title: Cannabinoid receptor blockade reduces the opportunity cost at which rats maintain operant performance for rewarding brain stimulation.
abstract: There is ample evidence that blockade of CB(1) receptors reduces reward seeking. However, the reported effects of CB(1) blockade on performance for rewarding electrical brain stimulation stand out as an exception. By applying a novel method for conceptualizing and measuring reward seeking, we show that AM-251, a CB(1) receptor antagonist, does indeed decrease performance for rewarding electrical stimulation of the medial forebrain bundle in rats. Reward seeking depends on multiple sets of variables, including the intensity of the reward, its cost, and the value of competing rewards. In turn, reward intensity depends both on the sensitivity and gain of brain reward circuitry. We show that drug-induced changes in sensitivity cannot account for the suppressive effect of AM-251 on reward seeking. Therefore, the role of CB(1) receptors must be sought among the remaining determinants of performance. Our analysis provides an explanation of the inconsistencies between prior reports, which likely arose from the following: (1) the averaging of data across subjects showing heterogeneous effects and (2) the use of methods that cannot distinguish between the different determinants of reward pursuit. By means of microdialysis, we demonstrate that blockade of CB(1) receptors attenuates nucleus accumbens dopamine release in response to rewarding medial forebrain bundle stimulation, and we propose that this action is responsible for the ability of the drug to decrease performance for the electrical reward.
authors.affiliation: Center for Research in Behavioral Neurobiology/FRSQ Groupe de recherche neurobiologie comportamentale, Concordia University, Montréal, Québec H4B 1R6, Canada.
authors.forename: Ivan
authors.initials: I
authors.lastname: Trujillo-Pisanty
authors.forename: Giovanni
authors.initials: G
authors.lastname: Hernandez
authors.forename: Ian
authors.initials: I
authors.lastname: Moreau-Debord
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Cossette
authors.forename: Kent
authors.initials: K
authors.lastname: Conover
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cheer
authors.forename: Peter
authors.initials: P
authors.lastname: Shizgal
mesh_terms: D000818:Animals; D003198:Computer Simulation; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism; D004558:Electric Stimulation; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects / Q000502:physiology*; D017551:Microdialysis / Q000379:methods; D008959:Models, Neurological; D009638:Norepinephrine / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000187:drug effects; D012201:Reward; D012653:Self Stimulation; D013997:Time Factors
chemical_list: C543264:Cnr1 protein, rat; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; D004298:Dopamine; D009638:Norepinephrine