Two hypotheses are described. The first predicts that psychotomimetic and hallucinogenic drugs that cause similar behaviors in humans may share a common locus of action in the limbic system. The second hypothesis states that some drugs of abuse may cause long-lasting behavioral, mood and cognitive deficits as a result of irreversible brain damage. The first hypothesis derives from several related observations. First is the fact that a number of compounds, many related structurally to amine neurotransmitters, induce behaviors in humans that are difficult to distinguish from some spontaneous psychotic behaviors. The second observation is that in idiopathic temporal lobe epilepsy, a neurological disorder characterized in part by abnormal hippocampal neurotransmission, non-psychotic patients often exhibit behaviors characteristic of psychosis and that these behaviors occur when hippocampal discharges arise. The first hypothesis to be tested is that the three parts of the triad described above, ie, psychotomimetic drugs, endogenous psychosis and psychotic manifestations of temporal lobe epilepsy, may share a common underlying locus. Specifically, abnormal hippocampal activity may cause behaviors common to all three hallucinatory states regardless of the molecular mechanism(s) involved. This hypothesis will be tested by determining the effects of drugs of abuse on hippocampal responses, excitability and inhibition in vivo using electrophysiological methods. The second hypothesis to be tested is that some drugs of abuse produce persistent behavioral deficits as the results of irreversible brain damage. Given recent advances on the subject of irreversible cell death and the mechanisms that cause it, it is important to determine if drugs of abuse cause irreversible damage, which drugs do so under what conditions and whether or not this cell damage can be prevented. This will be done using neuroanatomical methods, including silver stain for neuronal degeneration, immunocytochemistry of GABA-, amine- and peptide-positive neurons, as well as electron microscopy. The biomedical impact of preventing drug-induced brain damage, if it occurs, would be considerable.
