Behavioral and neuropharmacological characterization of nicotine as a conditional stimulus

In rats, the pharmacological (interoceptive) effects of 0.4 mg/kg nicotine can serve as a conditional stimulus in a Pavlovian conditioning task. Nicotine administration is paired with intermittent access to a liquid sucrose unconditional stimulus; sucrose is withheld on saline sessions. An increase in sucrose receptacle entries (goal tracking) on nicotine sessions indicates conditioning. Rats were trained on a nicotine dose ((-)-1-Methyl-2-(3-pyridyl)pyrrolidine; 0.1, 0.2, or 0.4 mg base/kg, s.c.). Generalization was examined using 0.025, 0.05, 0.1, 0.2, and 0.4 mg/kg nicotine and saline. Some behavioral effects of nicotine have been attributed to dopamine and glutamate. Accordingly, potential blockade of the nicotine cue via the dopamine system was examined by administering (R)-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390; 0.005, 0.01, and 0.03 mg/kg), 3-Chloro-5-ethyl-N-[[(2S)-1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxy-benzamide hydrochloride (eticlopride; 0.01, 0.03, 0.1, and 0.3 mg/kg), or N-[(1-Butyl-2-pyrrolidinyl)methyl]-4-cyano-1-methoxy-2-naphthalenecarboxamide (nafadotride; 0.03, 0.1, 0.3, 1, and 3 mg/kg) before nicotine. 2-Methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP; 0.3, 1, and 3 mg/kg) and (5S,10R)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801; 0.01, 0.03, 0.1, and 0.2 mg/kg; dizocilpine) were used to examine possible glutamatergic components. Substitution tests were conducted with MPEP and nafadotride. Differential conditioned responding was acquired in the 3 groups. Conditioned responding generally decreased as the nicotine test dose moved away from the training dose; responding increased when 0.4 mg/kg trained rats were tested with 0.2 mg/kg. SCH-23390, eticlopride, nafadotride, and MPEP decreased conditioned responding on nicotine at doses that also decreased chamber activity. In contrast, MK-801 decreased goal tracking on nicotine without decreasing chamber activity, indicating a role for N-methyl-d-aspartate receptors in expression of nicotine-evoked conditioned responding.