Norepinephrine-Dopamine Interactions in the Prefrontal Cortex and the Ventral Tegmental Area: Relevance to Mental Diseases

Abstract

Mesocortical dopaminergic (DA) neurons originate from the ventral tegmental area (VTA) and innervate different cortical structures, including the prefrontal cortex. The perticular anatomical distributions of noradrenergic (NE) and mesocortical DA neurons suggest the occurance of interactions between these two systems at the levels of either the DA nerve terminals (prefrontal cortex) or the DA cell bodies. Initially, a specific destruction of the ascending NE neurons innervating the VTA has been performed by injection of 6-hydroxydopamine (6-OHDA) in the vicinity of the NE pathway connecting the locus coeruleus to the ventral tegmental area (VTA). The observation suggests that NE neurons exert a specific tonic excitatory control on mesocortical DA neurons. Two groups of experiments have been performed to investigate what type of adrenergic receptor is responsible for the heteroregulation of cortical D1 receptors by NE. Both types of experiments indicate that the stimulation of cortical α ,-adrenergic receptors inhibits the cortical DA transmission mediated by D1 receptors. Correlation studies have indicated that the amplitude of locomotor hyperactivity is proportional to the extent of destruction of the DA fibers innervating the prefrontal cortex and to the development of D1-receptor supersensitivity in this area. Researches confirm that NE and DA neurons exert opposite functional roles in the prefrontal cortex. They also demonstrate that the stimulation by NE of cortical α ,-adrenergic receptors is necessary for a functional subcortical DA transmission. Different symptoms of depression have been related to a reduction of DA transmission in subcortical structures. On the other hand, the activation by NE of mesocortical DA neurons in the VTA may initiate a working memory processing. At birth, during REM sleep, and following the ingestion of psychostimulants, the mode of brain functioning would be essentially rapid and analogical with a preponderance of subcortical DA function.