The general purpose of this project continues to be the investigation of the electrophysiological actions of the indoleamine/phenethethylamine class of psychedelic hallucinogens on identified neurons of the rat brain. Specific aims are: 1. To investigate the pathways by which hallucinogenic drugs alter the activity and reactivity of locus coeruleus neurons in vivo: The role of major afferent inputs will be examined since the effect of psychedelic hallucinogens on locus coeruleus neurons does not appear to be due to a direct action on these cells. 2. To analyze cellular subtypes and membrane mechanisms underlying 5-HT2- receptor-mediated excitatory actions of serotonin and hallucinogenic drugs on identified neurons in brain slices. The membrane mechanisms underlying the excitatory/facilitatory effects of serotonin and hallucinogenic drugs will be studied on identified neurons in brain slices from facial nucleus and cerebral cortex. 3. To evaluate the role of G proteins and protein kinase C in modulating neuronal responses to serotonin and hallucinogenic drugs. The involvement of G proteins and protein kinase C in the mediation of 5-HT2 responses will be examined in brain slices from cerebral cortex and facial nucleus. 4. To study the cellular mechanisms of tolerance and sensitization to hallucinogenic drugs. Chronic studies will be conducted in terms of known changes in receptor and effector mechanisms (e.g., 5-HT2 receptor downregulation by hallucinogenic drugs). The value of the proposed research would be to advance knowledge about the mechanism of action of a major class of drugs, the psychedelic hallucinogens. In addition to any implications for the treatment of drug overdose (or other untoward reactions), this information could aid the rational development of more efficacious antipsychotic drugs, which, for example, might act upon convergent effector mechanisms and second messenger systems rather than the initial receptor site as is the case with currently available treatments.