Localization of 5-HT2A receptors on dopamine cells in subnuclei of the midbrain A10 cell group

Considerable evidence suggests that a dysfunction of the dopamine and serotonin (5-hydroxytryptamine or 5-HT) neurotransmitter systems contributes to a diverse range of pathological conditions including schizophrenia, depression and drug abuse. Recent electrophysiological and behavioral studies suggest that 5-HT modulates dopaminergic neurons in the ventral tegmental area via activation of 5-HT2A receptors. It is currently unknown if 5-HT2A receptors mediate their actions on dopaminergic, neurons in the ventral tegmental area via direct or indirect mechanisms. This study investigated whether 5-HT2A receptors were localized on dopamine cells within the A10 dopamine subnuclei of the rat, including the ventral tegmental area. We discovered that 5-HT2A receptor-like immunoreactivity colocalized with tyrosine hydroxylase, a marker for dopamine neurons, throughout the A10 dopamine cell population. Colocalization was most prominent in rostral and mid A10 regions, including the paranigral, parabrachial, and interfascicular subnuclei. Though more rare, non-dopaminergic neurons also expressed 5-HT2A receptor immunoreactivity in the ventral tegmental area. Additionally, although a dense population of 5-HT2A immunoreactive cells was observed in the rostral dorsal raphe nucleus, rarely were these cells immunoreactive for tyrosine hydroxylase. The linear raphe A10 dopamine subdivisions also displayed a low degree of 5-HT2A receptor and tyrosine hydroxylase colocalization. These findings provide an anatomical basis for the physiological modulation of dopamine neurons in the rostral ventral tegmental area either directly, by 5-HT2A receptors localized on dopamine cells, or indirectly, through a non-dopaminergic mechanism. Interestingly, 5-HT2A receptors were expressed on dopamine neurons in several A10 subnuclei that project to mesolimbic forebrain regions implicated in drug addiction, and recent evidence indicates that ventral tegmental area 5-HT2A receptor activation may modulate reward-related behavior in rodents. 5-HT2A receptors were also expressed on dopamine cells in A10 subnuclei that project to forebrain areas that have been implicated in schizophrenia, and atypical antipsychotic drugs have high affinities for 5-HT2A receptors. Thus, findings in this study could have important implications for understanding 5-HT and dopamine circuitry dysfunction in schizophrenia. Published by Elsevier Science Ltd on behalf of IBRO.