Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Abstract

The neurotransmitter dopamine (DA) has a long association with normal functions such as motor control, cognition, and reward, as well as a number of syndromes including drug abuse, schizophrenia, and Parkinson's disease. Studies show that serotonin (5-HT) acts through several 5-HT receptors in the brain to modulate DA neurons in all 3 major dopaminergic pathways. There are at least fourteen 5-HT receptor subtypes, many of which have been shown to play some role in mediating 5-HT/DA interactions. Several subtypes, including the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4 receptors, act to facilitate DA release, while the 5-HT2C receptor mediates an inhibitory effect of 5-HT on DA release. Most 5-HT receptor subtypes only modulate DA release when 5-HT and/or DA neurons are stimulated, but the 5-HT2C receptor, characterized by high levels of constitutive activity, inhibits tonic as well as evoked DA release. This review summarizes the anatomical evidence for the presence of each 5-HT receptor subtype in dopaminergic regions of the brain and the neuropharmacological evidence demonstrating regulation of each DA pathway. The relevance of 5-HT receptor modulation of DA systems to the development of therapeutics used to treat schizophrenia, depression, and drug abuse is discussed. Lastly, areas are highlighted in which future research would be maximally beneficial to the treatment of these disorders.

Fig.1. 5-HT1B receptors potentiate cocaine-induced dopamine release in the nucleus accumbens

A: In the absence of cocaine, serotonin (5-HT) binding to 5-HT1B receptors in the ventral tegmental area (VTA) does not alter basal dopamine (DA) release in the nucleus accumbens (NA). B: In the presence of systemic or intra-VTA cocaine, 5-HT transporters are blocked by cocaine causing an increase in extracellular 5-HT in the VTA, and increased stimulation of 5-HT1B receptors on the terminals of GABAergic projections from the NA. GABA release from these terminals is decreased in response to 5-HT1B receptor stimulation, resulting in a disinhibition of the mesolimbic pathway and increased DA release in the NA.

Fig.2. Putative neuronal circuitry mediating the regulation of mesocortical dopamine release by 5-HT2A and 5-HT2C receptors

The model assumes that 5-HT2A or 5-HT2C receptor agonism is excitatory. A: As depicted, presynaptic 5-HT2A receptors stimulate the release of glutamate which acts on AMPA receptors to stimulate corticotegmental projections that regulate mesocortical dopamine (DA) cell activity in B. Alternatively, stimulation of 5-HT2A receptors localized directly on pyramidal neurons may stimulate those that project to the ventral tegmental area. B: 5-HT2C receptors localized on γ-aminobutyric acid (GABA) interneurons stimulate the release of GABA which inhibits mesocortical DA cells. 5-HT2A receptors stimulate DA neurons directly. This is attenuated by a concomitant stimulatory action of 5-HT2A receptors on GABA interneurons which inhibit DA cells.