Serotonergic modulation of basal ganglia circuits

Abstract

DA= : dopamine; DRN= : dorsal raphe nucleus; GABA= : γ-aminobutyric acid; 5-HT= : 5-hydroxytryptamine; l-DOPA, levodopa= : l-dihydroxyphenylalanine; MPTP= : 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine; 6-OHDA= : 6-hydroxydopamine; PD= : Parkinson disease; SERT= : serotonin transporter; SNc= : substantia nigra pars compacta; SNr= : substantia nigra pars reticulata; VTA= : ventral tegmental area. Serotonergic innervation of the CNS originates from the raphe nuclei and exerts widespread influence on behavior. Serotonin (5-hydroxytryptamine, 5-HT) has an important neuromodulatory action that is mediated by a large variety of 5-HT receptor subtypes. The central serotonergic system has been implicated in mechanisms of cognition, emotion, impulse control, circadian and sleep-wake cycle regulation, pain modulation, and respiratory, cardiovascular, and motor functions. Experimental studies have provided a large amount of information on the multiple effects of 5-HT on the basal ganglia circuits at the levels of the prefrontal cortex, striatum, globus pallidus, and subthalamic nucleus, both directly and via 5-HT interactions with the dopaminergic system. Both the serotonergic and dopaminergic systems are affected in neurodegenerative disorders such as Parkinson disease (PD) and Alzheimer disease and have been implicated in the pathophysiology of depression, obsessive compulsive disorder, drug addiction, schizophrenia, and other disorders. The complex interactions between the serotonergic and dopaminergic systems at the levels of the basal ganglia and cerebral cortex, and their implications for PD and several psychiatric disorders, have been comprehensively reviewed.1–6 Some general concepts and potential clinical implications for PD are emphasized here. ### Anatomy. The raphe nuclei are located in the midline throughout the brainstem and are subdivided into a rostral and a caudal group.6 The rostral raphe nuclei include the dorsal raphe nucleus (DRN) and median raphe nucleus, which provide inputs to the forebrain and upper brainstem; the caudal raphe nuclei provide inputs to the lower brainstem and spinal cord. The DRN provides the major serotonergic input to basal ganglia circuits, including the dopaminergic neurons of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) and all their targets, including the striatum, globus pallidus, substantia nigra pars reticulata (SNr), subthalamic nucleus, and prefrontal cortex (figure 1).3–6 At all these levels, serotonergic …