An examination of NMDA receptor contribution to conditioned responding evoked by the conditional stimulus effects of nicotine

Abstract

Rationale: Research using a drug discriminated goal-tracking (DGT) task showed that the N-methyl-D: -aspartate (NMDA) channel blocker MK-801 (dizocilpine) reduced the nicotine-evoked conditioned response (CR).

Objectives: Given the unknown mechanism of the effect, Experiment 1 replicated the MK-801 results and included tests with NMDA receptor ligands. Experiments 2a and 2b tested whether MK-801 pretreatment blocked DGT via a state-dependency effect.

Methods: In Experiment 1, adult male Sprague-Dawley rats received intermittent access to liquid sucrose following nicotine (0.4 mg base/kg); no sucrose was delivered on intermixed saline sessions. Conditioning was indicated by increased anticipatory dipper entries (goal-tracking) on nicotine compared to saline sessions. Antagonism and/or substitution tests were conducted with MK-801, phencyclidine, CGP 39551, d-CPPene (SDZ EAA 494), Ro 25,6981, L-701,324, ACPC, and NMDA. In Experiment 2a, rats received nicotine and sucrose on every session-no intermixed saline sessions without sucrose. Tests combined MK-801 or the non-competitive nicotinic acetylcholine receptor antagonist, mecamylamine with either nicotine or saline. Experiment 2b had sucrose delivered on saline sessions and no sucrose on intermixed nicotine sessions followed by MK-801 antagonism tests of the saline CS.

Results: MK-801 and phencyclidine dose-dependently attenuated the CR in Experiment 1. Ro-25,6981 enhanced the CR, but did not substitute for nicotine. Other ligands showed inconsistent effects. In Experiment 2a, MK-801 pretreatment reduced goal-tracking when given before nicotine and saline test sessions; mecamylamine pretreatment had no effect. In Experiment 2b, MK-801 dose-dependently attenuated the saline-evoked CR.

Conclusions: Combined, the results suggest that MK-801 blocks discriminated goal-tracking by virtue of state-changing properties.

Fig. 1

Panel a shows dipper entry rate ± SEM for nicotine generalization tests. Panel b shows dipper entry rate ± SEM for antagonism tests with MK-801 and PCP. The solid line indicates the saline baseline dipper entry rate generated from the saline training session before each rat tested with 2 mg/kg PCP (dotted lines ± SEM). Panel c shows dipper entry rate ± SEM for antagonism testing with CGP 39551, d-CPPene, and Ro 25-6981. Panel d shows dipper entry rate ± SEM for substitution testing with NMDA and Ro 25-6981. Panel e shows dipper entry rate ± SEM of antagonism testing with ACPC. The solid line indicates saline baseline dipper entry rate generated from the saline training session before each rat tested with 300 mg/kg ACPC (dotted lines ± SEM). For all panels, ^# indicates difference from vehicle baseline, p<0.05; ^##p<0.01; ^###p<0.001. * indicates difference from vehicle pretreatment of nicotine or nicotine alone, p<0.05; **p<0.01; *** p<0.001. ^ indicates main effect of test drug in the absence of significant post-hoc comparisons

Fig. 2

Panel a shows dipper entry rate + SEM of the state-change testing in Experiment 2a. Panel b shows dipper entry rate ± SEM of antagonism testing with MK-801 of the saline CS in Experiment 2b. The solid line indicates nicotine baseline dipper entry rate generated from the nicotine training session before each rat tested with 0.1 mg/kg MK-801 (dotted lines ± SEM). For both panels, * indicates difference from vehicle pretreatment of nicotine or nicotine alone, p< 0.05; **p<0.01; ***p<0.001