The abuse of psychomotor stimulants has reached alarming proportions in the United States and is now a major national concern. While extensive recreational use of """"""""designer"""""""" stimulants (e.g., 3,4- methlenedioxymethamphetamine; """"""""ecstasy"""""""") has been reported, cocaine leads the list of abused stimulants. Indeed, the spread of acquired immuno- deficiency syndrome (AIDS) has been linked to the intravenous use of cocaine. Chronic abuse of cocaine has also been associated with development of psychiatric disorders including anxiety and panic attacks, depression and paranoid psychosis while repeated treatment of rodents with cocaine results in a progressive enhancement of some behaviors including locomotor activity, stereotypy and convulsions. We hypothesize that this long-lasting alteration in behavioral sensitivity to cocaine implies changes in neurophysiologic and neurochemical substrates subserving these behaviors; that is, behavioral sensitization is associated with specific modifications in the functional integrity of central monoamine systems. Limbic structures which are involved in processes including mood, emotion and motivation receive dense innervation from monoamine-containing neurons of the brain stem and could be sites of action for cocaine. The objective of the present research is, therefore, to systematically assess the development of behavioral sensitization to cocaine concomitant with measurements of induced electrophysiologic and neurochemical modifications in limbic circuitry; the amygdala and habenula were chosen as limbic sites of interest on the basis of the suggested importance of these regions in the in vivo effects of cocaine. Using extracellular single unit recording, microiontophoresis and stimulation techniques, we propose to investigate and characterize the cellular physiologic events in limbic neurons of animals treated with acute or chronic cocaine (intermittent or continual). Specifically, in cocaine-treated rats which express behavioral sensitization, we will investigate the sensitivity of amygdaloid and habenula neurons to microiontophoretic monoamines and stimulation-evoked synaptic activity. These miltidisciplinary studies will provide significant information about the processes which underlie the development of sensitization, and by analogy, the psychological disorders of chronic cocaine abusers.
