Interactions between Catecholamines and Serotonin: Relevance to the Pharmacology of Schizophrenia

Abstract

This chapter summarizes several recent pharmacological results demonstrating the implication of the mesoaccumbens dopamine (DA) pathway in the behavioral effects of MK-801 in the rat. The chapter also reports the stabilizing effects of potent 5-HT 2 and α 1 -adrenoceptor blocking agents on different dysfunctions in the mesocorticolimbic DA system produced by systemic administration of the N-methyl-D-aspartate (NMDA)-receptor antagonists, with associated behavioral correlates. The studies clearly suggest the potent antagonistic effect at central 5-HT 2A and α 1 -adrenergic receptors of several atypical neuroleptics may well contribute significantly to their clinical profile. Specifically, 5-HT 2A -receptor antagonism can help to improve defective phasic DA signaling in the mesocortical DA projection. It may also tentatively be of particular value against negative symptoms and cognitive dysfunction. On the other hand the α 1 -adrenoceptor blockade, at a presynaptic level, might add to the postsynaptic D 2 -receptor blockade in antagonizing a hyperactive or hyperresponsive mesolimbic DA projection, with a more efficient control of positive symptomatology. Thus, the potent 5-HT 2A and α 1 -adrenergic receptor blocking effects of a number of atypical neuroleptic drugs may, in different ways, act to stabilize several dysfunctions within the mesocorticolimbic DA system that may contribute to the generation of psychotic symptomatology.