title: 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.
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. luigi.cervo@marionegri.it
authors.forename: Luigi
authors.initials: L
authors.lastname: Cervo
authors.forename: Angelo
authors.initials: A
authors.lastname: Di Clemente
authors.forename: Alessandro
authors.initials: A
authors.lastname: Orrù
authors.forename: Federico
authors.initials: F
authors.lastname: Moro
authors.forename: Chiara
authors.initials: C
authors.lastname: Cassina
authors.forename: Emilio Merlo
authors.initials: EM
authors.lastname: Pich
authors.forename: Mauro
authors.initials: M
authors.lastname: Corsi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gozzi
authors.forename: Angelo
authors.initials: A
authors.lastname: Bifone
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects*; D003463:Cues; D004193:Discrimination Learning / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005108:Extinction, Psychological / Q000187:drug effects*; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D007171:Implosive Therapy; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage
chemical_list: C507205:2-chloro-N-((S)-phenyl((2S)-piperidin-2-yl)methyl)-3-trifluoromethyl benzamide; D001549:Benzamides; D050487:Glycine Plasma Membrane Transport Proteins; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C493266:Slc6a9 protein, rat; D013395:Sucrose; D009538:Nicotine
keywords: Drug-associated cues; GlyT1-inhibitors; nicotine-seeking behavior