Serotonin 5‐HT 2C Receptors in the Ventral Subiculum Regulate Hippocampal‐Mediated Behaviors in Rats

Abstract

Subregions of the ventral hippocampus (VH) CA1/subiculum (SUB) project to the prefrontal cortex, nucleus accumbens (NAc), and amygdala and these limbic-corticostriatal circuits regulate a number of behaviors, including stimulant-induced locomotor responses and affective processes (e.g. anxiety) in rats. The distribution of serotonin 5-HT2C receptors (5-HT2CR) in the output regions of the rat VH and the functional role of these receptors in VH-mediated behaviors remain under-explored. We hypothesized that 5-HT2CR in the SUB will be localized on GABA neurons and regulate VH-mediated behaviors. To this end, we assessed: a) immunohistochemical distribution of 5-HT2CR in the SUB and co-localization with glutamic acid decarboxylase [GAD67, marker for GABA neurons]; b) the effects of genetic knockdown of 5-HT2CR in the SUB on cocaine-evoked hyperactivity and anxiety-like behavior in rats. Immunoreactivity (IR) for the 5-HT2CR was observed primarily in cell bodies throughout the VH, with the greatest abundance in the SUB region. A small proportion of 5-HT2CR-IR in the SUB was co-localized with GAD67-IR, and this co-labeling was relatively restricted to the temporal axis. Selective knockdown of the 5-HT2CR in the SUB significantly suppressed cocaine-evoked hyperactivity, without altering basal locomotor activity or anxiety-like behavior in rats. These data indicate that a greater proportion of 5-HT2CR are localized to non-GABAergic projection neurons in the SUB and are engaged in functional circuits (hippocampal-NAc pathway) that mediate the locomotor-stimulating effects of cocaine.