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 highlyconserved catecholaminergic neurotransmitter, was dis-covered in the mammalian brain [1]. The first role iden-tified for DA was in the control of movement. Degen-eration of DA neurons within the substantia nigra parscompacta (SNc) and the consequential DA depletion inthe striatum were indeed shown by Oleh Hornykiewiczto be the cause of neurological symptoms in Parkinson’sdisease(PD)[2].ThisdiscoveryandthesubsequentuseofL-DOPA in such patients [3], which represents one of themost successful stories in neuropharmacology, has gen-erated such intense research that this little cluster of DAneurons has become the most studied in the brain to-day. DA neurons represent a tiny proportion of the totalneuronal population in the central nervous system (CNS)but, through their highly divergent branching networksof fibers, these few cells influence large territories of thebrain. The majority of brain DA cells resides in the ven-tralpartofmesencephalon.Essentially,theyarerestrictedto two nuclei, the ventral tegmental area of Tsai (VTA)and the lateral SNc. Nevertheless, cells expressing tyro-sine hydroxylase (TH), the rate-limiting enzyme in thebiosynthesis of catecholamines, have also been describedin the striatum of rodents, monkeys and even humans[4]. DA neurons in the midbrain are spontaneously ac-tive and show regular, irregular and bursting patterns ofactivity that are an essential component of the DA releaseprocess. DA neuronal activity can be modulated by di-verse life events, ranging from exposure to drugs, stress,or unpredictable rewards. Strikingly, it has been shownthat DA neuronal discharge is altered in an animal modelof depression and can be corrected by desipramine treat-ment [5]. The new field of optogenetics has furthered ourunderstanding of the causal role of DA cell action poten-tial patterns in driving behavioral changes [6], opening asecond exciting electrophysiological era for the dopamin-ergic neurons. Use of this new technique, together withthe subsequent advances gained by associated researchwill be beneficial for patients with various neurologicaland psychiatric disorders, including PD.It is evident that the discovery of DA as a neurotrans-mitter in the brain marked a turning point in modernneuroscience. Not only has it elucidated our understand-ingofbrainfunctioninbothhealthanddisease,ithasalsohelped link theories of brain chemistry and higher brainfunction, thus playing a vital part in the developmentof biological psychiatry. The importance of DA’s rolein all aspects of human behavior, including cognition,