The awardee is focusing his studies on the mechanisms involved in the regulation of short-term synthesis of dopamine (DA) and on the effects of antipsychotic drugs (APD) on the regulation of presynaptic and postsynaptic DA receptor subtypes. The phosphorylation and activation of tyrosine hydroxylase (TH) by multiple protein kinases at different serine (Ser)- containing phosphorylation sites of TH will be investigated. The mechanisms underlying the activation of TH by antibodies against segments of TH containing a specific phosphorylation site will be studied. We will determine whether specific antibodies increase TH activity by inducing a conformational change of the enzyme and/or by neutralizing a segment of the enzyme which exerts an inhibitory effect on the catalytic activity. The functional consequences of removal of Ser and substitution with another amino acid (AA), or substitution of an AA adjacent to Ser with another AA, on basal TH activity and on phosphorylation of the enzyme will be determined. The role of multiple TH forms will be investigated in non- human primates and in postmortem brains from patients with psychiatric and neurological disorders and from corresponding controls. The effects of acute and chronic treatment with typical and atypical APD on tyrosine hydroxylation in vivo and on the phosphorylation state of the enzyme will be investigated. The pharmacological and biochemical profiles of postsynaptic DA receptors rendered supersensitive by chronic treatment with APD and/or calcium antagonists will be studied. The effects of chronic treatment with APD on receptor reserves for DA agonists at postsynaptic striatal DA receptors regulating neuronal activity of acetylcholine will be investigated.
