Peripheral and central mechanisms involved in the discriminative stimulus effects of nicotine in monkeys

Nicotine (NIC), a psychoactive ingredient in tobacco, binds to nicotinic acetylcholine receptors (nAChRs) in the brain and ganglia to exert behavioral and physiological effects. In the present study, we investigated the role of central and peripheral nAChRs in the discriminative stimulus (S D ) effects of NIC through pharmacological evaluation of varenicline (VAR), an α4β2 nAChR partial agonist, and the peripheral nAChR antagonist hexamethonium (HEX) in ovariectomized female cynomolgus monkeys (n=4) trained to discriminate NIC (0.3 mg/kg, i.m., 10‐min pretreat) from saline under an FR 30 schedule of food reinforcement. VAR (0.03–0.3 mg/kg, i.m., 10‐min pre‐session) did not engender NIC‐like S D effects, nor affect response rates. In timecourse studies in combination with 0.3 mg/kg NIC, VAR (0.1–0.3 mg/kg) elicited emesis at early time points (10–120 min) and disrupted responding, but once responding was restored, antagonized the S D effects up to 5‐h post‐administration. When administered 5‐min prior to NIC, HEX (3.2–5.6 mg/kg, i.m.) did not ater the S D effects of NIC, but did antagonize the rate‐decreasing effects of NIC. HEX (3.2 mg/kg) attenuated the rate‐decreasing effects of VAR and NIC observed at early time points, but the S D effects of NIC were still blocked by VAR. These results suggest the S D effects of NIC are centrally mediated while peripheral nAChRs mediate rate‐decreasing effects of NIC. DA 12460