Travis Irving Thompson - US grants

This research is concerned with the extent to which acutely and chronically administered methadone may interfere with types of behavior commonly observed in man. The goals are to delineate behavioral mechanisms of methadone's actions and its interactions with other drugs. These investigations will include deprivation conditions, the scheduling of consequences, conditioned reinforcement, and the repeated learning of behavioral chains.

The purpose of the proposed research is to investigate the relationship of dose and plasma level of haloperidol to learning and maladaptive behavior in mentally retarded young adults. The goal is to develop a method for determining a dosage level of neuroleptic medication which maximally reduces problem behavior while minimally altering learning ability. Three dosage levels of haloperidol and placebo will be administered in increasing and decreasing dosages to 20 mentally retarded adults who have had a history of psychoactive drug mediction. Dosages will be gradually increased or decreased to target levels over one week and maintained at that level for three weeks. Effects of haloperidol dosage upon several variables will be investigated. Learning will be measured using a repeated acquisition technique in which the subjects learn a new, but similar, responses sequence each day. Maladaptive behavioral effects will be analyzed through daily ratings of target problem behaviors on a Maladaptive Behavior Scale and direct frequency recordings. Scores on each subscale of the Adaptive Behavior Scale, which will be administered pre-intervention and at placebo, will be analyzed also. Adverse side effects will be measured weekly through use of the Dyskinesia Identification System. The Peabody Picture Vocabulary Test, given pre-intervention and at placebo, will measure effects of neuroleptic dosage on intellectual functioning. Blood, drawn twice in the final week under each dosage level, will be analyzed to correlate plasma levels of haloperidol with dosage levels as well as to the learning and behavioral data. This research should provide a useful model for evaluating clinical efficacy and adverse effects of this neuroleptic drug as it relates to levels of such agents in biological fluids.

This research is concerned with the extent to which acutely and chronically administered methadone may interfere with types of behavior commonly observed in man. The goals are to delineate behavioral mechanisms of methadone's actions and its interactions with other drugs. These investigations will include deprivation conditions, the scheduling of consequences, conditioned reinforcement, and the repeated learning of behavioral chains.

The proposed research will evaluate treatment of self-injurious behavior of 24 mentally retarded adults in institutional settings using the opiate antagonist naltrexone alone and with the alpha adrenergic agonist clonidine. A double-blind, within-subject dosage comparison (placebo, 50 and 100 mg/day naltrexone) and across group comparison of naltrexone alone versus naltrexone plus clonidine (0.3 mg/day) will be made. Recent data reveal some self-injury may be responsive to opiate antagonists, suggesting the endorphin/enkephalin ligand system may be involved in maintaining self-injury in some individuals. It is hypothesized some mentally retarded individuals initially injure themselves accidentally, causing release of endogeneous opioid ligand. It is known that enkephalins serve as powerful rewards, substituting for opiates such as morphine in laboratory self- administration arrangements. After repeated self-injury, with associated endorphin/enkephalin release and occupation of the opiate receptor, it is proposed the mentally retarded person becomes "addicted" to the reinforcing effects of these ligands which are released by self-injury. Since discontinuation of self- injury would induce an opiate-type abstinence syndrome, the mentally retarded person may (in part) continue to engage in self- injury to avoid withdrawal distress. Independent evidence shows clonidine diminishes opiate withdrawal symptoms in laboratory and clinical settings. It is proposed that naltrexone will block the reinforcing effect of the opioid ligand at the opiate receptor, and clonidine will diminish the tendency for the retarded individual to continue self-injuring to avoid opiate-like withdrawal. In the proposed research, standardized assessment instruments (Adaptive Behavior Scale, Part II; Aberrant Behavior Checklist) and direct observational techniques will be used. In addition to evaluating effects on self-injury, measures of other maladaptive behaviors and learning ability using a laboratory matching-to-sample procedure will be used.

Methadone maintenance is currently the pharmacological treatment of choice dependence in the United States. Buprenorphine, a mixed agonist-antagonist opiate, has been proposed as an alternative to methadone in the treatment of opiate abuse. The current proposal is designed to compare these two treatments in terms of their efficacy in reducing opiate self-administration and in terms of the motivational deficits produced by the two drugs. Two of the studies proposed examine and compare the ability of methadone and buprenorphine to reduce self-administration of etonitazene (ETZ). Rats self-administering ETZ under an operant schedule and in their home cage will be treated with acute and chronic methadone and buprenorphine. In addition, the response cost for ETZ will be manipulated under the chronic regimen, to assess the contribution of this variable in suppressing opiate self-administration. A third study assesses the efficacy of making a highly preferred alternative reinforcer available during periods when the self- administered opiate is also available. A fourth study investigates the contribution the onset of abstinence symptoms plays as a mechanisms of action for ETZ self-administration. The motivational deficits produced by methadone treatment have been a continuing theme in our research throughout the previous project periods. The current research proposal continues this line of inquiry and extends it to allow comparison of motivational effects of methadone with those of buprenorphine. Four studies are dedicated to this theme. Two studies, one using rats and one using pigeons, compare buprenorphine and methadone effects under progressive ratio schedules. These schedules are used to assess reinforcer efficacy and strength and have shown consistent sensitivity to changes in motivational variables. Using the same schedule, another experiment assesses the effect that varying reinforcer quality will have on the dose-effect curves established under methadone and buprenorphine. The final experiment motivational properties of buprenorphine and methadone will compare these drugs under a schedule (multiple-5 ply VI) that purportedly is able to differentiate between motivational effects and motoric effects across drugs and doses.

Core support is requested to establish a research center on mental retardation and related developmental disabilities at the University of Minnesota. The University of Minnesota proposes to consolidate and integrate its far-reaching research activities in the area of developmental disabilities, by focusing on interdisciplinary research concerned with preventing behavior disorders associated with developmental disabilities and intervening in those disabilities to reduce behavior problems while promoting competence. The program combines basic science and applied research approaches, drawing upon biomedical and behavioral science strategies. The goal for the proposed research will be to provide an objective knowledge base for understanding the basic mechanisms underlying behavior disorders among persons with developmental disabilities, making it possible to prevent or treat developmental disorders associated with disturbed behavior within integrated community settings. The research programs are organized around Prevention and Intervention Clusters. The Prevention Cluster includes a Neurogenetics Group, a Neurotoxicity and Neuropharmacology group, and a Neuropathology and Cognitive Risks subgroup. The Interventions Cluster is divided into a Family and Developmental Risks Intervention Group, a Community Psychoeducational Interventions Group, and a Biobehavioral Interventions group. To organize and facilitate this research, a support system is proposed composed of six core Units as follows: 1) Administrative Core, 2) Participant Recruitment and Transportation Core, 3) Communication and Information Media Services Core, 4) Quantitative and Data Base Management Core, 5) Biomedical Lab Core, and 6) Psychological and Behavioral Lab Core.

The proposed research will evaluate the effectiveness of the opiate antagonist naltrexone and positive behavioral intervention programs in treating self-injurious behavior in 24 adults with developmental disabilities in community residential settings. Several converging lines of evidence suggest that self-injurious behavior is a multiply determined phenomenon with several distinct etiologies and/or current regulatory mechanisms. While many forms of self-injury appear to be maintained by environmental consequences (e.g., attention from others, escape from unpleasant or demanding tasks, access to preferred objects or activities), others appear to have a neurochemical basis. Recent research reveals that some forms of self-injury are responsive to treatment with opiate antagonist drugs, suggesting the involvement of the endorphin/enkephalin ligand system in the maintenance of self-injurious behavior. In addition to attenuating pain, endorphins serve as powerful reinforcing stimuli. It is proposed that after repeated self-injury, with associated endorphin release, an individual becomes physically dependent upon the endogenous opioid chemicals. Because discontinuation of self-injury would induce an opiate-type abstinence syndrome, the individual may continue to engage in self-injury to avoid withdrawal distress. Our preliminary work on this topic, together with the results of several published reports, implicate opioid mechanisms in self-injury in people with developmental disabilities. In a majority of cases, treatment with opiate antagonist drugs reduce or eliminate self-injury. However, some patterns of self-injury are not responsive to opiate antagonists, suggesting the involvement of other factors. Recent evidence indicates that patterns of self-injury can be distinguished on the basis of the environmental circumstances under which it occurs, which may provide a basis for isolating distinct subgroups of self-injurious individuals. The goal of the proposed research is to integrate these environment-based approaches with those based on opioid mechanisms in the treatment of self-injurious behavior. A two-phase experimental/treatment strategy is proposed, wherein two groups of 12 subjects each will receive either naltrexone or behavioral interventions during one phase and a combination of both treatments during a second phase. The naltrexone trial will consist of a double-blind crossover design with placebo and 100 mg/day naltrexone. The behavioral interventions will focus on replacing self-injurious behavior with functional, adaptive skills. Frequency and intensity of self-injury constitute primary dependent variables, as measured by direct observational methods and by staff ratings. In addition, the present research will include a detailed microanalysis of the ongoing environmental circumstances accompanying both self-injury and other response classes that covary with self-injury. This will not permit greater specification of the environmental mechanisms through which self-injury occurs under normal (pre-intervention) conditions, it will also reveal how the ongoing stream of behavior, including adaptive functioning, is modified by naltrexone, by behavioral interventions, and by their combination.