title: Endocannabinoids promote cocaine-induced impulsivity and its rapid dopaminergic correlates.
abstract: BACKGROUND
  Impaired decision making, a hallmark of addiction, is hypothesized to arise from maladaptive plasticity in the mesolimbic dopamine pathway. The endocannabinoid system modulates dopamine activity through activation of cannabinoid type 1 receptors (CB1Rs). Here, we investigated whether impulsive behavior observed following cocaine exposure requires CB1R activation.
  
  
  METHODS
  We trained rats in a delay-discounting task. Following acquisition of stable performance, rats were exposed to cocaine (10 mg/kg, intraperitoneal) every other day for 14 days and locomotor activity was measured. Two days later, delay-discounting performance was re-evaluated. To assess reversal of impulsivity, injections of a CB1R antagonist (1.5 mg/kg, intraperitoneal) or vehicle were given 30 minutes before the task. During the second experiment, aimed at preventing impulsivity rather than reversing it, CB1Rs were antagonized before each cocaine injection. In this experiment, subsecond dopamine release was measured in the nucleus accumbens during delay-discounting sessions before and after cocaine treatment.
  
  
  RESULTS
  Blockade of CB1Rs reversed and prevented cocaine-induced impulsivity. Electrochemical results showed that during baseline and following disruption of endocannabinoid signaling, there was a robust increase in dopamine for immediate large rewards compared with immediate small rewards, but this effect reversed when the delay for the large reward was 10 seconds. In contrast, dopamine release always increased for one-pellet options at minimal or moderate delays in vehicle-treated rats.
  
  
  CONCLUSIONS
  Endocannabinoids play a critical role in changes associated with cocaine exposure. Cannabinoid type 1 receptor blockade may thus counteract maladaptive alterations in afferents to dopamine neurons, thereby preventing changes in dopaminergic activity underlying a loss of self-control.
authors.affiliation: Department of Physiology, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Hernandez
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Erik B
authors.initials: EB
authors.lastname: Oleson
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Ronny N
authors.initials: RN
authors.lastname: Gentry
authors.affiliation: Center for Studies in Behavioral Neurobiology, Concordia University, Montréal, Quebec, Canada.
authors.forename: Zarish
authors.initials: Z
authors.lastname: Abbas
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: David L
authors.initials: DL
authors.lastname: Bernstein
authors.affiliation: Center for Studies in Behavioral Neurobiology, Concordia University, Montréal, Quebec, Canada.
authors.forename: Andreas
authors.initials: A
authors.lastname: Arvanitogiannis
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland. Electronic address: jchee001@umaryland.edu.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cheer
mesh_terms: D000818:Animals; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D003042:Cocaine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism*; D007175:Impulsive Behavior / Q000187:drug effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012201:Reward; D000077285:Rimonabant; D013997:Time Factors
chemical_list: D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; D003042:Cocaine; D000077285:Rimonabant; D004298:Dopamine
keywords: CB1 receptors; cocaine; decision-making; dopamine; fast-scan cyclic voltammetry; self-control