BEHAVIORAL & PHARMACOLOGICAL ANALYSIS OF DRUGS OF ABUSE

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Nearly all drugs of abuse are able to assume stimulus control in animals. This fact provides a sensitive and informative approach to the study of the mechanism of action of a variety of drugs habitually chosen for non-medical use by humans. On a different organizational level, recent developments in radioligand binding techniques have made it possible to identify and characterize the receptors for many drugs and endogenous neurotransmitters. The proposed investigation combines drug-induced stimulus control with receptor binding in a study of hallucinogens of the indoleamine type; drugs which are, for a variety of reasons, thought to exert their actions via 5-hydroxytryptamine (5-HT). 5-HT is widely believed to function as a neurotransmitter and to play a significant role in a variety of behaviors including sleep, sexual activity, appetite, mood, and psychosis. It is the changes in mood and perception that are responsible for the primary reinforcing properties, hence the abuse liability, of indoleamine hallucinogens such as LSD. In the proposed investigation, a variety of drugs thought to act as 5-HT agonists or antagonists will be studied in animals trained to discriminate the effects of either LSD or 5-HTP, the amino acid precursor of 5-HT. Each drug will be characterized as either an agonist or an antagonist and, based on its dose-response curve, either the ED50 or the AD50 will be calculated. Concomitantly, the binding of each drug to the 5-HT1 receptor in rat hippocampal tissue ((3H)5-HT) and the 5-HT2 receptor in rat cortical tissue (3H)ketanserin) will be measured. The affinities of the drugs will be determined by analysis of competition curves. Finally, the behavioral and receptor-binding data will be combined in a series of correlations, e.t., between the ED50's of agonists substituting for LSD and their affinities for the 5-HT1 receptor. In this way, the relative role of the receptor subtypes in the behavioral effects of the drugs will be determined. It is expected that the direct comparison of behavioral activities with reference to LSD, an exogenous 5-HT agonist, and 5-HTP, precursor for the endogenous agonist, will be particularly informative in that the pharmacological effects of LSD and 5-HTP are markedly different in humans.