Schizophrenia is a debilatating disease that affects nearly 1% of the world population, some of cardinal signs of which are fear, paranoia, inappropriate emotional responses, and social withdrawal. One of the more consistent findings from the brains of schizophrenia patients has been a decreased grey matter volume in the temporal lobe, especially in the region of the amygdala. The amygdala has long been associated with emotional processing, and is thought to be a critical locus where cognitive events acquire their emotional significance. Lesions of the amygdala induce a permanent disruption of APDs, such as clozapine, are particularly efficacious in treating negative symptoms of schizophrenia. In addition to their being dopamine receptor antagonists, the atypical APDs, are also potent 5-HT receptor antagonists. It is possible, that the efficacy of atypical APDs in treating negative symptoms lies in their ability to disrupt 5-HT transmission in areas such as the amygdala. Unfortunately, little is known about signal processing in the amygdala at the cellular level. The long-term objectives of this application are to use whole-cell patch clamp recording from identified amygdala neurones in the in vitro slice preparation to determine how information is processed within the amygdala, how it may be regulated by neurotransmitters such as 5-HT, and how alterations in transmission/modulation may contribute to pathological states such as schizophrenia. The hypothesis to be tested is that: one of the primary models of action of chronic atypical APDs application is an alteration of 5-HTergic modulation of neurotransmission in the amygdala, and that this is related to their clinical efficacy in alleviating negative symptoms of schizophrenia. The following specific aims will address this hypothesis: (1) Characterization of intrinsic membrane properties of neurones within the BLA and ACe nuclei of the amygdala, and determination of the neurotransmitters involved in signal transduction in these same nuclei. (2) Examination of the effects of 5-HTergic modulation of intrinsic membrane properties and synaptic transmission in the BLA and ACe, and its interaction with acute administration of the atypical APDs, clozapine and risperidone. Application of 5-HT receptor subtype specific agonists, and antagonists, will be used to determine the nature of the 5-HT receptor/s involved in reach response. (3) Examination of the effects of chronic APDs administration on intrinsic membrane properties, synaptic transmission, and 5-HTergic modulation of BLA and ACe neurones.
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