title: Differential effects of cannabinoid CB1 inverse agonists and antagonists on impulsivity in male Sprague Dawley rats: identification of a possibly clinically relevant vulnerability involving the serotonin 5HT1Areceptor.
abstract: Cannabinoid CB1 inverse agonists hold therapeutic promise as appetite suppressants but have produced suicidal behaviors among a small subpopulation in clinical trials. Anatomical and pharmacological evidence implicate the 5HT1Aserotonin receptor in suicide in humans and impulsivity in humans and animals.
  
  
  
  The objective of the study is to assess whether 5HT1Ablockade is necessary for CB1 ligands to produce impulsivity.
  
  
  
  Sprague Dawley rats were administered the CB1 inverse agonist AM 251, the CB1 antagonist AM 6527, or the peripherally restricted antagonist AM 6545, with or without pretreatment with the 5HT1Aantagonist WAY 100,635 (WAY) on the paced fixed consecutive number (FCN) task, which measures choice to terminate a chain of responses prematurely. As FCN is sensitive to changes in time perception, which have been demonstrated with CB1 blockade, a novel variable consecutive number task with discriminative stimulus (VCN-SD) was also performed and proposed to be less sensitive to changes in timing.
  
  
  
  Pretreatment with WAY enabled mild but significant reductions in FCN accuracy for AM 251 and AM 6527. No effects were found for AM 6545. On the VCN-SDtask, substantial impairments were found for the combination of WAY and AM 251.
  
  
  
  AM 251, but not the antagonists AM 6527 or AM 6545, produced impulsivity only following systemic 5HT1Ablockade. Although preliminary, the results may indicate that disrupted serotonin signaling produces a vulnerability to undesirable effects of CB1 inverse agonists, which is not evident in the general population. Furthermore, neutral CB1 antagonists do not produce this effect and therefore may have greater safety.
authors.affiliation: Department of Psychology, Edinboro University of Pennsylvania, 210 East Normal Street, Edinboro, PA, 16444, USA. pmclaughlin@edinboro.edu.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McLaughlin
authors.affiliation: Department of Psychology, Edinboro University of Pennsylvania, 210 East Normal Street, Edinboro, PA, 16444, USA.|Department of Psychology, University of Kentucky, Lexington, KY, 40506, USA.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Jagielo-Miller
authors.affiliation: Department of Psychology, Edinboro University of Pennsylvania, 210 East Normal Street, Edinboro, PA, 16444, USA.|Department of Biomedical Sciences, Kent State University, Kent, OH, 44242, USA.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Plyler
authors.affiliation: Department of Psychology, Edinboro University of Pennsylvania, 210 East Normal Street, Edinboro, PA, 16444, USA.|Department of Counseling, Psychology, and Special Education, Duquesne University, 600 Forbes Avenue, G8B Canevin Hall, Pittsburgh, PA, 15282, USA.
authors.forename: Kerry K
authors.initials: KK
authors.lastname: Schutte
authors.affiliation: Center for Drug Discovery, Northeastern University, 360 Huntington Avenue, Boston, MA, 02115, USA.
authors.forename: V Kiran
authors.initials: VK
authors.lastname: Vemuri
authors.affiliation: Center for Drug Discovery, Northeastern University, 360 Huntington Avenue, Boston, MA, 02115, USA.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D000818:Animals; D001067:Appetite Depressants; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology*; D002755:Choice Behavior / Q000187:drug effects; D054314:Drug Inverse Agonism; D007175:Impulsive Behavior / Q000187:drug effects*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D044282:Receptor, Serotonin, 5-HT1A; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology*
chemical_list: C539490:AM 6527; C551825:AM6545; D001067:Appetite Depressants; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D009025:Morpholines; D010879:Piperazines; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C103505:AM 251; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
keywords: Cannabinoid; Impulsivity; Individual differences; Individualized medicine; Rimonabant; Serotonin; Suicide