title: Effects of the cannabinoid CB₁ receptor allosteric modulator ORG 27569 on reinstatement of cocaine- and methamphetamine-seeking behavior in rats.
abstract: BACKGROUND
  Cannabinoid CB1 receptors play an essential role in drug addiction. Given the side effect profiles of orthosteric CB1 antagonism, new strategies have been attempted to modulate this target, such as CB1 receptor allosteric modulation. However, the effect of CB1 allosteric modulation in drug addiction is unknown. The present study examined the effects of the CB1 receptor allosteric modulator ORG27569 on the reinstatement of cocaine- and methamphetamine-seeking behavior in rats.
  
  
  METHODS
  Rats were trained to self-administer 0.75 mg/kg cocaine or 0.05 mg/kg methamphetamine in 2-h daily sessions for 14 days which was followed by 7 days of extinction sessions in which rats responded on the levers with no programmed consequences. On reinstatement test sessions, rats were administered ORG27569 (1.0, 3.2, 5.6 mg/kg, i.p.) or SR141716A (3.2 mg/kg, i.p.) 10 min prior to re-exposure to cocaine- or methamphetamine-paired cues or a priming injection of cocaine (10mg/kg, i.p.) or methamphetamine (1mg/kg, i.p.).
  
  
  RESULTS
  Both cues and a priming injection of cocaine or methamphetamine significantly reinstated the extinguished active lever responding. Pretreatment with ORG27569 resulted in a dose-related attenuation of both cue- and drug-induced reinstatement of cocaine- and methamphetamine-seeking behavior. SR141716A also exhibited similar inhibitory action on reinstatement of drug-seeking behavior.
  
  
  CONCLUSIONS
  Negative allosteric modulation of CB1 receptors can produce similar functional antagonism as orthosteric CB1 receptor antagonists on reinstatement of drug-seeking behavior. Thus, ORG27569 or other negative allosteric modulators deserve further study as potentially effective pharmacotherapy for drug addiction.
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA; Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
authors.forename: Li
authors.initials: L
authors.lastname: Jing
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Research Triangle Institute, Research Triangle Park, NC, USA.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA. Electronic address: junxuli@buffalo.edu.
authors.forename: Jun-Xu
authors.initials: JX
authors.lastname: Li
mesh_terms: D000494:Allosteric Regulation; D019969:Amphetamine-Related Disorders / Q000503:physiopathology*; D000818:Animals; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D003463:Cues; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008694:Methamphetamine; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects* / Q000502:physiology*; D012008:Recurrence; D000077285:Rimonabant; D012646:Self Administration
chemical_list: C572504:5-chloro-3-ethyl-1H-indole-2-carboxylic acid (2-(4-piperidin-1-yl-phenyl)ethyl)amide; D007211:Indoles; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D008694:Methamphetamine; D000077285:Rimonabant
keywords: CB(1) allosteric modulator; Cocaine; Methamphetamine; Rats; Reinstatement; Self-administration