Inhibition of glycine transporter 1 attenuates nicotine- but not food-induced cue-potentiated reinstatement for a response previously paired with sucrose

Abstract

Rationale Compounds which decrease NMDA receptor functioning, such as PCP and ketamine have abuse liability, whereas co-agonists of the NMDA receptor attenuate some of the behavioral and neurochemical effects of stimulant drugs. Here we examined the effects of a glycine transporter (GlyT1) inhibitor, which elevates glycine and hence NMDA signaling, on the behavioral effects of nicotine. Objectives To examine the influence of a novel potent, selective, and brain penetrant GlyT1 inhibitor, compound 5 {(2-chloro-N-[1-(ethylsulfonyl)-4-isobutylpiperidin-4-yl]methyl)}-4-(trifluoromethyl)benzamide; human IC 50 = 22 nM; rat = 30 nM), on nicotine-induced potentiation of progressive ratio responding for a food reward and nicotine- and food-induced cue-potentiated reinstatement for a response previously paired with sucrose. Results Compound 5 (33 mg/kg; p.o.; achieving ∼62% GlyT1 blockade) significantly attenuated nicotine-, but not food-induced cue-potentiated reinstatement for a response previously paired with sucrose whereas a lower dose (11 mg/kg, which achieved ∼34% GlyT1 blockade) did not. The effect of the higher dose was similar to that observed for mecamylamine (1 mg/kg i.p.), a non-selective nicotinic receptor antagonist. Conclusions These results suggest that compound 5 influences the ability of nicotine to promote reinstatement in the presence of a cue embedded with incentive motivation. Given the hypothesized contribution of reinstatement and conditioned stimuli to drug abuse and relapse, these findings suggest that GlyT1 inhibitors could have utility for treating nicotine addiction.