title: Comparisons of Δ9-Tetrahydrocannabinol and Anandamide on a Battery of Cognition-Related Behavior in Nonhuman Primates.
abstract: The primary psychoactive ingredient of marijuana, Δ(9)-tetrahydrocannabinol (Δ(9)-THC), has medicinal value but also produces unwanted deleterious effects on cognitive function, promoting the search for improved cannabinergic therapeutics. The present studies used a battery of touchscreen procedures in squirrel monkeys to compare the effects of different types of cannabinergic drugs on several measures of performance including learning (repeated acquisition), cognitive flexibility (discrimination reversal), short-term memory (delayed matching-to-sample), attention (psychomotor vigilance), and motivation (progressive ratio). Drugs studied included the cannabinoid agonist Δ(9)-THC, fatty acid amide hydrolase (FAAH) inhibitor cyclohexylcarbamic acid 3-carbamoylbiphenyl-3-yl ester (URB597), and endocannabinoid anandamide and its stable synthetic analog methanandamide [(R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide]. The effects of Δ(9)-THC and anandamide after treatment with the cannabinoid receptor type 1 inverse agonist/antagonist rimonabant [5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1Hpyrazole-3-carboxamide] and the FAAH inhibitor URB597, respectively, also were examined. The results showed the following: 1) Δ(9)-THC produced dose-related impairments of discrimination-based cognitive behavior with potency that varied across tasks (discriminative capability < learning < flexibility < short-term memory); 2) anandamide alone and URB597 alone were without effect on all endpoints; 3) anandamide following URB597 pretreatment and methanandamide had negligible effects on discriminative capability, learning, and reversal, but following large doses affected delayed matching-to-sample performance in some subjects; 4) all drugs, except anandamide and URB597, disrupted attention; and 5) progressive ratio breakpoints were generally unaffected by all drugs tested, suggesting little to no effect on motivation. Taken together, these data indicate that metabolically stable forms of anandamide may have lesser adverse effects on cognitive functions than Δ(9)-THC, possibly offering a therapeutic advantage in clinical settings.
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (B.D.K., J.B.); Preclinical Pharmacology Laboratory, McLean Hospital, Belmont, Massachusetts (B.D.K., M.Z.L., J.B.); and Center for Drug Discovery, Northeastern University, Boston, Massachusetts (V.G.S., S.O.A., S.P.N., A.M.) bkangas@mclean.harvard.edu.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Kangas
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (B.D.K., J.B.); Preclinical Pharmacology Laboratory, McLean Hospital, Belmont, Massachusetts (B.D.K., M.Z.L., J.B.); and Center for Drug Discovery, Northeastern University, Boston, Massachusetts (V.G.S., S.O.A., S.P.N., A.M.).
authors.forename: Michael Z
authors.initials: MZ
authors.lastname: Leonard
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (B.D.K., J.B.); Preclinical Pharmacology Laboratory, McLean Hospital, Belmont, Massachusetts (B.D.K., M.Z.L., J.B.); and Center for Drug Discovery, Northeastern University, Boston, Massachusetts (V.G.S., S.O.A., S.P.N., A.M.).
authors.forename: Vidyanand G
authors.initials: VG
authors.lastname: Shukla
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (B.D.K., J.B.); Preclinical Pharmacology Laboratory, McLean Hospital, Belmont, Massachusetts (B.D.K., M.Z.L., J.B.); and Center for Drug Discovery, Northeastern University, Boston, Massachusetts (V.G.S., S.O.A., S.P.N., A.M.).
authors.forename: Shakiru O
authors.initials: SO
authors.lastname: Alapafuja
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (B.D.K., J.B.); Preclinical Pharmacology Laboratory, McLean Hospital, Belmont, Massachusetts (B.D.K., M.Z.L., J.B.); and Center for Drug Discovery, Northeastern University, Boston, Massachusetts (V.G.S., S.O.A., S.P.N., A.M.).
authors.forename: Spyros P
authors.initials: SP
authors.lastname: Nikas
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (B.D.K., J.B.); Preclinical Pharmacology Laboratory, McLean Hospital, Belmont, Massachusetts (B.D.K., M.Z.L., J.B.); and Center for Drug Discovery, Northeastern University, Boston, Massachusetts (V.G.S., S.O.A., S.P.N., A.M.).
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (B.D.K., J.B.); Preclinical Pharmacology Laboratory, McLean Hospital, Belmont, Massachusetts (B.D.K., M.Z.L., J.B.); and Center for Drug Discovery, Northeastern University, Boston, Massachusetts (V.G.S., S.O.A., S.P.N., A.M.).
authors.forename: Jack
authors.initials: J
authors.lastname: Bergman
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001288:Attention / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects*; D004193:Discrimination Learning / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D063388:Endocannabinoids / Q000494:pharmacology*; D007858:Learning / Q000187:drug effects; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D009042:Motivation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D012193:Reversal Learning / Q000187:drug effects; D000077285:Rimonabant; D012453:Saimiri
chemical_list: D001095:Arachidonic Acids; D001549:Benzamides; D002219:Carbamates; D063388:Endocannabinoids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; D013759:Dronabinol; D000077285:Rimonabant; C078814:anandamide
references.citation: Front Behav Neurosci. 2011 Sep 13;5:57
references.pmid: 21949506
references.citation: Psychopharmacology (Berl). 1980;71(3):247-56
references.pmid: 6256795
references.citation: Physiol Rev. 2003 Jul;83(3):1017-66
references.pmid: 12843414
references.citation: Neuroscience. 2013 Apr 3;235:51-8
references.pmid: 23333671
references.citation: J Pharmacol Exp Ther. 1997 Sep;282(3):1526-32
references.pmid: 9316868
references.citation: Psychopharmacology (Berl). 1998 May;137(1):33-42
references.pmid: 9631954
references.citation: J Neurosci Methods. 2012 Aug 15;209(2):331-6
references.pmid: 22790109
references.citation: J Pharmacol Exp Ther. 2013 Feb;344(2):319-28
references.pmid: 23197773
references.citation: J Exp Anal Behav. 2011 Mar;95(2):221-36
references.pmid: 21541127
references.citation: Neurosci Biobehav Rev. 2006;30(5):680-95
references.pmid: 16574226
references.citation: Nat Med. 2003 Jan;9(1):76-81
references.pmid: 12461523
references.citation: J Exp Anal Behav. 1959 Apr;2:151-60
references.pmid: 13801643
references.citation: J Med Chem. 2008 Dec 11;51(23):7327-43
references.pmid: 18983142
references.citation: Mol Pharmacol. 1993 Sep;44(3):498-503
references.pmid: 8371711
references.citation: Mol Pharmacol. 2006 Sep;70(3):986-96
references.pmid: 16760363
references.citation: Behav Neural Biol. 1992 Jan;57(1):2-36
references.pmid: 1567331
references.citation: Psychopharmacology (Berl). 2008 Feb;196(3):389-95
references.pmid: 17992520
references.citation: Psychopharmacology (Berl). 2014 Feb;231(3):603-12
references.pmid: 24043345
references.citation: J Pharmacol Exp Ther. 1997 Jul;282(1):243-7
references.pmid: 9223560
references.citation: Int Rev Neurobiol. 2009;85:57-72
references.pmid: 19607961
references.citation: Cancer Manag Res. 2013 Aug 30;5:301-13
references.pmid: 24039449
references.citation: Behav Neurosci. 2011 Jun;125(3):327-43
references.pmid: 21639603
references.citation: Neurobiol Aging. 2010 Jun;31(6):1020-31
references.pmid: 18760505
references.citation: Curr Drug Abuse Rev. 2008 Jan;1(1):81-98
references.pmid: 19630708
references.citation: Proc Nutr Soc. 2014 Feb;73(1):96-105
references.pmid: 24135210
references.citation: Curr Opin Pharmacol. 2005 Feb;5(1):69-72
references.pmid: 15661628
references.citation: Anim Cogn. 2014 Mar;17(2):221-8
references.pmid: 23794073
references.citation: Physiol Behav. 2009 Apr 20;97(1):121-4
references.pmid: 19239915
references.citation: Behav Pharmacol. 1999 Sep;10(5):497-511
references.pmid: 10780256
references.citation: Can J Psychol. 1968 Apr;22(2):85-95
references.pmid: 5649040
references.citation: Psychopharmacology (Berl). 2006 Nov;188(4):425-44
references.pmid: 17019571
references.citation: Pharmacol Biochem Behav. 2009 Dec;94(2):305-11
references.pmid: 19772870
references.citation: Science. 1961 Sep 29;134(3483):943-4
references.pmid: 13714876
references.citation: Psychopharmacology (Berl). 1999 Apr;143(3):315-7
references.pmid: 10353436
references.citation: J Pharmacol Exp Ther. 1988 Apr;245(1):178-86
references.pmid: 2834536
references.citation: J R Soc Med. 1992 Jul;85(7):399-402
references.pmid: 1629849
references.citation: J Psychopharmacol. 2012 Oct;26(10):1299-306
references.pmid: 22526684
references.citation: Life Sci. 2013 Mar 19;92(8-9):446-52
references.pmid: 22940268
references.citation: Br J Pharmacol. 2011 Sep;164(2b):655-66
references.pmid: 21449917
references.citation: Psychopharmacology (Berl). 2007 Feb;190(2):135-43
references.pmid: 17111174
references.citation: Eur J Pharmacol. 2014 Jan 5;722:134-46
references.pmid: 24184696
references.citation: J Addict Med. 2011 Mar;5(1):1-8
references.pmid: 21321675
references.citation: Psychopharmacology (Berl). 1998 Dec;140(4):519-22
references.pmid: 9888629
references.citation: Mol Psychiatry. 2012 Jun;17(6):642-9
references.pmid: 21747398