Robert A. Frank - US grants

In order to develop new drugs for use in the treatment of behavioral disorders and central nervous system dysfunction, a battery of behavioral tests must be available for the assessment of the psychoactive properties of these substances. One behavioral paradigm that has been employed for this purpose has examined the effect of various pharmalogical agents on the self-administration of brain stimulation reward (BSR). In particular, this approach has proven useful in determining the addiction potential of drugs and in investigating the behavioral effects of anti-psychotic agents. However, the potential of this paradigm for characterizing the multitude of behavioral effects that might be produced by a drug has not been fully exploited. For example, although there is evidence that the effect of a drug on self-stimulation may depend on the joint effects of the stimulation site and response requirements, no systematic attempt has been made to explore this relationship. The proposed studies would examine the influence of response topography and differences in electrode placement on drug-induced changes in intracranial self-stimulation. Self-stimulation thresholds, response rates and response patterns will be assessed using a novel measurement strategy that manipulates brain stimulation train durations. Since little or no account is taken of differences in response topographies or stimulation site in most self-stimulation reserach, the results of the proposed studies may indicate that significant changes are needed in the methods currently used to assess the behavioral effects of pharmacological agents on BSR. They may also initiate a rethinking of how central reward and response control mechanisms jointly regulate goal directed behavior.

Cocaine abuse has risen sharply over the past 10 years, and with this increase has come a commensurate increase in the health and social problems associated with chronic cocaine use. Effective strategies for dealing with this problem depend on an appreciation of the factors that contribute to drug use. In the case of cocaine, it is generally believed that drug-induced changes in affect (both euphoria and dysphoria) are important determinants of the pattern of drug self-administration. However, few studies have attempted to evaluate the time course of cocaine's mood-altering effects. The research described in this proposal explores the time course of cocaine-induced changes in affect using an intracranial self- stimulation paradigm. Fluctuations in train durations thresholds will be used to investigate the effects of chronic cocaine administration of central reward mechanisms. In addition, the ability of drugs coadministered with cocaine (i.e., ethanol and morphine) will be evaluated for their ability to modify cocaine- induced changes in self-stimulation. Finally, the influence of imipramine on cocaine's effects will be assessed to determine whether this drug, which has been proposed as a treatment for cocaine dependence, alters cocaine-induced euphoria and/or dysphoria.

biomedical equipment purchase;

health science research support; university;

Increases in psychomotor stimulant abuse have lead to a national effort to curtail use of these substances. For the most part, recent efforts have focused on stemming the tide of cocaine abuse. Attempts have been made to reduce both the supply of and demand for cocaine. In addition, the search has begun for effective treatment programs for those who have developed chronic patterns of cocaine abuse. Pharmacological treatments are being viewed as a potentially important adjunct to behaviorally-oriented treatment strategies. Given recent evidence that the reinforcing effects of many drugs of abuse are mediated through a common neural substrate, drugs developed for the treatment of cocaine abuse may be useful for treating the abuse of other substances. The long-term objectives of the proposed research are an elucidation of the neural substrates/mechanisms which mediate psychomotor stimulant reinforcement, and the development of pharmacological treatments for psychomotor stimulant abuse. These objectives will be pursued in the following experiments. 1. One series of experiments will evaluate the role of the nucleus accumbens (and possibly other dopamine terminal fields) in the self- stimulation threshold-lowering effects of amphetamine and cocaine. These experiments are intended to identify the neuroanatomical loci that mediate cocaine and amphetamine's reinforcing effects by assessing the influence of 6-hydroxydopamine (6-OHDA) lesions on amphetamine and cocaine-induced enhancement of brain stimulation reward. 2. A subsequent series of experiments will focus on the capacity of mixed D2/5-HT2 antagonists to reverse amphetamine and cocaine-induced decreases in self-stimulation thresholds. Preliminary evidence suggests that these drugs attenuate the reinforcing properties of psychomotor stimulants. The proposed experiments will systematically investigate the ability of compounds with varying specificity for the D2 and 5-HT2 receptor subtypes to antagonize cocaine and amphetamine's effects on brain stimulation reward. The relative contribution of dopamine and serotonin mechanisms will be clarified by using antagonists that differ in their spectra of dopaminergic and serotonergic activity. 3. A set of neurochemical and electrophysiological experiments will be performed based on the outcomes of the 6-OHDA and antagonist studies. These experiments will be conducted to elucidate the mechanism(s) by which an antagonist reverses cocaine or amphetamine's effects. Drug-induced changes in dopamine metabolism an release will be measured using in vivo microdialysis, while extracellular recording techniques will be used to measure dopamine cell activity. The neuroanatomical loci for the microdialysis and recording studies will be determined by the 6-OHDA experiments, and the antagonists will be selected based on their ability to reverse cocaine or amphetamine's effects on self-stimulation thresholds. The combination of behavioral, neurochemical and electrophysiological techniques used in the proposed experiments should provide insights into dopaminergic and serotonergic modulation of psychomotor stimulant reinforcement. In addition, these experiments will provide information concerning the potential value of D2 and 5-HT2 antagonists as pharmacotherapies for psychomotor stimulant abuse.

Increases in psychomotor stimulant abuse have lead to a national effort to curtail use of these substances. For the most part, recent efforts have focused on stemming the tide of cocaine abuse. Attempts have been made to reduce both the supply of and demand for cocaine. In addition, the search has begun for effective treatment programs for those who have developed chronic patterns of cocaine abuse. Pharmacological treatments are being viewed as a potentially important adjunct to behaviorally-oriented treatment strategies. Given recent evidence that the reinforcing effects of many drugs of abuse are mediated through a common neural substrate, drugs developed for the treatment of cocaine abuse may be useful for treating the abuse of other substances. The long-term objectives of the proposed research are an elucidation of the neural substrates/mechanisms which mediate psychomotor stimulant reinforcement, and the development of pharmacological treatments for psychomotor stimulant abuse. These objectives will be pursued in the following experiments. 1. One series of experiments will evaluate the role of the nucleus accumbens (and possibly other dopamine terminal fields) in the self- stimulation threshold-lowering effects of amphetamine and cocaine. These experiments are intended to identify the neuroanatomical loci that mediate cocaine and amphetamine's reinforcing effects by assessing the influence of 6-hydroxydopamine (6-OHDA) lesions on amphetamine and cocaine-induced enhancement of brain stimulation reward. 2. A subsequent series of experiments will focus on the capacity of mixed D2/5-HT2 antagonists to reverse amphetamine and cocaine-induced decreases in self-stimulation thresholds. Preliminary evidence suggests that these drugs attenuate the reinforcing properties of psychomotor stimulants. The proposed experiments will systematically investigate the ability of compounds with varying specificity for the D2 and 5-HT2 receptor subtypes to antagonize cocaine and amphetamine's effects on brain stimulation reward. The relative contribution of dopamine and serotonin mechanisms will be clarified by using antagonists that differ in their spectra of dopaminergic and serotonergic activity. 3. A set of neurochemical and electrophysiological experiments will be performed based on the outcomes of the 6-OHDA and antagonist studies. These experiments will be conducted to elucidate the mechanism(s) by which an antagonist reverses cocaine or amphetamine's effects. Drug-induced changes in dopamine metabolism an release will be measured using in vivo microdialysis, while extracellular recording techniques will be used to measure dopamine cell activity. The neuroanatomical loci for the microdialysis and recording studies will be determined by the 6-OHDA experiments, and the antagonists will be selected based on their ability to reverse cocaine or amphetamine's effects on self-stimulation thresholds. The combination of behavioral, neurochemical and electrophysiological techniques used in the proposed experiments should provide insights into dopaminergic and serotonergic modulation of psychomotor stimulant reinforcement. In addition, these experiments will provide information concerning the potential value of D2 and 5-HT2 antagonists as pharmacotherapies for psychomotor stimulant abuse.