Reward and somatic changes during precipitated nicotine withdrawal in rats: Centrally and peripherally mediated effects

The negative affective aspects of nicotine withdrawal have been hypothesize d to contribute to tobacco dependence. In the present studies in rats, brai n stimulation reward thresholds, conditioned place aversions, and somatic s igns of withdrawal were used to investigate the role of central and periphe ral nicotinic acetylcholine and opioid receptors in nicotine withdrawal. Ra ts prepared with s.c. osmotic mini-pumps delivering 9.0 mg/kg/day nicotine hydrogen tartrate or saline were administered various doses of the nicotini c antagonists mecamylamine (s.c.), chlorisondamine (s.c. or i.c.v.), dihydr o-b-erythroidine (s.c.), or the opiate antagonist naloxone (s.c.). Nicotine -treated rats receiving mecamylamine or i.c.v. chlorisondamine exhibited el evated thresholds and more somatic signs than saline-treated rats. Nicotine -treated rats receiving s.c. chlorisondamine, at doses that do not readily cross the blood-brain barrier, exhibited more somatic signs than saline-tre ated rats with no threshold elevations. Naloxone administration produced th reshold elevations and somatic signs only at high doses that induced simila r magnitude effects in both nicotine- and saline-treated subjects. Mecamyla mine or dihydro-b-erythroidine administration induced conditioned place ave rsions in nicotine-treated rats but required higher doses than those needed to precipitate threshold elevations. In contrast, naloxone administration induced conditioned place aversions at lower doses than those required to p recipitate threshold elevations and somatic signs. These data provide evide nce for a dissociation between centrally mediated elevations in reward thre sholds and somatic signs that are both centrally and peripherally mediated. Furthermore, threshold elevations and somatic signs of withdrawal appear t o be mediated by cholinergic neurotransmission, whereas conditioned place a versions appear to be primarily mediated by the opioid system.