Serotonin-2C receptor agonists decrease potassium-stimulated GABA release in the nucleus accumbens

Abstract

The serotonin 5-HT2C receptor has shown promise in vivo as a pharmacotherapeutic target for alcoholism. For example, recently, a novel 4-phenyl-2-N,N-dimethylaminotetralin (PAT) drug candidate, that demonstrates 5-HT2C receptor agonist activity together with 5-HT2A/2B receptor inverse agonist activity, was shown to reduce operant responding for ethanol after peripheral administration to rats. Previous studies have shown that the 5-HT2C receptor is found throughout the mesoaccumbens pathway and that 5-HT2C receptor agonism causes activation of ventral tegmental area (VTA) GABA neurons. It is unknown what effect 5-HT2C receptor modulation has on GABA release in the nucleus accumbens core (NAcc). To this end, microdialysis coupled to capillary electrophoresis with laser-induced fluorescence was used to quantify extracellular neurotransmitter concentrations in the NAcc under basal and after potassium stimulation conditions, in response to PAT analogs and other 5-HT2C receptor modulators administered by reverse dialysis to rats. 5-HT2C receptor agonists specifically attenuated stimulated GABA release in the NAcc while 5-HT2C antagonists or inverse agonists had no effect. Agents with activity at 5-HT2A receptors had no effect on GABA release. Thus, in contrast to results reported for the VTA, current results suggest 5-HT2C receptor agonists decrease stimulated GABA release in the NAcc, and provide a possible mechanism of action for 5HT2C-mediated negative modulation of ethanol self-administration.

Mapping the connectivity of serotonin transporter immunoreactive axons to excitatory and inhibitory neurochemical synapses in the mouse limbic brain

“…The proximity of 5-HT-positive axon terminals to GABA terminals engaged in symmetrical (inhibitory) synapses revealed by electron microscopy in rats (Van Bockstaele et al 1996) suggests that 5-HT could influence the release of GABA. This is supported by functional studies showing a modulation of GABA release in the NAC by 5-HT2C receptors in rats (Kasper et al 2015). Interestingly, we found a significantly higher proportion of SYN SERT+ boutons located closer to the presynaptic component of putative inhibitory synapses within the NAC shell, suggesting that 5-HT could have a modulatory effect on GABA release from GABAergic synapses in this area.…”

Gamma-Aminobutyric Acidergic Projections From the Dorsal Raphe to the Nucleus Accumbens Are Regulated by Neuromedin U

“…Probe was inserted and rats were allowed to freely move around the CMA 120 system. Two hours after implantation (29), samples were collected every 30 minutes.…”

Serotonergic Systems in the Pathophysiology of Ethanol Dependence: Relevance to Clinical Alcoholism

“…In the VTA, activation of 5-HT 2C receptors expressed in GABAergic interneurons enhance GABA release 104 and inhibit reward signaling. In the NAc, however, GABA release is attenuated 105 . Taken together, these studies suggest that 5-HT, via 5-HT 2C receptors, inhibits GABA signaling in the NAc which in turn potentiates reward 37 .…”