title: CB1 receptor antagonism blocks stress-potentiated reinstatement of cocaine seeking in rats.
abstract: BACKGROUND
  Under some conditions, stress, rather than directly triggering cocaine seeking, potentiates reinstatement to other stimuli, including a subthreshold cocaine dose. The mechanisms responsible for stress-potentiated reinstatement are not well defined. Endocannabinoid signaling is increased by stress and regulates synaptic transmission in brain regions implicated in motivated behavior.
  
  
  OBJECTIVE
  The objective of this study was to test the hypothesis that cannabinoid type 1 receptor (CB1R) signaling is required for stress-potentiated reinstatement of cocaine seeking in rats.
  
  
  METHODS
  Following i.v. cocaine self-administration (2 h access/day) and extinction in male rats, footshock stress alone does not reinstate cocaine seeking but reinstatement is observed when footshock is followed by an injection of an otherwise subthreshold dose of cocaine (2.5 mg/kg, i.p.). CB1R involvement was tested by systemic administration of the CB1R antagonist AM251 (0, 1, or 3 mg/kg, i.p.) prior to testing for stress-potentiated reinstatement.
  
  
  RESULTS
  Stress-potentiated reinstatement was blocked by both 1 and 3 mg/kg AM251. By contrast, AM251 only attenuated food-reinforced lever pressing at the higher dose (i.e., 3 mg/kg) and did not affect locomotor activity at either dose tested. Neither high-dose cocaine-primed reinstatement (10 mg/kg, i.p.) nor footshock stress-triggered reinstatement following long-access cocaine self-administration (6 h access/day) was affected by AM251 pretreatment. Footshock stress increased concentrations of both endocannabinoids, N-arachidonylethanolamine and 2-arachidonoylglycerol, in regions of the prefrontal cortex.
  
  
  CONCLUSIONS
  These findings demonstrate that footshock stress increases prefrontal cortical endocannabinoids and stress-potentiated reinstatement is CB1R-dependent, suggesting that CB1R is a potential therapeutic target for relapse prevention, particularly in individuals whose cocaine use is stress-related.
authors.affiliation: Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA.
authors.forename: Jayme R
authors.initials: JR
authors.lastname: McReynolds
authors.affiliation: Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Doncheck
authors.affiliation: Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Vranjkovic
authors.affiliation: Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA.
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Ganzman
authors.affiliation: Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Baker
authors.affiliation: Department of Pharmacology and Toxicology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
authors.forename: Cecilia J
authors.initials: CJ
authors.lastname: Hillard
authors.affiliation: Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA. john.mantsch@marquette.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Mantsch
mesh_terms: D000818:Animals; D001095:Arachidonic Acids; D016739:Behavior, Addictive / Q000517:prevention & control* / Q000523:psychology; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000517:prevention & control* / Q000523:psychology; D063388:Endocannabinoids; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D005989:Glycerides; D008297:Male; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D012054:Reinforcement, Psychology; D012646:Self Administration; D013315:Stress, Psychological / Q000517:prevention & control* / Q000523:psychology
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; C094503:glyceryl 2-arachidonate; D003042:Cocaine
keywords: Addiction; Cocaine; Endocannabinoid; Reinstatement; Relapse; Self-administration; Stress