Evidence for topographically organized endogenous 5‐HT‐1A receptor‐dependent feedback inhibition of the ascending serotonin system

Raphe and extra‐raphe 5‐HT‐1A receptors contribute to feedback inhibition of serotonin (5‐HT) neurons; however, the endogenous function of 5‐HT‐1A receptor‐dependent feedback inhibition remains poorly understood. Here, the possibility that 5‐HT‐1A‐mediated feedback inhibition of the raphe nuclei is topographically organized was examined. This was done by testing the effect of systemic blockade of 5‐HT‐1A receptors on Fos expression in 5‐HT neurons in the dorsal raphe (DR) and median raphe (MR). The premise was that appearance of Fos after 5‐HT‐1A receptor blockade would implicate endogenous inhibition via 5‐HT‐1A‐dependent processes. 5‐HT‐1A receptor antagonist administration (WAY‐100635) in rats returned to their home cage significantly increased the number of Fos‐containing 5‐HT cells in the lateral wings and the ventral caudal part of the DR as compared to vehicle‐injected controls, suggesting that tonic activity of brain 5‐HT‐1A receptors impacts on these regions. In rats receiving vehicle injections, swim, a behavior known to influence 5‐HT neurotransmission, increased the number of Fos‐containing 5‐HT cells only in the caudal third of DR. Administration of WAY‐100635 preceding a swim did not change the amount of Fos in the caudal DR, but increased the number of Fos‐containing 5‐HT cells in the rostral DR, lateral wings of the DR, and MR. These results confirm, using an imaging approach, that 5‐HT‐1A receptor‐dependent feedback inhibition depends on behavioral state (return to home cage vs. swim). Moreover, they reveal that the effect of 5‐HT‐1A receptor blockade in each case is subregionally organized.