered in a manner consistent with the known dopaminergic actions or hedonic effects of the drugs and VTA stimulation. It was predicted that test stimuli that could enhance dopamine neurotransmission or produce positive hedonic effects might augment the stimulus properties of 111 amphetamine and elevate stimulus generalization functions relative to a control curve. Conversely, test stimuli that inhibited dopamine neurotransmission or reduced positive affect might interfere with the amphetamine stimuli and lower the generalization functions. The results indicated that amphetamine stimulus generalization functions were altered in a manner that generally reflected the known actions of each test stimulus on dopamine neurotransmission. Thus, the generalization functions were elevated by stimuli that enhanced dopamine neurotransmission (cocaine, a dose of apomorphine affecting post-synaptic dopamine receptor sites, nicotine and VTA stimulation) and lowered by stimuli that interfered with dopamine neurotransmission (haloperidol, midazolam, and a dose of apomorphine that acts preferentially at presynaptic dopamine autoreceptors). Ethanol, which has not been found to consistently affect dopamine neurotransmission, did not generalize with the stimulus properties of amphetamine. Only morphine was found to affect amphetamine stimulus generalization functions (a lowering) in a manner that was inconsistent with the drug's facilitatory actions on dopamine neurotransmission. The amphetamine stimulus generalization functions were not affected in a manner consistent with the hedonic actions of each test stimulus. Certain drugs that could produce positive hedonic effects (morphine, midazolam and ethanol) failed to elevate the generalization functions. In fact, the iv functions were elevated only by stimuli that appear to produce most of their rewarding effects by enhancing mesoaccumbens dopamine neurotransmission (cocaine, apomorphine, nicotine, and VTA stimulation). Two additional experiments suggested that this property could have been responsible for the ability of VTA stimulation to elevate amphetamine stimulus generalization functions. In one experiment, the ability of the VTA stimulation to substitute for the stimulus properties of amphetamine was found to be correlated positively with its rewarding efficacy measured during ICSS tests. A subsequent experiment indicated that dopamine neurons could indeed mediate discriminative stimuli produced by VTA stimulation, as the brain stimulation cues were augmented by amphetamine and attenuated by the dopamine receptor antagonist, haloperidol. Together, the findings of this thesis indicated that amphetamine stimulus generalization paradigms might be useful for detecting the dopaminergic actions of certain psychoactive drugs. However, such procedures may not detect the abuse potential of all compounds. This latter result indicates that certain drugs of abuse do not produce amphetamine-like stimulus properties, and that this may be due to differences in the neural mechanisms that mediate their positive hedonic effects. V TABLE OF CONTENTS Abstract ii Table of Contents v List of Tables ix List of Figures xi Acknowledgment xiii Introduction 1 Procedures for Measuring the Rewarding Effects of Drugs 4 Drug Discrimination Procedures: General Overview .. 9 The Relation of Drug Discrimination Performance to the Stimulus Properties of Drugs 11 Relations Between the Stimulus Properties and Hedonic Actions of Drugs 16 Pharmacological Specificity of Amphetamine Stimuli 18 Neurochemical Substrates for Amphetamine Stimuli .. 19 The Role of Specific Dopamine Projections in Mediating the Stimulus Properties of Amphetamine .. 21 Common Neurochemical Substrates for the Stimulus Properties and Rewarding Effects of Amphetamine ... 23 Issues to be Addressed in the Present Thesis 24 Discrimination Training Procedures 27 The Amphetamine Stimulus Generalization Paradigm .. 28 Predicted Effects of Different Test Stimuli on Amphetamine Stimulus Generalization Functions 33 vi General Methods 40 Subjects 40 Surgery and Histology 40 Apparatus 41 Drug Discrimination Training 43 Generalization Tests 44 Locomotor Activity Tests 45 Drugs 46 Statistical Analyses 47 Experiment 1: The Effects of Cocaine, Apomorphine, and Haloperidol on Amphetamine Stimulus Generalization Functions 50 Methods 52 Results 53 Discussion 62 Experiment 2: The Effects of Nicotine on Amphetamine Stimulus Generalization Functions 67 Methods 69 Results 69 Discussion 76 Experiment 3: The Effects of Morphine on Amphetamine Stimulus Generalization Functions 81 Methods 83 Results 83 Discussion 89 vii Experiment 4: The Effects of Midazolam on Amphetamine Stimulus Generalization Functions 94 Methods 95 Results 96 Discussion 101 Experiment 5: The Effects of Ethanol on Amphetamine Stimulus Generalization Functions 105 Methods 106 Results 107 Discussion 113 Experiment 6: The Effects of Electrical Stimulation of the VTA on Amphetamine Stimulus Generalization Functions 117 Methods 118 Results 119 Discussion 128 Experiment 7: The Relationship Between the Rewarding Effects of VTA Stimulation and its Ability to Generalize with the Stimulus Properties of Amphetamine 131 Methods 132 Results 133 Discussion 147 Experiment 8: The Effects of Amphetamine and Haloperidol on Discriminative Stimuli Produced by Electrical Stimulation of the VTA 151 Methods 153 viii Results 156 Discussion 162 General Discussion 165 Implications of the Present Findings for a Theory of the Stimulus Properties of Amphetamine 177 The Utility of Amphetamine Stimulus Generalization Paradigms as Screening Procedures for Assessing the Dopaminergic and Hedonic Properties of Drugs 184 Implications of the Present Findings for Theories of Drug Abuse 188 References 192 ix LIST OF TABLES Table 1: The actions on dopamine neurotransmission and the hedonic effects of the test stimuli employed for Experiments 1 through 6 35 Table 2: Percentages of responses on the initially selected lever after cocaine, apomorphine and haloperidol 59 Table 3: Total number of responses after cocaine, apomorphine and haloperidol 61 Table 4: Percentages of responses on the initially selected lever after nicotine 73 Table 5: Total number of responses after nicotine 75 Table 6: Percentages of responses on the initially selected lever after morphine 87 Table 7: Total number of responses after morphine 88 Table 8: Percentages of responses on the initially selected lever after midazolam 99 Table 9: Total number of responses after midazolam .... 100 Table 10: Percentages of responses on the initially selected lever after ethanol 111 Table 11: Total number of responses after ethanol 112 Table 12: Percentages of responses on the initially selected lever during VTA stimulation 126 Table 13: Total number of responses durinng VTA stimulation 127 X Table 14: Percentages of responses on the initially selected lever during substitution tests with different parameters of VTA stimulation 140 Table 15: Total number of responses during substitution tests with different parameters of VTA stimulation . 141 LIST OF FIGURES Figure 1: Theoretical outcomes of stimulus generalization experiments 31-32 Figure