Dopamine interaction with other neurotransmitter systems : relevance in the pathophysiology and treatment of CNS disorders

Abstract

Decades ago, in the late 1950s, dopamine (DA), a highly conserved catecholaminergic neurotransmitter, was discovered in the mammalian brain. The first role identified for DA was in the control of movement. Degeneration of DA neurons within the substantia nigra pars compacta (SNc) and the consequential DA depletion in the striatum were indeed shown by Oleh Hornykiewicz to be the cause of neurological symptoms in Parkinson's disease (PD). This discovery and the subsequent use of L-DOPA in such patients, which represents one of the most successful stories in neuropharmacology, has generated such intense research that this little cluster of DA neurons has become the most studied in the brain today. DA neurons represent a tiny proportion of the total neuronal population in the central nervous system (CNS) but, through their highly divergent branching networks of fibers, these few cells influence large territories of the brain. The majority of brain DA cells resides in the ventral part of mesencephalon. Essentially, they are restricted to two nuclei, the ventral tegmental area of Tsai (VTA) and the lateral SNc. Nevertheless, cells expressing tyrosine hydroxylase (TH), the rate-limiting enzyme in the biosynthesis of catecholamines, have also been described in the striatum of rodents, monkeys and even humans. DA neurons in the midbrain are spontaneously active and show regular, irregular and bursting patterns of activity that are an essential component of the DA release process. DA neuronal activity can be modulated by diverse life events, ranging from exposure to drugs, stress, or unpredictable rewards. Strikingly, it has been shown that DA neuronal discharge is altered in an animal model of depression and can be corrected by desipramine treatment. The new field of optogenetics has furthered our understanding of the causal role of DA cell action potential patterns in driving behavioral changes, opening a second exciting electrophysiological era for the dopaminergic neurons. Use of this new technique, together with the subsequent advances gained by associated research will be beneficial for patients with various neurological and psychiatric disorders, including PD.