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Extracellular levels of serotonin [5-hydroxytryptamine (5-HT)] in the nucleus accumbens (NAc) can influence both cognitive and motor functions involving extensive connections with the frontal cortex. The 5-HT levels reflect vesicular release and plasmalemmal reuptake through the serotonin transporter (SERT). We used electron microscopic immunocytochemistry to determine the sites for SERT activation in the limbic shell and motor-associated core of the rat NAc. Of the SERT-immunoreactive profiles in each region, >90% were serotonergic axons and axon terminals; the remainder were nonserotonergic dendrites and glia. Axonal SERT immunogold labeling was seen mainly at nonsynaptic sites on plasma membranes and often near 5-HT-containing large dense core vesicles (DCVs). SERT-labeled axonal profiles were larger and had a higher numerical density in the shell versus the core but showed no regional differences in their content of SERT immunogold particles. In contrast, immunoreactive dendrites had a lower numerical density in the shell than in the core. SERT labeling in dendrites was localized to segments of plasma membrane near synaptic contacts from unlabeled terminals and/or dendritic appositions. Our results suggest that in the NAc (1) reuptake into serotonergic axons is most efficient after exocytotic release from DCVs, and (2) increased 5-HT release without concomitant increase in SERT expression in individual axons may contribute to higher extracellular levels of serotonin in the shell versus the core. These findings also indicate that SERT may play a minor substrate-dependent role in serotonin uptake or channel activity in selective nonserotonergic neurons and glia in the NAc.

Ultrastructural Localization of the Serotonin Transporter in Limbic and Motor Compartments of the Nucleus Accumbens