HT2C Receptors and Serotonergic or GABAergic Neurons

The cellular localization of 5-HT2C receptor mRNA in relation to serotonergic and GABAergic neurons has been studied in the anterior raphe nuclei of the rat (Serrats et al. 2005). In the dorsal and median raphe nuclei, 5-HT2C receptor mRNA is not detected in serotonergic cells identified as those expressing serotonin (5-HT) transporter mRNA. In contrast, 5-HT2C receptor mRNA is found in the majority of GABAergic cells of the anterior raphe nuclei, mainly located in the lateral and inter-mediolateral parts of the dorsal raphe and lateral part of the median raphe, supporting previous hypotheses that proposed a negative-feedback loop involving reciprocal connections between GABAergic interneurons bearing 5-HT2A/2C receptors and 5-HT neurons in the dorsal raphe and surrounding areas. According to this model, the excitation of GABAergic interneurons through these 5-HT2C (and also 5-HT2A) receptors would result in the suppression of 5-HT cell firing.

The finding of 5-HT2C-immunoreactive cells in the raphe nuclei has led to the proposal that some 5-HT neurons might express these receptors (Clemett et al. 2000). In contrast, electrophysiological data suggest that 5-HT2C receptors are located on local GABAergic neurons, inside or close to the dorsal raphe (Liu et al. 2000), being part of a local negative-feedback circuit that would involve reciprocal connections between GABAergic and 5-HT neurons. This model has been proposed to explain the increases in the frequency of inhibitory postsynaptic currents (IPSCs) induced by 5-HT and the 5-HT2A/2C agonist DOI [1-(2,5)-dimethoxy-4-io-dophenyl-2-aminopropane] when applied to rat brain slices containing the dorsal raphe.

The localization of the 5-HT2C receptor in GABAergic cells has been also described in other brain areas. Immunohistochemical analyses on the 5-HT2C receptor reveals that this receptor is mainly expressed in deep layers of the rat medial prefrontal cortex (Liu et al. 2007) and cortex (Abramowski et al. 1995) in agreement with the presence of the mRNA coding for this receptor in layers IV and V of PFC of mice (Mengod et al. 1990a), rat (Pompeiano et al. 1994), monkey (Lopez-Gimenez et al. 2001a), and human (Pasqualetti et al. 1999). Around 50% of the neurons expressing 5-HT2C receptor immunoreactivity in the prelimbic region of the medial prefrontal cortex also expressed GAD67 immunoreactivity (Liu et al. 2007), a marker of GABAergic interneurons. We have detected abundant expression of 5-HT2C receptor mRNA in layer V cells of the mouse cingulate cortex that were not GABAergic. A detail of these results is shown in Fig. 2.2.

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