The overall goal of the present proposed project studying glutamate-serotonin interactions in the prefrontal cortex is to bridge cellular and behavioral levels of analysis for 5-HT2A receptor-mediated responses that will lead to the development of novel treatments for mood and psychotic disorders. The serotonin2A (5-HT2A) receptor has been implicated in the pathophysiology of depression, suicide and schizophrenia. Regulation of the 5-HT2A receptor by many antidepressant and atypical antipsychotic drugs. may conthbute to their therapeutic effects. Clinical studies have found functional and structural abnormalities in the prefrontal cortex in depressed patients. 5-HT2A receptors are known to be strongly expressed in the apical dendritic region of layer V pyramidal cells throughout the neocortex. This localization may underly the most prominent effect of 5-HT2A receptor activation throughout the cortex: the 5-HT-induced increase in the frequency of excitatory postsynaptic currents/potentials (EPSCs/EPSPs) that appear to be the result of an increase in glutamate release. These excitatory effects of 5-HT also lead to an activity-dependent increase in the expression of brain-derived neurotrophic factor (BDNF) mRNA throughout the neocortex, including the medial prefrontal cortex. Activation of prefrontal cortical 5-HT2A receptors by hallucinogenic drugs may also mediate behavioral effects in rodents such as head shakes and the disruption of operant behavior. Since blockade of 5-HT2A receptors appears may be related to the thymoleptic action of atypical antidepressant/antipsychotic drugs, the overall aim of the present proposal is to determine the inhibitory metabotropic glutamate (mGlu) and 5-HT receptor subtypes that suppress the effects of 5-HT,A receptor activation on a electrophysiological, biochemical, and behavioral level. Intracellular recording using in vitro medial prefrontal cortical slice preparation, in situ hybridization of BDNF mRNA expression, and study of the effects of both systemic and local (medial prefrontal cortex) administration of the hallucinogen and 5-HT2 agonist DOl on head shakes and operant behavior will be used to study interactions of glutamate and 5-HT in the medial prefrontal cortex. MGlu autoreceptors and 5-HT heteroceptors that suppress glutamate release in response to 5-HT2A receptor activation might also suppress glutamate release in response to a variety of deleterious agents. As such, this multi-disciplinarian study may provide new strategies to develop novel antidepressant treatments that would be more efficacious than simply blocking 5-HT2A receptors.
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