For treatment of drug dependencies and associated toxicities, last year's report noted potential for drug development of a phencyclidine (PCP) antagonist based upon the lead candidate PD 128,907, a dopamine D3 receptor agoinst. Additional work has confirmed the predictive efficacy of this and related compounds as PCP blockers and potential atypical antipsychotic agents. We have also demontrated for the first time a role for dopamine D3 receptors in the toxic effects of acutely administered cocaine and methamphetamine. This work based upon classical pharmacological and toxicological methods has led to the following conclusions: D3 receptors are involved in convulsant and lethal effects of cocaine and methamphetamine and D3 receptors may also be involved in psychomotor stimulant abuse. D3 receptor agonists may have clinical utility in the emergency management of stimulant abuse-related toxicities. Ongoing research efforts are involved with mouse strains deficient in dopamine D3 receptors to provide confirmation of the proposed mechanism. Our work on neuroactive steroids has also continued. These compounds, which have been suggested as potential drug abuse treatment agents, have now been shown to have prominent effects against the sensitizing effects of drugs on the nervous system, an action which makes them compelling candidates for both drug abuse treatment and the toxic sequella resulting from drug abuse.
