Effect of a D3 receptor antagonist on context-induced reinstatement of nicotine seeking.
Despite the existence of several treatment options for smoking cessation, the rate of relapse after treatment is very high. We and others have proposed that targeting the dopamine D3 receptor (DRD3) may be a good strategy for treatment of nicotine dependence. In human participants, reintroduction to an environment previously associated with drug-taking may induce relapse. In animals, such phenomenon can be studied using the context-induced reinstatement paradigm. As the role of DRD3 in context-induced reinstatement of nicotine-seeking has not yet been explored, we investigated the effects of different doses of the selective DRD3 antagonist SB-277011-A on this reinstatement. Sprague-Dawley adult rats were first trained to self-administer nicotine and subsequently underwent extinction in a second context for 5-7 days. We evaluated the effect of 1, 3 or 10mg/kg of SB-277011-A administered prior to the reintroduction to the training context. We used two different designs: 1) a between-subjects design with a unique reinstatement test; and 2) a counterbalanced within-subjects design, with 4 reinstatement tests. Our findings indicate that, in the within-subjects design, the magnitude of responding induced by the context-induced reinstatement of nicotine seeking was robust during the first reinstatement test, but significantly decreased with repeated testing. SB-277011-A (10mg/kg) blocked context-induced reinstatement of nicotine-seeking at first exposure to the context (between-subjects design), but not after repeated context exposure which produced weaker reinstatement over days. Our results support a role for DRD3 mediating context-induced reinstatement of nicotine seeking, but these effects may not be sustained over time. Further studies should explore this in human participants for validation.
Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, Toronto, Canada.
Pamela
P
Sabioni
Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, Toronto, Canada.
Patricia
P
Di Ciano
Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, Toronto, Canada; Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments, Centre for Addiction and Mental Health, Toronto, ON, Canada; Campbell Family Mental Health Research Institute, CAMH, Toronto, ON, Canada; Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada. Electronic address: Bernard.lefoll@camh.ca.
Bernard
B
Le Foll
D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D005502:Food; D009538:Nicotine / Q000008:administration & dosage; D018722:Nicotinic Agonists / Q000008:administration & dosage; D009570:Nitriles / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012201:Reward; D012646:Self Administration; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D014029:Tobacco Use Disorder / Q000188:drug therapy* / Q000378:metabolism
D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; D018722:Nicotinic Agonists; D009570:Nitriles; D050637:Receptors, Dopamine D3; C409982:SB 277011; D044005:Tetrahydroisoquinolines; D009538:Nicotine
Context-induced reinstatement; D3; Dopamine; Rat; SB-277011-A; Self-administration