Nicotinic acetylcholine and dopamine receptors contribute to the discriminative stimulus effects of nicotine in nonhuman primates

Abstract

Nicotinic acetylcholine receptors (nAChRs) are potential therapeutic targets for neurological disorders for their ability to indirectly modulate neurotransmitter activity including dopamine (DA). The present study investigated the role of nAChR (α4β2, α3β4, α7) and DA D2‐like receptors (D2, D3) in the discriminative stimulus (SD) effects of nicotine (NIC) in cynomolgus monkeys (n=4) trained to discriminate NIC (0.3 mg/kg, i.m., 10‐min pretreat) from saline under a fixed‐ratio 30 schedule of food reinforcement. We found that neither the α4β2 nAChR partial agonist varenicline (0.03–0.3 mg/kg, 1‐h pretreat, i.m.), nor the α3β4/α4β2 nAChR partial agonist cytisine (0.1–1.0 mg/kg, 10‐min pretreat, i.m.) engendered NIC‐like SD effects, but both compounds antagonized the SD effects of NIC. While the peripheral nAChR antagonist hexamethonium (3.2–5.6 mg/kg, i.m.) did not alter the SD effects of NIC, the nonselective nAChR antagonist mecamylamine (0.56–1.7 mg/kg, i.m., 30‐min pretreat) and the competitive α4β2 nAChR antagonist DHβE (0.1–1.0 mg/kg, i.m., 10‐min pretreat) attenuated NIC discrimination. The D2‐like antagonist haloperidol (0.001–0.1 mg/kg, 10‐min pretreat) antagonized NIC. D3 receptors may contribute as the partial agonist PG 619 (0.03 mg/kg, i.m., 10‐min pretreat) attenuated NIC's SD effects. These findings suggest α4β2 nAChRs and DA D2‐like receptors contribute to the SD effects of NIC. DA12460