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


OBJECTIVE
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 approximately 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 approximately 34% GlyT1 blockade) did not. The effect of the higher dose was similar to that observed for mecamylamine (1mg/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.
Uslaner
Jason M
JM
Department of Schizophrenia Research, Merck & Co., Inc., Ann Arbor, MI 48019-1109, USA. Jason_Uslaner@merck.com
Drott
Jason T
JT
Sharik
Steven S
SS
Theberge
Cory R
CR
Sur
Cyrille
C
Zeng
Zhizhen
Z
Williams
David L
DL
Hutson
Pete H
PH
D000704:Analysis of Variance; D000818:Animals; D016739:Behavior, Addictive; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004305:Dose-Response Relationship, Drug; D005108:Extinction, Psychological / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D005502:Food; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D009538:Nicotine / Q000008:administration & dosage*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage
C546327:((2-chloro-N-(1-(ethylsulfonyl)-4-isobutylpiperidin-4-yl)methyl))-4-(trifluoromethyl)benzamide; D001549:Benzamides; D050487:Glycine Plasma Membrane Transport Proteins; D018733:Nicotinic Antagonists; D010880:Piperidines; D011978:Receptors, Nicotinic; D013395:Sucrose; D008464:Mecamylamine; D009538:Nicotine