title: Effects of 7-day repeated treatment with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in male rhesus monkeys.
abstract: Preclinical drug vs. food choice is an emerging group of drug self-administration procedures that have shown predictive validity to clinical drug addiction. Emerging data suggest that serotonin (5-HT)2A receptors modulate mesolimbic dopamine function, such that 5-HT2A antagonists blunt the abuse-related neurochemical effects of monoamine transporter substrates, such as amphetamine or methamphetamine. Whether subchronic 5-HT2A antagonist treatment attenuates methamphetamine reinforcement in any preclinical drug self-administration procedure is unknown. The study aim was therefore to determine 7-day treatment effects with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in monkeys.
  
  
  
  Behavior was maintained under a concurrent schedule of food delivery (1g pellets, fixed-ratio 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=3). Methamphetamine choice dose-effect functions were determined daily before and during 7-day repeated pimavanserin (1.0-10mg/kg/day, intramuscular) treatment periods.
  
  
  
  Under control conditions, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Repeated pimavanserin administration failed to attenuate methamphetamine choice and produce a reciprocal increase in food choice in any monkey up to doses (3.2-10mg/kg) that suppressed rates of operant responding primarily during components where behavior was maintained by food pellets.
  
  
  
  Repeated 5-HT2A receptor inverse agonist/antagonist treatment did not attenuate methamphetamine reinforcement under a concurrent schedule of intravenous methamphetamine and food presentation in nonhuman primates. Overall, these results do not support the therapeutic potential of 5-HT2A inverse agonists/antagonists as candidate medications for methamphetamine addiction.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA; Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA. Electronic address: Matthew.Banks@vcuhealth.org.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Banks
mesh_terms: D000818:Animals; D002755:Choice Behavior / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D054314:Drug Inverse Agonism; D005247:Feeding Behavior / Q000187:drug effects* / Q000502:physiology; D005502:Food; D008253:Macaca mulatta; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage*; D010880:Piperidines / Q000008:administration & dosage*; D012054:Reinforcement, Psychology; D012646:Self Administration; D058826:Serotonin 5-HT2 Receptor Agonists / Q000008:administration & dosage*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000008:administration & dosage*; D016896:Treatment Outcome; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D010880:Piperidines; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D008694:Methamphetamine; D014508:Urea; C510793:pimavanserin
keywords: 5-HT(2A); Addiction; Choice; Methamphetamine; Pimavanserin; Rhesus monkey