Patrick M. Beardsley, Ph.D. - US grants

More effective measures for prevention and treatment of drug abuse and its consequences will not proceed until we increase our understanding of the control drugs have over behavior. It has been well established that drugs can control behavior as discriminative stimuli setting the occasion for the occurrence of specific behaviors and as reinforcing stimuli increasing the probability of drug self-administration. As discriminative stimuli, drugs may actually set the occasion for their own self- administration or the self-administration of other drugs. When one drug serves as a discriminative stimulus for the self- administration of other drugs, self-perpetuating polydrug abuse can be generated: not only its drug-seeking behavior reinforced by a drug's effects, but its effects, functioning as discriminative stimuli, also engender behavior directed at the acquisition of yet other drugs. In this project, aspects of the discriminative stimulus and the reinforcing stimulus functions of drugs will be examined. In particular, animal models will be used to study conditioning factors that may be responsible for relapse, for the abuse of drug combinations, and for the propensity of the abuse of one drug to precede and lead to the abuse of another. Specific drugs that will be studied, sometimes alone and sometimes in combination with one another, include tetrahydrocannabinol (THC), the principal active constituent of marihuana, phencyclidine (PCP), and ethanol.

The objectives of this contract are to determine the in vivo efficacy of novel compounds in a animal model of relapse, including the following tests in animals trained to self-administer cocaine; (1) the ability of a test compound to block footshock- or other stressor-induced reinstatement of responding after a period of experimental extinction, (2) the ability of a test compound to block cocaine-priming-induced reinstatement of responding after a period of extinction, and (3) the ability of a test compound to block the effects of a conditioned cue (previously paired with cocaine) to reinstate responding for cocaine after a period of extinction. The development of methods, and the design, evaluation, and implementation of protocols is understood to be an integral part of this work, because although all of the methodologies have been described in the literature, some of them have been used in only a few laboratories and with variable success. This contract shall also support follow-up rodent pharmacology studies of compounds identified as promising potential drug-dependence treatment agents. The details of these latter studies cannot be specified in advance of contract award; they will depend upon specific successes in NIDA's medication discovery efforts and scientific advances in the general field of drug abuse research. The anticipated end results of this contract are written reports detailing study findings that will be used by the Cocaine Treatment Discovery Program of the Division of Treatment Research and Development.

There are no approved medications for preventing relapse to cocaine abuse. Previous clinical evaluations of drug candidates have been disappointing. Stress has often been implicated in relapse to drug abuse. Converging evidence from genetic, neuroanatomical and pharmacological studies suggest that the kappa opioid receptor (KOR) system interacts with the hypothalamic-pituitary-adrenocortical axis and modulates the effects of stress on behavior. Importantly, KOR agonists have been reported to exacerbate, and KOR antagonists have been reported to attenuate the behavioral effects of environmental stressors. We have synthesized a novel, KOR antagonist, (3R)-7-Hydroxy-N-{(1S)-1-{[(3R,4fR)-4-(3-hydroxyphenyl)-3,4-dimethyl- 1-piperidinyl]methyl}-2-methylpropyl}-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic) which has shown high potency and selectivity for the KOR and potent and extremely long-lasting KOR antagonist activity. Recently, we found that JDTic was able to block footshock-induced stress reinstatement of cocaine-seeking in rats, an effect hypothesized predictive of medications which would be useful in treating cocaine relapse. These observations, and others, have led us to propose JDTic as a candidate medication for treating relapse to cocaine abuse. The purpose of this project is to evaluate four JDTic analogs identified in Project 1. In this project, the four analogs will be evaluated at least three doses each in footshock-induced reinstatement procedures using Long-Evans hooded rats with histories of self-administering 0.5 mg/kg cocaine during daily, 2-h experimental sessions. Candidates demonstrating an ability to significantly attenuate the effects of footshock-induced stress will then be evaluated in cocaine-prime reinstatement procedures to assess their specificity and to delineate their range of effectiveness. Candidates attenuating stress-induced reinstatement of cocaine seeking which minimally affect cocaine-prime reinstatement or attenuate it will be promoted onto toxicity studies for further evaluation as a backup to JDTic. JDTic is an exciting compound which offers a novel mechanism for potentially treating relapse to cocaine abuse, an unfilled therapeutic niche. This project will identify successors to JDTic in the event future studies during its development necessitate a replacement for it.

Another part of this work is to develop methods and to design and implement protocols for the evaluation of test compounds.

This contract provides support for the in vivo evaluation, in rodents, of potential pharmacotherapies that would specifically prevent relapse to cocaine and other drugs of abuse. It also provides support for the development of methods and protocols to be used for compound evaluation.

This contract provides support for the in vivo evaluation, in rodents, of potential pharmacotherapies that would specifically prevent relapse to cocaine and other drugs of abuse. It also provides support for the development of methods and protocols to be used for compound evaluation.

This contract provides support for evaluation of potential pharmacotherapies for drug dependence disorders in both rodents and primates. It also provides support for abuse liability-related testing of new street drugs, medications, or potential medications in rodents and primates. The primary emphasis is on testing conducted for NIDA's Addiction Treatment Discovery Program (ATDP). To a lesser extent, the contract will generate abuse liability data for use in decisions pertaining to scheduling of drugs under domestic laws (Controlled Substances Act) and international treaties (Single Convention and Psychotropic Convention). NIDA's testing needs for this contract will be dynamic, due to the influences of such factors as opportunities for NIDA/pharmaceutical company collaboration, advances in the field of drug addiction research, and advice from consultants to the ATDP.

This contract provides support for the in vivo evaluation, in rodents, of potential pharmacotherapies that would specifically prevent relapse to cocaine and other drugs of abuse. It also provides support for the development of methods and protocols to be used for compound evaluation.