Louis S. Harris - US grants

The purpose of this grant is to bring a variety of scientific disciplines to bear on a number of specific drug abuse problems. We propose to carry out major projects in the areas of chemical receptor probes, narcotic agonists and antagonists, the active principles of marihuana and methododlogy development. In the area of chemical receptor probes, we plan to synthesize specific compounds for studies of the postulated "cough", PCP, sigma agonist, nicotine, and THC receptors. In the narcotic areas, we plan to extend our studies toward the elucidation of the "cough" and sigma agonist receptors. We will continue to pharmacologically characterize opiate agonists and antagonists from our synthetic and drug abuse programs. Our studies with the cannabinoids will concentrate on assessing the dependence potential of Delta9-THC, the active principle of marihuana. We also plan to detemrine whether there are specific anatomical sites in the brain responsible for the typical behavioral effects of the cannabinoids. We plan to develop methods for better evaluating the rreinforcing efficacy of drugs of abuse. That is, why do some drugs act as more powerful reinforcers of behavior than others and what can we do to alter this? We will use cocaine as the first drug in these studies.

minority institution research support; secondary schools;

The Committee on Problems of Drug Dependence (CPDD) will hold its 53rd Annual Scientific Meeting in Palm Beach, FL, June 16 through 20, 199 1. Them will be four days of scientific sessions which will be made up of volunteer oral presentations and poster sessions as well as a number of outstanding and timely symposia. The CPDD Program Committee has selected the following symposia: "Perinatal Substance Abuse" (Drs. Braude and Finnegan), "Novel Strategies for Cocaine Dependence: Animal Studies" (Dr Kantak), "Serotonin and Drugs of Abuse" (Drs. Lucki and Cunningham), "Cannabinoids" (Dr. Martin), "New Possible Pharmacotherapy for the Chemical Dependencies" (Drs. Vocci and Rice), "Molecular Biology of Alcoholism" (Dr. Tabakoff) and "Current Status of Treatment of Chemical Dependencies" (Drs. O'Brien and Kreek). One or two additional symposia may be scheduled. Plenary and award lectures, as well as satellite meetings, reports from the drug evaluation program of CPDD, and specialty workshops will complete the program. The proceedings will be published as an archival NIDA monograph. The monograph will contain symposium papers, plenary lectures, volunteer papers, and complete reports of the CPDD drug evaluation program. The Proceedings continue to be a valuable compendium of important scientific work in all aspects of drug abuse research.

The purpose of this grant is to bring a variety of scientific disciplines to bear on a number of specific drug abuse problems. We propose to carry out major projects in the areas of chemical receptor probes, narcotic agonists and antagonists, the dependence potential of the cannabinoids, effects of opioid and other drugs of dependence on the immune system and methodology development. In the area of chemical receptor probes, we plan to synthesize specific compounds for studies of the postulated opioid "cough" , PCP, sigma agonist and nicotine receptors. In the narcotic area, we plan to extend our studies toward the elucidation of the various opioid "cough" and sigma agonist receptors. We will continue to pharmacologically characterize opiate agonists and antagonists from our synthetic and drug abuse programs. Our studies with the cannabinoids will concentrate on assessing the dependence potential of delta-9-THC, the active principle of marijuana. We will then extend these findings to other cannabinoids as well as other classes of hallucinogens. We plan to continue our efforts to develop methods for better evaluating the reinforcing efficacy of drugs of abuse. That is, why do some drugs act as more powerful reinforcers of behavior than others and what can we do to alter this? We will complete our studies of cocaine and proceed to other classes of abused drugs. We will initiate a major study on the effects of drugs of abuse and the dependence cycle on the immune system. We will begin with the opioids and extend our studies to other classes of dependence producing substances. The increasing incidence of AIDS in the intravenous drug abusing population calls for detailed studies on the effects of drugs of abuse and the cycle of dependence and withdrawal on the immune system.

In this contract compounds will be obtained from the pharmaceutical industry, academic and Governmental laboratories. These compounds will be studied as potential pharmacotherapies for opiate abuse. Their abuse liability will be assessed as well. Test to be used include: antinociceptive assays in rodents, intrapentoneal infusion in rats, single dose abstinence suppression precipitated withdrawal in opiate-dependent non-human primates, physical dependence in naive non-human primates as well as self-administration and discrimination in primates. Compounds showing sufficient promise as pharmacotherapies will become candidates for clinical trial in human subjects. Abuse liability data developed by this contract are used to make decision as to scheduling of compounds under domestic as well as international drug control legislation.

In this contract compounds will be obtained from the pharmaceutical industry, academic and Governmental laboratories. These compounds will be studied as potential pharmacotherapies for opiate abuse. Their abuse liability will be assessed as well. Test to be used include: antiociceptive assays in rodents, intraperitoneal infusion in rats, single dose abstinence suppression precipitated withdrawal in opiate-dependent non-human primates, physical dependence in naive non-human primates as well as self-administration and discrimination in primates. Compounds showing sufficient promise as pharmacotherapies will become candidates for clinical trial in human subjects. Abuse liability data developed by this contract are used to make decision as to scheduling of compounds under domestic as well as international drug control legislation.

This mentorship program is designed to increase the pool of minority individuals interested in and capable of pursuing a career in the biomedical sciences. Minority high school students are recruited from all the schools in the Richmond, Virginia metropolitan area. They are selected on the basis of grades, letters of recommendation, and expressed personal interest. K-12 teachers and teachers-in-training are recruited from the same catchment area and are selected on the basis of expressed interest, letters of recommendation, and personal interviews. All trainees participate in a ten week summer research program, under the supervision of a wide multidisciplinary group of biomedical scientists. This experience includes both oral and written presentations and they are encouraged to take advantage of a number of available additional learning opportunities. The high school students are also assigned to a mentor who will serve as a guide and advisor. We follow these students through high school, college, and hopefully, graduate or professional school. The teachers are expected to carry back to their classrooms the beauty and excitement of biomedical research. They will be aided in preparing lesson plans and laboratory experiments for use in their schools.

This represents a competitive renewal of a major portion of NIDA contract N01DA38200. The portion of N01DA38200 being renewed herein, the entire contract (NIDA contract 271-90-7200) which preceded it, and several previous contracts dating back 19 years have focused on the generation of data related to the pharmacological properties and abuse liability profiles of a large number of opioid agonist, antagonist, and mixed agonist/antagonist agents. This project represents an extension of a search for potent analgesics with reduced abuse potential. In addition, data generated by this project are part of the scientific database used in decisions pertaining to scheduling of drugs under domestic laws (Controlled Substances Act) and international treaties (Single Convention and Psychotropic Convention). In brief, the objectives of this contract are: (1) to evaluate the antinociceptive activity of test compounds in mice; (2) to evaluate the effects of test compounds in opiate-dependent rats and/or monkeys; (3) to evaluate the intrinsic physical dependence capacity of test compounds in drug-naive monkeys; add (4) to assess the reinforcing properties of test compounds in monkey self-administration studies. The anticipated end results of this contract are written reports detailing the findings.

This represents a competitive renewal of a portion of NIDA contract N01DA38200, entitled "Evaluation of New Pharmacotherapies for Treatment of Opiate Abuse. The portion of N01DA-3-8200 being renewed herein is that which serves the NIDA Opioid Treatment Discovery Program, the goal of which is to discover potential new medications for improved treatment of opioid abuse and dependence. The NIDA Opioid Treatment Discovery Program currently is focused on three clinical needs: (1) medications effective in preventing relapse following the cessation of opioid use (e.g., following medically facilitated withdrawal); (2) adjunct medications for converting patients from opioid agonist therapy to opioid antagonist or non-opioid therapy; and (3) improved non-opioid medications for treating opioid withdrawal symptoms. In brief, the objectives of this contract are: (1) to determine the in vivo activity and opiate receptor selectivity of novel opioid compounds; (2) to determine the effects of compounds in opiate-dependent animals, primarily during opiate withdrawal; (3) to evaluate compounds for their potential suitability for clinical trials as relapse prevention agents; and (4) to identify and acquire standard compounds which merit the aforementioned types of evaluation. The anticipated end results of this contract are written reports detailing study findings. These preclinical findings will, to a great extent, determine the NIDA Medication Development Division's future clinical trials in the area of improved treatments for heroin dependence.

This represents a competitive renewal of a NIDA contract N)1DA-5-8060, entitled "Rodent and Monkey Testing for NIDA Opiate Treatment Discovery Program." It provides support for in vivo testing, both in rodents and primates, of potential pharmacotherapies for drug dependence disorders. The primary emphasis is on testing conducted for NIDA's Opioid Treatment Discovery Program. However, flexability exists with in the contract to support the testing of potential pharmacotherapies for non-opioid (e.g., cocaine or methamphetamine) dependence disorders. The NIDA Opioid Treatment Discovery Program currently is focused on three clinical needs: (1) medications effective in preventing relapse following the cessation of opioid use (e.g., following medically facilitated withdrawal); (2) adjunct medications for converting patients from opioid agonist therapy to opioid antagonist or non-opioid therapy; and (3) improved non-opioid medications for treating opioid withdrawal symptoms. Following contract award, the program will be served by two NIDA contracts. One contract (N01DA-7-8072; SRI International) supports in vitro evaluations of the activity of novel compounds at mu-, kappa-, and delta-opioid receptors, as well as at numerous non-opioid receptors. The present contract (N01DA-8-8088) will support follow-up in vivo opioid receptor activity and selectivity testing in rodents, as well as all other non-human pharmacology studies required by the program.

This contract provides support for evaluations, in both rodents and primates, of potential pharmacotherapies for drug dependence disorders. It also studies abuse liability-related testing of new street drugs and medications. The primary emphasis is on testing conducted for NIDA's Addiction Treatment Discovery Program.

Conduct specific pharmacological evaluations of potential drug addiction treatment medications and to conduct preclinical abuse liability studies of new street drugs, medications, or potential medications in rodents and primates. 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 NIOA ATDP. As a result, the details of all tests to be conducted under this contract cannot be specified in advance of contract award.

Conduct specific pharmacological evaluations of potential drug addiction treatment medications and to conduct preclinical abuse liability studies of new street drugs, medications, or potential medications in rodents and primates. 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 NIOA ATDP. As a result, the details of all tests to be conducted under this contract cannot be specified in advance of contract award.