RECEPTOR HETEROREGULATION - AN INDICATION OF FUNCTIONAL-RELATIONSHIPSBETWEEN NEURONAL SYSTEMS

To study the functional interrelations between the ascending dopaminer gic (DA) systems, we have focused our attention on the regulation of o ne type of DA receptor, the D1 receptor, which is positively coupled t o adenylate cyclase. The initial experiments revealed that the sensiti vity of DI receptors was not only regulated by afferent DA fibres but also by neurotransmitters released by non-DA nerve terminals. Cortical as well as subcortical D1 receptors seem to be subject to this hetero regulation process. Analyses of the nature and the origin of the non-D A fibres implicated in the heteroregulation of D1 receptors indicated that these neurons were part of well-defined anatomical circuits and s uggested that this heteroregulation had functional significance. an in tact cortical DA innervation appeared to be of major importance to obt ain a denervation hypersensitivity of the D1. receptors in the nucleus accumbens as well as in the striatum. This indicated that the DA stim ulation of cortical or subcortical structures have opposite effects on functions regulated by these structures. Behavioural experiments have indeed confirmed the antagonistic functional roles of cortical and su bcortical DA innervations. In the prefrontal cortex, sensitivity of D1 receptors appears to be regulated by ascending noradrenergic (NB) fib res. The physiological role of these ascending NA fibres, and more par ticularly of the alpha 1-adrenergic receptors, has been confirmed in b ehavioural. experiments which indicated that the deficits induced by t he destruction of the DA mesocortical pathway could be compensated by the superimposed destruction of the ascending NA fibres or by the phar macological blockade of the alpha 1-adrenergic receptors by prazosin.