Shifting topographic activation and 5-HT1A receptor-mediated inhibition of dorsal raphe serotonin neurons produced by nicotine exposure and withdrawal

Abstract

Nicotine activates serotonin [5-hydroxytryptamine (5-HT)] neurons innervating the forebrain, and this is thought to reduce anxiety. Nicotine withdrawal has also been associated with an activation of 5-HT neurotransmission, although withdrawal increases anxiety. In each case, 5-HT1A receptors have been implicated in the response. To determine whether there are different subgroups of 5-HT cells activated during nicotine administration and withdrawal, we mapped the appearance of Fos, a marker of neuronal activation, in 5-HT cells of the dorsal raphe nucleus (DR) and median raphe nucleus (MR). To understand the role of 5-HT1A receptor feedback inhibitory pathways in 5-HT cell activity during these conditions, we administered a selective 5-HT1A receptor antagonist and measured novel disinhibited Fos expression within 5-HT cells. Using these approaches, we found evidence that acute nicotine exposure activates 5-HT neurons rostrally and in the lateral wings of the DR, whereas there is 5-HT1A receptor-dependent inhibition of cells located ventrally at both the rostral level and mid-level. Previous chronic nicotine exposure did not modify the pattern of activation produced by acute nicotine exposure, but increased 5-HT1A receptor-dependent inhibition of 5-HT cells in the caudal DR. This pattern was nearly reversed during nicotine withdrawal, when there was evidence for caudal activation and mid-level and rostral 5-HT1A receptor-dependent inhibition. These results suggest that the distinct behavioral states produced by nicotine exposure and withdrawal correlate with reciprocal rostral-caudal patterns of activation and 5-HT1A receptor-mediated inhibition of DR 5-HT neurons. The complementary patterns of activation and inhibition suggest that 5-HT1A receptors may help to shape distinct topographic patterns of activation within the DR.