NEUROTOXIC HALLUCINOGENS: EFFECTS ON LEARNING

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Pavlovian conditioning of the rabbit's corneal-VIth nerve reflex involving extension of the nictitating membrane provides a reliable measure of the full range of associative learning and memory and has been demonstrated to be an excellent model system for examining the behavioral and pharmacological mechanisms by which drugs affect learning and memory. Associative learning, in particular, has been demonstrated to be highly sensitive to the actions of hallucinogenic drugs due to their ability to alter the sensory processing of the stimuli used during conditioning. Thus the indole hallucinogen d-lysergic acid diethylamide (LSD) and the phenethylamine hallucinogen 2,5- dimethoxy-4-methylamphetamine (DOM) produce changes in learning at doses required to produce reliable hallucinations in humans (1 and 50 Mu g/kg, respectively). Recently, two other penethylamine hallucinogens 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA) have been demonstrated to produce apparently irreversible neurotoxicity to serotonin neurons. The basic purpose of the present studies is fivefold. First, to describe in detail the doses of MDA and MDMA required to alter the acquisition and retention of conditioned responses and identify the behavioral mechanisms through which the drugs exert their effects. Second, to determine whether the damage to serotonin neurons produced by MDA and MDMA results in a long-term deficit in learning and memory. Neurotoxic effects will be evaluated by histological methods and by measurement of monoamine content two to three weeks after cessation of drug treatment and by long-term changes in protein content of brain as measured by two-dimensional gel electrophoresis. Third, we will examine the ability of drugs such as serotonin antagonists and reuptake blockers to block the behavioral and neurotoxic effects of MDA and MDMA. Fourth, we will determine whether animals sustaining MDA and MDMA induced brain damage might be at risk with respect to subsequent impairment of serotonin, dopamine and cholinergic functions, as might occur during aging. Fifth, and last, we will carry out similar studies with LSD, DOM, d-amphetamine and d- methamphetamine to verify the specificity of our behavioral and neurotoxic effects. These studies should provide needed information on the growing population of humans that abuse these hallucinogenic agents and the long-term consequences of such abuse.