ALCOHOL AND DRUG ABUSE RESEARCH CENTER
Behavioral Science Laboratory
The Behavioral Science Laboratory uses models of drug self-administration and drug discrimination to study the determinants and consequences of substance abuse. One focus of this research is to evaluate the safety and effectiveness of novel compounds for the medication-based treatment of drug abuse. The potential drug abuse treatment medications are acquired through collaborations with a number of medicinal chemists throughout the nation, and with the ADARC Medicinal Chemistry Program. The effects of abused substances on neuroendocrine and reproductive function, and the interactions between gender, hormones and the abuse-related effects of drugs are also being examined in preclinical models. In addition, a model of thermal analgesia is used to examine the analgesic effects of mu and delta receptor selective opioids. The neural mechanisms underlying cocaine abuse are genetically engineered models being studied in genetically engineered models. In collaborative studies conducted with the McLean Hospital Brain Imaging Center, scientists are beginning to explore the neural correlates of analgesia, and the effects of chronic drug self-administration.
The ADARC Behavioral Science Laboratory was designed and developed by the Director, Nancy K. Mello, Ph.D. The laboratory consists of four component research programs: (1) the Behavioral Pharmacology Program (2) the Behavioral Endocrinology Program; (3) the Neuroscience Program directed by S. Barak Caine, Ph.D. The laboratory is supported by grants and contracts from the National Institute on Drug Abuse, NIH and by foundations and private donors. Training opportunities for postdoctoral fellows are available each year, supported by a training grant from the National Institute on Drug Abuse, NIH. A description of each of the four research programs in the Behavioral Science Laboratory and some representative publications appears below.
- The Behavioral Pharmacology Program
The Behavioral Pharmacology Program uses operant behavioral procedures to analyze the abuse-related effects of a wide range of commonly abused drugs and prescription medications. One goal is to determine how drug self-administration is modified both by manipulation of behavioral contingencies and administration of putative treatment agents. The abuse liability of novel anxiolytics is being compared with benzodiazepines using both drug discrimination and drug self-administration procedures. In addition, a novel choice procedure is used to evaluate the reinforcing properties of drugs. In vivo microdialysis procedures are also being used to characterize the relation between extracellular dopamine release in the caudate nucleus and the discriminative stimulus effects of a number of stimulant drugs (methamphetamine, cocaine, methylphenidate). Ongoing studies are concerned with the effects of dopaminergic compounds on the abuse-related effects of cocaine.
- The Behavioral Endocrinology Program
The Behavioral Endocrinology Program is concerned with the interactions between abused drugs and the neuroendocrine system. The ways in which abused drugs modulate the hormonal milieu and contribute to reproductive dysfunction are poorly understood. Drug self-administration procedures are used to study the consequences of chronic drug exposure on the menstrual cycle. The endocrine effects of single and repeated drug doses administered during the follicular and the luteal phase of the menstrual cycle are also being examined. In addition, recent studies suggest that drug-induced alterations in hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal hormones may contribute to the reinforcing effects of cocaine. Drug self-administration and the drug discrimination procedures are used to examine the effects of acute and chronic hormone administration on the abuse-related effects of cocaine. An improved understanding of the neuroendocrine correlates of drug reinforcement may lead to the development of more effective treatment medications.
- The Neuroscience Program (S. Barak Caine, Ph.D., Director)
The Neuroscience Program conducts preclinical studies designed to identify new targets for medications development using a combination of genetic engineering and operant behavioral procedures. Current research is evaluating the roles of distinct monoamine transporters and receptor subtypes in the abuse-related effects of cocaine, and assessing the potential of novel compounds as candidate medications for cocaine abuse and dependence. Behavioral pharmacology procedures are used to evaluate pharmacological mechanisms underlying the discriminative stimulus and reinforcing effects of cocaine and related drugs. For example, extramurally funded projects include "Screening Compounds for Utility as Cocaine Abuse Pharmacotherapies," in collaboration with the Cocaine Treatment Discovery Program at the National Institute on Drug Abuse. A second major line of investigation includes studies on genes that may be related to cocaine abuse and dependence, using both "reverse genetics" and "forward genetics" approaches to assess the roles of candidate genes and novel genes, respectively, in addiction-related behaviors. These studies of drugs and genes that may be related to drug abuse and dependence are conceptualized within a neuroscientific framework aimed at understanding brain systems that regulate both normal and abnormal behavior.
Representative Publications from the ADARC Behavioral Science Laboratory
Please contact the investigators for additional information
- Bergman J, France CP, Holzman SG, Katz JL, Koek W and Stephens DN (2000) Agonist efficacy, drug dependence, and medications development: preclinical evaluation of opioid, dopaminergic, and GABAA-ergic ligands. Psychopharmacol. 153:67-84.
- Bergman J and Katz JL (1998) Behavioral pharmacology of cocaine and the determinants of abuse liability, in Cocaine Abuse: Behavior, Pharmacology, and Clinical Applications (Katz JL and Higgins ST eds) pp 51-79, Academic Press, New York.
- Caine B (1998) Cocaine abuse: Hard knocks for the dopamine hypothesis? Nature Neuroscience 1:90-92.
- Caine SB (2000) Cocaine abuse. Pharmaceutical News 7:33-39.
- Mello NK and Mendelson JH (2002) Cocaine, hormones and behavior: Clinical and preclinical studies, in Hormones, Brain and Behavior (Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE and Rubin RT eds) pp 665-745, Academic Press, New York.
- Mello NK and Negus SS (1996) Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures. Neuropsychopharmacology 14:375-424.
- Mello NK and Negus SS (2000) Interactions between kappa opioid agonists and cocaine: Preclinical studies, in The Archer Conference on Drug Abuse: New Medications (Glick SD and Maisonneuve IM eds) pp 104-132, New York Academy of Sciences, New York.
- Miczek KA and Caine SB (1999) Genes, drugs and behavior: polygenic behavioral phenotypes and single gene manipulations. Psychopharmacology 147:1.
- Negus SS (2004) Delta opioids and substance abuse, in The Delta Receptor (Chang KJ, Porreca F and Woods JH eds) pp 401-430, Marcel Dekker, New York.
- Negus SS, Mello NK and Caine SB (2004) The utility of "tolerance" as a concept in the study of drug self-administration. Psychopharmacology 171:362-363.