title: 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.
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Children's Hospital Boston, 300 Longwood Ave., Enders 307, Boston, MA 02115, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Sperling
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Commons
mesh_terms: D000818:Animals; D005731:Ganglionic Stimulants / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011903:Raphe Nuclei / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*
chemical_list: D005731:Ganglionic Stimulants; D016760:Proto-Oncogene Proteins c-fos; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D009538:Nicotine