5-HT(2C) receptors localize to dopamine and GABA neurons in the rat mesoaccumbens pathway

PLoS One. 2011;6(6):e20508. doi: 10.1371/journal.pone.0020508. Epub 2011 Jun 7.

Abstract

The serotonin 5-HT(2C) receptor (5-HT(2C)R) is localized to the limbic-corticostriatal circuit, which plays an integral role in mediating attention, motivation, cognition, and reward processes. The 5-HT(2C)R is linked to modulation of mesoaccumbens dopamine neurotransmission via an activation of γ-aminobutyric acid (GABA) neurons in the ventral tegmental area (VTA). However, we recently demonstrated the expression of the 5-HT(2C)R within dopamine VTA neurons suggesting the possibility of a direct influence of the 5-HT(2C)R upon mesoaccumbens dopamine output. Here, we employed double-label fluorescence immunochemistry with the synthetic enzymes for dopamine (tyrosine hydroxylase; TH) and GABA (glutamic acid decarboxylase isoform 67; GAD-67) and retrograde tract tracing with FluoroGold (FG) to uncover whether dopamine and GABA VTA neurons that possess 5-HT(2C)R innervate the nucleus accumbens (NAc). The highest numbers of FG-labeled cells were detected in the middle versus rostral and caudal levels of the VTA, and included a subset of TH- and GAD-67 immunoreactive cells, of which >50% also contained 5-HT(2C)R immunoreactivity. Thus, we demonstrate for the first time that the 5-HT(2C)R colocalizes in DA and GABA VTA neurons which project to the NAc, describe in detail the distribution of NAc-projecting GABA VTA neurons, and identify the colocalization of TH and GAD-67 in the same NAc-projecting VTA neurons. These data suggest that the 5-HT(2C)R may exert direct influence upon both dopamine and GABA VTA output to the NAc. Further, the indication that a proportion of NAc-projecting VTA neurons synthesize and potentially release both dopamine and GABA adds intriguing complexity to the framework of the VTA and its postulated neuroanatomical roles.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Dopamine / biosynthesis
  • Dopamine / metabolism*
  • Glutamate Decarboxylase / metabolism
  • Humans
  • Male
  • Neurons / cytology
  • Neurons / enzymology
  • Neurons / metabolism*
  • Neurotransmitter Agents / biosynthesis
  • Neurotransmitter Agents / metabolism
  • Nucleus Accumbens / cytology*
  • Nucleus Accumbens / metabolism
  • Protein Transport
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Staining and Labeling
  • Tyrosine 3-Monooxygenase / metabolism
  • Ventral Tegmental Area / cytology*
  • Ventral Tegmental Area / metabolism
  • gamma-Aminobutyric Acid / biosynthesis
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Neurotransmitter Agents
  • Receptor, Serotonin, 5-HT2C
  • gamma-Aminobutyric Acid
  • Tyrosine 3-Monooxygenase
  • Glutamate Decarboxylase
  • Dopamine