Phencyclidine (PCP) is a drug of abuse with multiple sites of action. Current thinking is that the most relevant of these is blockade of the NMDA receptor ionophore complex and blockade of dopamine and norepinephrine uptake. The proposed study will focus on the function of the; NMDA receptor and how it interacts with other excitatory amino acid receptors as well as with dopaminergic and noradrenergic receptors in signal transduction mechanisms at the intracellular level. These experiments will attempt to determine how PCP alters the glutamatergic and catecholaminergic regulation of these second messengers and how this change alters transmitter release from the predominant neurons in brain slices from three brain regions. There are five specific aims: 1. The basic regulation of GABA and glutamate release by dopaminergic and glutamatergic agonists in slices of the striatum-globus pallidus and frontal cortex and by noradrenergic and glutamatergic agonists in hippocampal slices will be determined. In addition, in the striatum only, where nitric oxide synthase (NOS) and somatostatin are colocalized, the regulation of somatostatin release by glutamate, GABA and DA will be determined. Finally the effect of PCP on glutamatergic and catecholaminergic regulation of transmitter release will be determined. 2. The regulation of NOS activity in these areas by glutamate and catecholamines will be determined. 3. The potential role of nitric oxide (NO) in the effects of glutamate and excitatory amino acid agonists on transmitter release will be determined. In addition, the mechanisms by which NO generators such as hydroxylamine and sodium nitroprusside alter transmitter release will be studied. 4. The regulation of IP3 and cAMP formation by glutamate and catecholamines will be studied, with particular attention being paid to the effect that inhibition of catecholamine reuptake and blockade of the NMDA receptor by PCP has on this regulation. Changes in cAMP and IP3 levels will also be correlated with NOS activity. 5. The changes in these second messengers resulting from activation of glutamatergic and catecholaminergic receptors will be correlated with their effect on transmitter release. Finally, the extent to which PCP alteration of transmitter release is dependent on alterations in second messengers will be determined. Because of the role of NMDA receptor in cocaine and amphetamine sensitization, methamphetamine and HIV neurotoxicity, morphine tolerance and dependence, learning, neural plasticity, and stroke-induced brain damage, this study could have implications beyond understanding the neurochemical mechanisms of action of PCP.
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