A STUDY OF FACTORS INVOLVED IN THE DEVELOPMENT OF TOLERANCE TO D- AND L-AMPHETAMINE
Abstract
The anorectic action of amphetamine has been known for over forty years. However, the central mechanisms mediating the initial suppression of eating and subsequent tolerance to the hypophagic effects of amphetamine are not clearly understood. The precise relationship between the enantiomeric forms of the drug in producing anorexia also is not known. To date, studies have utilized primarily racemic amphetamine or its d-isomer in the analysis of feeding behavior. In the present investigation, a detailed examination of the effects of single and repeated doses of d- and l-amphetamine on food consumption by adult male rats was undertaken with emphasis on studying the aspects of tolerance and the underlying biochemical mechanisms involved. Tolerance to the anorexigenic effects of both isomers was seen at three equipotent dosages. Weight loss and pattern of daily food intake differed depending upon the isomer, dose and degree of tolerance. Rats tolerant to the anorectic effects of d-amphetamine showed a slightly enhanced consummatory response and a different pattern of consummatory behavior when challenged with an equipotent anorectic dose of l-amphetamine. In contrast, rats tolerant to the anorectic effects of l-amphetamine showed a significantly depressed food intake and eating pattern when challenged with an equipotent dose of d-amphetamine. A stereoselective effect on synaptosomal reuptake of dopamine, norepinephrine, and serotonin was observed in tolerant and non-tolerant rats following in vivo administration of equipotent anorectic doses. Single injections of d- and l-amphetamine decreased the rate and amount of monoamine uptake in virtually all brain areas tested. The magnitude of this reduction differed depending upon the isomer. In contrast, the chronic dosage regimen of d- and l-amphetamine altered rates and amount of uptake in an amine and area specific fashion. The return toward control reuptake of hypothalamic catecholamines observed in d- and l-amphetamine tolerant rats may contribute to their anorexigenic tolerance. The differential effects of equipotent anorexic doses of d- and l-amphetamine on serotonin uptake in the hypothalamus and telencephalon may partially explain the different temporal patterns of consummatory behavior and lack of cross tolerance observed with the two enantiomers.
Degree
Ph.D.
Subject Area
Pharmacology
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.