The serotonin/noradrenaline-link in brain. I. The role of noradrenaline and serotonin in the regulation of density and function of beta adrenoceptors and its alteration by desipramine.

Abstract

The present studies were undertaken to assess the role of noradrenaline (NA) and serotonin (5HT) in the regulation of the NA receptor coupled adenylate cyclase system and its alteration by desipramine (DMI) in brain structures with or without noradrenergic neuronal projections. In contrast to cortex and limbic forebrain, where chronic DMI administration caused subsensitivity of the NA sensitive adenylate cyclase linked to a down-regulation of beta adrenoceptors, the drug failed to alter the NA receptor coupled adenylate cyclase system in the striatum. Selective lesions of serotonergic axons with 5,7-dihydroxytryptamine caused a significant increase in the density of beta adrenoceptors in cortex, limbic forebrain and striatum and prevented the down-regulation by DMI of beta adrenoceptors in cortex and limbic forebrain while the responsiveness of the NA sensitive adenylate cyclase was reduced to the same extent as in sham-lesioned control animals. The discrepancy between beta adrenoceptor number and NA responsiveness following lesions of 5HT axons was particularly profound in the striatum. The analysis of high- and low-affinity components of agonist binding demonstrated that the increase in striatal beta adrenoceptors is due to a marked increase in receptors with low affinity while the number of receptors with high affinity is unchanged. The results lend further support to the view that the synaptic availability of NA is a prerequisite for the induction of subsensitivity of the NA sensitive adenylate cyclase and for the down-regulation of its beta adrenoceptor population by DMI and that 5HT plays a pivotal role in both the regulation of the number and the function of central beta adrenoceptors.