This K08 Career Development Award will provide Assistant Professor Kennon Heard, MD, protected time so he can obtain the basic research training and experience that he requires to become a successful independent investigator focusing on poisoning from drugs of abuse. As an emergency physician and medical toxicologist, Dr. Heard encounters patients suffering from acute abused drug intoxication every day. His long-term objective as an independent investigator is to evaluate novel therapies for such acute poisoning. He will work closely with his sponsor, Dr. Nancy R. Zahniser, an experienced cocaine researcher who has successfully mentored 20 graduate and post-graduate trainees. His proposed career development program includes writing a scholarly review summarizing the mechanisms of cocaine toxicity, taking graduate classes in CMS pharmacology and the responsible conduct of research, and completing a project to help him develop effective mentoring skills. His proposed research project arose from the observation that while almost a quarter of cocaine users have serious mental illness, little is known about the effects of psychiatric medications on the toxic effects of cocaine. A mouse model will be used to study the effect of long-term antipsychotic medication (ARM) administration on the toxic effects of a single high dose of cocaine. Cocaine blocks all three monoamine transporters, and chronic ARM administration increases the density of several neurotransmitter receptors. Dr. Heard hypothesizes that long-term administration of particular APMs will differentially alter the regional density of receptors that mediate cocaine toxicity and that these changes will differentially alter the dose-response for cocaine toxicity. Aim 1 will measure regional receptor and monoamine transporter density in mice treated for 28 days with continuous infusions of clinically relevant APMs (haloperidol, clozapine, ziprasidone, and aripiprazole) or placebo. In vitro radioligand binding and autoradiography will be used to measure the regional density of D1 and D2 dopamine;5-HT1A, 5-HT2A, 5-HT2C and 5-HT3 serotonin;a1- and a2-adrenergic;NMDA and AMPA glutamate;GABAA;muscarinic cholinergic;and sigma receptors and of monoamine transporters. Aim 2 will determine the effect of the 28-day APM infusion on the cocaine dose required to produce seizures and lethality (ED50 and apparent LD50, respectively). Aim 3 will determine whether selective antagonists of the receptors found to be increased in Aim 1 will attenuate any altered sensitivity to cocaine observed in Aim 2. The results will identify which receptors are altered and how the susceptibility to cocaine toxicity is related to these receptor changes. This experiment will model acute cocaine use by patients taking APMs. Identifying the involved receptor systems will facilitate future studies to determine if chronic APM therapy causes the same receptor changes in humans and, therefore, may cause similar altered susceptibility to cocaine poisoning.