Behavioral and neuropharmacological characterization of nicotine as a conditional stimulus

Abstract

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-1 H-3-benzazepine hydrochloride (SCH-23390; 0.005, 0.01, and 0.03 mg/kg), 3-Chloro-5-ethyl- N-[[(2 S)-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 (5 S,10 R)-(+)-5-Methyl-10,11-dihydro-5 H-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.