Inhibition of glycine transporter-1 reduces cue-induced nicotine-seeking, but does not promote extinction of conditioned nicotine cue responding in the rat

Abstract

Pharmacological stimulation of N-methyl-D-aspartate receptors (NMDAr) could enhance the outcome of cue-exposure therapy for smoking cessation. NMDAr stimulation can be achieved by increasing pharmacologically the synaptic levels of glycine, a necessary co-agonist. Here, we evaluate the effects of SSR504734, a selective inhibitor of glycine type I transporter (GlyT1) in an extinction-reinstatement procedure inducing robust and lasting nicotine-seeking behavior in rats. Male Wistar rats were trained to associate discriminative stimuli (S(D)s) with the availability of nicotine (0.03 mg/kg/65 μL/2 second/infusion) or sucrose (45-mg pellet) versus non-reward in two-lever operant cages. Reinforced response was followed by cue signaling 20-second time-out (CSs). Once the training criterion was met, rats underwent extinction of lever presses, in the absence of reinforcers, S(D) s and CSs. Re-exposure to nicotine or sucrose S(D+)/CS(+), but not non-reward S(D-)/CS(-), revived responding at the previously reinforced lever. Acute pre-treatment with SSR504734 (10 mg/kg i.p.) reduced nicotine-seeking but not sucrose-seeking behavior without influencing rats' locomotor activity. Sub-chronic treatment (10 mg/kg i.p. for 5 days) during daily exposure to S(D+)/CS(+) reduced nicotine-seeking; however, this effect was transient, with return to S(D+)/CS(+) responding at 72 hours. Full recovery to S(D+)/CS(+) responding was observed after 1 month suggesting that SSR504734 sub-acute treatment did not engage the long-term plasticity mechanisms probably involved in nicotine-seeking. In conclusion, GlyT1-inhibitors might offer a therapeutic opportunity for acute cue-controlled nicotine-seeking, but the lack of persistent effects of the sub-chronic treatment associated with nicotine cues exposure suggests that short-term administration of GlyT1-inhibitor SSR504734 is not sufficient to promote extinction of nicotine-cue conditioned responding.

Effects of menthol and its interaction with nicotine-conditioned cue on nicotine-seeking behavior in rats

“…The interactive effect of pre-session menthol administration as an occasion setter and discrete nicotine-conditioned cue is consistent with results that were obtained in rats that were trained to self-administer other drugs of abuse (e.g., cocaine and alcohol) or natural rewards (e.g., Cervo et al, 2013; Katner et al, 1999; Moro et al, 2016; Weiss et al, 2001). It could be postulated that pre-session menthol administration produced an interoceptive state (an occasion setter) that signaled the availability of nicotine reward and brought the rats into contact with the lever while the response-contingent presentation of the cue then served as conditioned reinforcement to support responding on the lever.…”

Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy

“…The day before electrode implantation, rats were anesthetized with 1.5% isoflurane and surgically prepared with jugular catheters (56) for i.v. injection of drugs.…”

mGluR2/3 mediates short‐term control of nicotine‐seeking by acute systemic N‐acetylcysteine

“…; Cervo et al . ). Rats designated for nicotine self‐administration were surgically prepared with jugular catheters and given a week of recovery before self‐administration training (see Supporting Information).…”

“…; Cervo et al . ). Thus, treatments that reduce vulnerability to nicotine conditioned cues in rodents may help prevent relapse to smoking.…”

“…; Cervo et al . ). This enduring behavioral effect resembles the persistence of conditioned cue reactivity and cue‐induced craving in humans, a factor implicated in high rates of recidivism (O'Brien et al .…”