The deficits in working memory evident in schizophrenia are hypothesized to arise from a dysfunction of prefrontal cortex. Neurons in this area of the primate display memory for the location and identity of salient stimuli in working memory tasks. The prefrontal cortex is dependent on adequate dopaminergic tone for its function, and atypical antipsychotics which influences serotonin receptors may also have an important influence at this cortical site. Previous studies in this laboratory have shown that both D1 and 5-HT2 receptors strongly influence this mnemonic coding. Both receptor subtypes have important facilitatory actions on glutamate receptor input to prefrontal neurons. Thus, in order to elucidate the mechanisms of neuromodulation in the working memory process, our first aim is to determine the relative contribution of NMDA and non-NMDA receptors in producing mnemonic activity. With this knowledge, the selective monoaminergic regulation of these excitatory inputs can be ascertained while neurons are active engaged in the working memory process. Moreover, 5-HT2 and other subtypes of dopamine and serotonin receptors also influence interneurons which regulate the mnemonic coding of pyramidal cells through local circuits. We therefore propose to distinguish direct actions of dopaminergic and serotonergic receptors on glutamate receptors input from indirect actions mediated by inhibitory interneurons. Knowledge of the effects of systemically applies therapeutic and psychotogenic agents on the mnemonic coding of prefrontal neurons is extremely limited. By comparing iontophoretic versus systemic actions of these drugs we intend to determine their effects at the level of the cortex and to identify which dopamine and serotonin receptors are involved. Most antipsychotic drugs elevate cortical dopamine levels, an effect which may be a primary route of their action on prefrontal neurons subserving cognitive processes. Thus, or final aim is to reveal electrochemically for the first time, the significance of cortical dopamine and serotonin levels in mnemonic coding, and the importance of alteration of these levels for drug action. This research will reveal the mechanisms by which dopamine and serotonin regulate the cellular basis of working memory and the involvement of these mechanisms in clinically- relevant drug events. By revealing key aspects of the neuromodulation of glutamatergic and inhibitory processes in mnemonic coding, this work will substantially enhance our knowledge of the neurobiology of cognition. Discerning essential sites for drug action, will advance our understanding of the neuropathology of schizophrenia and aid in the development of improved antipsychotic therapy.
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