Alice Young - US grants

This research will investigate behavioral and pharmacological variables that modify the development and expression of tolerance to the behavioral actions of morphine and related opioids. The experimental methods of behavioral pharmacology will be used to identify ways in which the tolerance produced by acute or chronic opioid administration can be manipulated. The behavioral end-points assessed will include effects on ongoing rates and patterns of schedule-controlled behavior, the discriminative stimulus functions of opioids, and the reinforcing functions of opioids. Preliminary studies have found that the initial behavioral consequences of morphine exposure can influence the course of behavioral tolerance development. We will extend these studies by examining behavioral tolerance development under a wider range of pharmacological and environmental conditions. Specific experiments will first assess the rate and degree of the development and loss of behavioral tolerance during chronic osmotic infusions of opioids. Tolerance development will be characterized as a function of the maintenance opioid employed (morphine or etorphine), and its dose and duration of administration. Subsequent studies will assess the degree of cross-tolerance to other opioids, and will evaluate the contributions of behavioral variables (practice factors and the reinforcement consequences of initial morphine exposure) to the rate and degree of tolerance to morphine's rate-altering effects. The roles of pharmacological and behavioral factors in the development of tolerance to the discriminative stimulus properties of morphine will be examined by comparing changes in generalization functions after selected chronic opioid dosing regimens. Similar studies will assess the rate, degree, and specificity of any tolerance to the reinforcing properties of opioids during chronic opioid administration. Such identification of the behavioral consequences of long-term opioid administration, and of the ways such consequences can be modified by both pharmacological and psychological factors, may have implications for our understanding of both of tolerance processes in general and of the factors underlying opiate abuse.

The objective of this Research Scientist Development Award (Level II) is to free Dr. Young of the majority of her teaching and administrative responsibilities so she can focus her efforts on a research program investigating behavioral and pharmacological variables that modify the development and expression of tolerance to opioid agonists and agonist-antagonists. The experimental methods of behavioral pharmacology will be used to identify ways in which the tolerance and dependence produced by acute or repeated opioid administration can be manipulated. The behavioral end-points assessed will include 1) ongoing rates and patterns of schedule-controlled behavior and 2) the discriminative stimulus properties of morphine. Specific experiments will assess the development and degree of tolerance to the rate-altering effects of morphine, etorphine, ad buprenorphine during repeated injection or osmotic infusion. Other experiments will evaluate the behavioral sequelae of long-term administration of the antagonist naltrexone. A third group of experiments will evaluate the contributions of the behavioral demands imposed by the reinforcement schedule to the development of tolerance to the rate-altering effects of morphine. A final group of experiments will assess changes in the discriminative stimulus profile of morphine and related compounds during repeated administration of opioid agonists, antagonists, and mixed agonist-antagonists. Pharmacotherapies are gaining increasing importance in the treatment of human drug abuse. Pre-clinical identification of the behavioral consequences of long-term opioid administration, and of the ways such consequences can be modified by both pharmacological and psychological factors, may have implications for our understanding both of tolerance processes in general and of the factors underlying opiate abuse.

DESCRIPTION: (Applicant's Abstract) Current treatments for human opioid abuse incorporate a variety of chronic pharmacotherapies, including methadone maintenance and newer or experimental treatments with low efficacy opioid agonists (e.g., buprenorphine) or opioid antagonists (e.g., naltrexone). Preclinical studies of the behavioral sequelae of such maintenance therapies may be useful in predicting their psychomotor and subjective effects in humans. The proposed projects will use drug discrimination assays as a model system to assess how pharmacological and behavioral factors modulate development of tolerance during repeated treatment with selected opioid agonists, alone and in combination with non-opioid agents proposed to modulate opioid tolerance and/or dependence. We will pay particular attention to patterns of tolerance and cross-tolerance among opioids that appear to differ in intrinsic efficacy as agonists. Related experiments will evaluate several behavioral effects of opioids in opioid-dependent subjects, and in subjects treated with irreversible opioid receptor antagonists. The first proposed project will characterize patterns of tolerance and cross-tolerance to discriminative stimulus and antinociceptive effects of mu opioids as a function of agonist efficacy. Planned studies will focus on chronic administration of low efficacy mu agonists. The second project will study antagonism of antinociceptive and stimulus effects of agonists by irreversible antagonists, in order to provide an independent test of the hypothesis that differences in tolerance are related to differences in relative intrinsic efficacy. The third and fourth projects will characterize acute and chronic interventions that may modulate development of opioid tolerance or dependence. Specific compounds to be studied include putative neutral opioid antagonists, kinase inhibitors, NMDA-antagonists CCK-antagonists and NO synthase inhibitors. Experiments will determine effects of acute and chronic treatment with selected agents on development and expression of tolerance and dependence, using behavioral assays of antinociception, acute dependence, and discriminative stimulus effects of mu opioids.

DESCRIPTION (provided by applicant): Current treatments for human opioid abuse incorporate a variety of chronic pharmacotherapies, including methadone maintenance and newer therapies incorporating low efficacy opioid agonists (e.g., buprenorphine) or opioid antagonists (e.g., naltrexone). Preclinical studies of behavioral sequelae of such maintenance therapies may be useful in predicting behavioral and subjective effects of repeated opioid use in humans. The proposed projects will use drug discrimination assays and other behavioral assays as model systems to assess how pharmacological and behavioral factors modulate the development and expression of opioid tolerance and dependence during repeated treatment with clinically important opioid agonists. A primary goal during the upcoming period is to evaluate the hypothesis that abstinence precipitated by classical opioid antagonists in dependent organisms arises from inverse agonist actions, rather than from competitive antagonism, per se We will pay particular attention to the possibility that behavioral abstinence responses, as measured in free-operant, drug discrimination, and place conditioning assays, may represent uniquely sensitive indices of inverse agonist effects. Building on studies conducted during the previous award period, other experiments will evaluate whether the magnitude of dependence varies with the intrinsic efficacy of the agonist used to establish physical dependence Project 1 will define the doses, routes of administration, and pretreatment times over which compounds will function as antagonists of acute agonist actions of the classic [unreadable] agonists morphine and DAMGO. As controls for potential non-[unreadable], or non-opioid, mechanisms in morphine dependence, key antagonists will be compared for their ability to alter effects of ? and [unreadable] opioid agonists and selected non-opioids. Project 2 will assess the ability of classical and putative neutral opioid antagonists to provoke abstinence in acutely and chronically dependent organisms, focusing on performance altering and discriminative stimulus effects. Project 3 will assess the ability of compounds to produce a functional up regulation of opioid receptors. In order to begin an initial characterization of the potential aversive actions of classical and putative neutral opioid antagonists, Project 4 will assess the ability of promising compounds to establish place aversions.

Through its S-STEM Scholarships program, Marymount University is:

1. Recruiting and maintaining an S-STEM cohort of approximately 20 students who have a demonstrated financial need and are interested and capable of majoring in the STEM disciplines of biology, mathematics and information technology/computer science.
2. Providing the scholarship recipients with an active leaning community engaged in scholarly and social activities in order to increase retention and STEM career-awareness of the students. The learning community includes monthly lunches with STEM faculty, field trips to local STEM industries, an interdisciplinary seminar series, Supplemental Instruction in key courses, and service learning opportunities through tutoring in mathematics or science for local K-12 students. Through the interdisciplinary seminars, the scholarship recipients are introduced to a variety of traditional and nontraditional STEM career options while coming to understand the interrelationships of biology, mathematics and information technology/computer science and the importance of each in the study of the other.
3. Providing opportunities for scholarship recipients to learn of the many career options available to STEM majors through interactions with potential future employers in the Washington, DC area.
4. Providing encouragement for S-STEM students to participate in STEM research programs.
5. Providing career counseling and graduate school preparation to help students understand their options and make wise professional decisions.