Susan Schenk - US grants

The use and abuse of cocaine and other drugs has increased in recent years. The use has been tied to the ability of this class of drugs to produce positively reinforcing effect ie. euphoria. These properties exhibit marked across subject variability. That is, not all individuals find the drug rewarding. The reasons for this heterogeneity are not well understood but it has been suggested that some antecedent conditions exists that cause some individuals to be more sensitive than others. The identification of these antecedent conditions seems imperative if we are to institute effective programs aimed at prevention. Environmental conditions can markedly influence the propensity of rats to self-administer cocaine but not amphetamine. Thus, it was suggested that environmental conditions influence the development of specific neurochemical systems which then determine the response to specific classes of abused drugs. The present proposal extends from these initial findings. It will attempt to establish the means by which the enviromental conditions can effect the sensitivity of adult rats to the reinforcing properties of cocaine. The first section will investigate the neurochemical bases for the acquisition and maintenance of cocaine self-administration through the usage of the intravenous self-administration paradigm. The second section will address more specifically the interaction between central dopaminergic substrates and environmental conditions that predispose rats to the reinforcing properties of cocaine. The third section will test the notion that environmentally determined changes in sensitivity to cocaine can be reversed through an alternate form of environmental manipulation. The results of these studies may point to etiological and therapeutic directions for cocaine abuse.

It is the purpose of these experiments to examine the process of sensitization to cocaine following pretreatment with a number of pharmacological agents. It is our aim to evaluate the idea that at least part of the basis for variability in response to the rewarding effects of cocaine Is due to differences in the development of specific neurochemical systems, which in turn is due to environmental conditions. Rats will be exposed to four compounds (nicotine, caffeine, cocaine or amphetamine) for various periods of time. We will compare the ability for exposure to these compounds to alter the motor activating effects of cocaine and the propensity to self-administer this drug. Should the results show that preexposure to some agents can after the acquisition of cocaine self-administration, they will provide us with a realistic approach to prevention of abuse of this compound. We will also examine the neurochemical basis for changes in sensitivity produced by the preexposure regimen using microdialysis probes to measure the changes in extracellular dopamine within the nucleus accumbens and medial prefrontal cortex. Taken together, it is our hope that this line of investigation will demonstrate the importance of environmental factors as predisposing to drug abuse and will provide avenues leading to prevention of this compulsive self-destructive behavior.

The National Institute on Drug Abuse (NIDA), Medications Development Division (MDD) has established a Cocaine Treatment Discovery Program (CTDP) to identify potential treatments for the medical management of cocaine dependence. This program involves testing compounds through a decision-based screening scheme which consists of a number of in vitro and in vivo assays and which is designed to identify potential treatment agents which either substitute for cocaine or antagonize the effects of cocaine. The purpose of this contract is to evaluate the effects of 20 test compounds on the reinforcing effects of cocaine, as assessed by the drug self-administration procedure. Specifically, the ability of the test compound to antagonize the reinforcing effects of cocaine will be determined by assessing the nature and magnitude of the shift in the cocaine dose-effect curve. The ability of the test compound to maintain self-administration behavior will be used to assess whether the test compound can substitute for the reinforcing effects of cocaine. Compounds will, in general, be submitted by NIDA to the contractor "blind" with a coded identification number and information about the compound such as their physical properties and solubility. CTDP data. generated from this contract on proprietary compounds will be maintained in confidence by NIDA for three (3) years from the date of reporting of the first test result to the compound submitter. After three (3) years, NIDA will disclose this information into the public domain through its MDD structure-activity database. Compound submitters are free to disclose CTDP data generated on their compounds prior to the three (3) year period of non-disclosure.

DESCRIPTION: (Applicant's Abstract) The proposed studies aim to characterize the site and mechanism of action of kappa-opioid receptor agonists in preventing the sensitization or "reverse-tolerance" which develops to the rewarding effects of cocaine following its repeated administration. Our objectives are to determine whether: 1) activation of kappa-opioid receptors located in regions comprising the mesocorticolimbic dopamine (DA) system, is sufficient to prevent the sensitization which develops to the rewarding effects of cocaine; 2) the modulatory effects of systemically and intracerebrally administered kappa-agonists upon sensitization are correlated with a suppression of cocaine-induced increases in extracellular DA levels within the nucleus accumbens (NAC), a projection site of mesocorticolimbic neurons and 3) inactivation of kappa-opioid receptors exacerbates the development of the sensitization process. The conditioned place preference and intravenous self-administration paradigms, will be used to map the site of action of kappa-agonists in modulating the development of sensitization and to examine whether microinjection of a kappa-opioid receptor antagonists exacerbate the development of sensitization. The technique of microdialysis will be used to monitor extracellular DA levels within the NAC in response to the administration of cocaine and kappa-opioid receptor ligands. We hypothesize that exogenously applied kappa-opioid agonists prevent sensitization to the rewarding effects of cocaine by activating opioid receptors located within the NAC and thereby suppressing cocaine-induced increases in extracellular DA levels within this specific brain region. These studies will provide important information regarding the site of action of kappa-opioid agonists in modulating adaptive behavioral responses which occur in response to repeated cocaine administration and may contribute to the development of an effective pharmacological treatment for cocaine addiction.