For treatment of drug dependencies and associated toxicities, last year's report noted potential for drug development in three major areas: low affinity NMDA antagonists, neuroactive steroids, and dopamine D3 receptor agonists. We have continued to document the efficacy of certain NMDA receptor blockers as candidates for drug development in treatment of both cocaine-induced toxicities and behavioral effects. We have devised methods for prediction of subjective side-effects of these agents in humans. We have continued to document a role for D3 receptor agonists as selective blockers of the behavioral effects of phencylidine (PCP) and related psychotomimetic agents. PD 128,907 is the most selective drug discovered thus far that binds to dopamine D3 receptors. This compound, like the atypical anti-psychotic, clozapine, dose-dependently blocks the behavioral effects of the selective PCP-site antagonist, dizocilpine. Like clozapine, PD 128,907 is only marginally effective against dopaminergically-driven behavioral toxicities. Thus, in addition to the potential role of D3 receptor agonists in the treatment of PCP-intoxication and toxicity, this is the first time the D3 receptor population has been directly shown to have relevance to the treatment of schizophrenia. Experiments with selective antagonists and other stucture-activity data have continued to support a role for D3 receptors in these effects. We have also extended our work this year to the area of psychomotor stimulant toxicity. D3 receptors appear to play a prominent role in these toxicities and fatalites and suggest avenues for emergency therapeutic intervention. Finally, we have extended our work on the neuroactive steroids. We reported last year that these compounds can protect against the convulsant effects of cocaine that are relatively unresponsive to treatment by standard anticonvulsant drugs. We now demonstrate an important role for this novel class of compounds in the increased convulsant effects produced by repeated exposure to convulsant agents. Our work on these compounds also suggests a possible use of these drugs in the treatment of post- cocaine-induced anxiety and drug craving.
