Funds for Wynne Schiffer: Neurochemistry of Nicotine Dependence in Schizophrenia

DESCRIPTION (provided by applicant): Nicotine abuse is three times more prevalent in schizophrenic over non-psychiatric populations. It has not been established whether this phenomenon is inherent to schizophrenia or an effect of chronic neuroleptic treatment. Nicotine related increases in brain dopamine are associated with its abuse. Schizophrenic patients or animals given NMDA antagonists to putatively model schizophrenia, express an enhanced dopamine response to stimulants. This response is similar in many respects to that exhibited by animals chronically treated with the neuroleptic, haloperidol. We suggest that the pathology associated with dysfunctional NMDA receptors enhances excitatory input to brain dopamine systems. While chronic antipsychotic therapy might reduce inhibitory control over dopamine. Although different in origin, these imbalances may result in a similar. Amplified, response to nicotine, It follows that the enhanced response to nicotine may be regulated by either decreasing excitatory or increasing inhibitory neurochemical activity, respective of the underlying pathophysiology. We propose to examine this hypothesis with micro PET imaging techniques and microdialysis to explore the effects of a nicotine challenge on brain dopamine in pharmacologically altered biologically states. By chronically treating rodents with the NMDA antagonist, PCP, haloperidol, or both, we intend to examine the effects of haloperidol in the absence or presence of disease on the response to nicotine. In separate groups, we propose to use additional drugs to reduce excitatory activity with the glutamate antagonist, topiramate. Or increase inhibitory activity with the GABA agonist, gamma-vinyl GABA, prior to the nicotine challenge. We hope to guide the development of novel therapies for dual-diagnosis schizophrenia.