Postsynaptic receptors are not essential for dopaminergic feedback regulation

Abstract

ANTIPSYCHOTIC drugs (neuroleptics) which block central dopamine (DA) receptors increase the synthesis and metabolism of striatal DA and the firing of dopaminergic neurones in the substantia nigra. These effects have been postulated to be secondary to the drug-induced blockade of striatal postsynaptic DA-receptors and mediated by a negative feedback loop impinging on nigral DA-neurones^1,2. However, the existence of alternative mechanisms has been recently postulated^3–5. In particular, it has been suggested that neuroleptics stimulate dopaminergic firing by blocking nigral DA-receptors, thus relieving DA-neurones from the inhibitory action of DA released from dopaminergic dentrites (self-inhibition)⁶. Indirect support for this possibility derives from the recent discovery of a DA-sensitive adenylate cyclase within the substantianigra^7–9. We report here that destruction of striatal DA-sensitive adenylate cyclase by kainic acid¹⁰ fails to reduce the effect of neuroleptics and of apomorphine, a DA-receptor agonist¹¹, on striatal DA-metabolism. These data indicate that an interaction with postsynaptic DA receptors is not essential for the changes in DA-metabolism produced by neuroleptics and apomorphine and provide in vivo evidence for the existence of a dopaminergic negative feedback independent from postsynaptic DA-receptors.