Receptor Mediated Control of Monoamine Transmission

Westfall, Thomas

Abstract

There is convincing evidence to suggest that dopamine autoreceptors are present on dopaminergic nerve terminals in the striatum which regulate the release and the synthesis of this neurotransmitter. The major objectives of the present proposal are first, to gain an understanding of pharmacological differences between autoreceptor and postsynaptic receptors; and second, to gain an understanding of the mechanism(s) by which activation of dopamine autoreceptors results in an inhibition of dopamine release and synthesis. One major strategy is to examine the relative potency of selected agonists and antagonists in activating or antagonizing autoreceptors or postsynaptic receptors. Dopamine autoreceptors will be studied by examining the effect of selective dopamine agonists and antagonists on the evoked release of endogenous dopamine (measured by high performance liquid chromatography coupled to electrochemical detection) or the synthesis of dopamine (measured by the incorporation of 3H-tyrosine into 3H-dopamine) in striatal slices or synaptosomes. Postsynaptic receptor function will be studied by examining the effect of the same drugs on the evoked release of 3H-acetylcholine, 3H-glutamate and endogenous glutamate. The second major strategy will be to examine the mechanism by which activation of dopamine autoreceptors cause a release of dopamine utilizing several probes and perturbations. These probes and perturbations will assess the role of calcium ions, Na+ K+ ATPase, cyclic nucleotides (cAMP, cGMP) and the recruitment of varicosities vs. electrosecretion coupling as possible mechanisms of the inhibition of dopamine release. These studies should provide a better understanding of dopamine autoreceptors. This is of obvious importance since the use of dopamine autoreceptor agonists may represent a novel approach to various diseases such as schizophrenia, Huntington's Disease and tardive dyskinesia where overactivity of central dopamine neurons may be etiological. Moreover, the dopamine blocking action of neuroleptic drugs may be achieved by various combinations of pre- and postsynaptic effects and the relative importance may vary from one class of neuroleptics to another. These studies will provide a better understanding of the physiology and pharmacology of central dopaminergic neurotransmission.