The aim of the proposed research is to elucidate the neuronal mechanisms underlying the behavioral effects of indoleamine (LSD-like) and phenylalkylamine (mescaline-like) hallucinogens, central nervous system (CNS) stimulants (amphetamine, cocaine), and drugs of abuse which appear to have both hallucinogenic and stimulant properties (MDA, MDMA). While our primary focus will be on serotonin (5-HT), we will also be concerned with other, monoaminergic transmitter systems and with sub-systems involving putative multiple receptor subtypes. Our principle behavioral method will be drug discrimination but, when the nature of the problem or technical considerations demand it, other assays will be used; for example, disruption of schedule-controlled, operant responding or assessment of """"""""conflict"""""""" (behavior simultaneously maintained by food and suppressed by painful stimuli). The neural substrates of drug effects in intact, behaving organisms (rats) will be studied both pharmacologically (indirectly) and physiologically (directly). In pharmacological experiments: 1) Groups of animals will be trained to discriminate relatively low doses of various drugs of interest (from saline or, in some instances, from each other) and be tested with recently developed, specific receptor subtype agonists (""""""""substitution"""""""" or """"""""generalization"""""""" tests) or antagonists (""""""""combination"""""""" tests); 2) independent groups of animals will be trained to discriminate subtype agonists and be tested with hallucinogenic, stimulant and hallucinogenic/stimulant drugs of abuse as well as with receptor antagonists. In order to determine sites of drug actions more precisely, direct, """"""""physiological"""""""" interventions will also be used; that is, 1) drugs will be administered intracerebrally; 2) brain areas which are thought to contain monoaminergic neuronal cell bodies (raphe, nucleus accumbens, caudate nucleus, locus ceruleus, etc.) will be chemically-lesioned with specific neurotoxins; and 3) the effects of electrical stimulation of different brain regions will be compared to the stimulation caused by systemically administered drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA002543-15
Application #
3207408
Study Section
Drug Abuse Clinical and Behavioral Research Review Committee (DACB)
Project Start
1980-04-01
Project End
1989-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
15
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of South Carolina at Columbia
Department
Type
Schools of Arts and Sciences
DUNS #
111310249
City
Columbia
State
SC
Country
United States
Zip Code
29208
Appel, James B; West, William B; Buggy, James (2004) LSD, 5-HT (serotonin), and the evolution of a behavioral assay. Neurosci Biobehav Rev 27:693-701
Appel, J B; West, W B; Rolandi, W G et al. (1999) Increasing the selectivity of drug discrimination procedures. Pharmacol Biochem Behav 64:353-8
Van Groll, B J; Appel, J B (1992) Stimulus effects of d-amphetamine 1: DA mechanisms. Pharmacol Biochem Behav 43:967-73
Callahan, P M; Appel, J B; Cunningham, K A (1991) Dopamine D1 and D2 mediation of the discriminative stimulus properties of d-amphetamine and cocaine. Psychopharmacology (Berl) 103:50-5
Appel, J B; Baker, L E; Barrett, R L et al. (1991) Use of drug discrimination in drug abuse research. NIDA Res Monogr :369-97
Callahan, P M; Appel, J B (1990) Differentiation between the stimulus effects of (+)-lysergic acid diethylamide and lisuride using a three-choice, drug discrimination procedure. Psychopharmacology (Berl) 100:13-8
Appel, J B; Callahan, P M (1989) Involvement of 5-HT receptor subtypes in the discriminative stimulus properties of mescaline. Eur J Pharmacol 159:41-6
Barrett, R L; Appel, J B (1989) Effects of stimulation and blockade of dopamine receptor subtypes on the discriminative stimulus properties of cocaine. Psychopharmacology (Berl) 99:13-6
Callahan, P M; Appel, J B (1988) Differences in the stimulus properties of 3,4-methylenedioxyamphetamine and 3,4- methylenedioxymethamphetamine in animals trained to discriminate hallucinogens from saline. J Pharmacol Exp Ther 246:866-70
Appel, J B; Weathersby, R T; Cunningham, K A et al. (1988) Stimulus properties of dopaminergic drugs: comparisons involving selective agonists and antagonists. Psychopharmacol Ser 4:44-56

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