Effects of endocannabinoid neurotransmission modulators on brain stimulation reward.
BACKGROUND
The endogenous cannabinoid system is responsive to the neurobiological actions of Delta9-tetrahydrocannabinol (THC) and other cannabinoid ligands. While numerous studies have focused on the behavioral and pharmacological effects of THC and cannabinoid agonists in experimental animals, most recent work focuses on compounds that modulate endocannabinoid neurotransmission. However, the relevant studies concerning the ability of endocannabinoid modulators to modify reward processes in experimental animals remain rather scarce.


OBJECTIVE
The present study examined the effects of drugs modulating endocannabinoid neurotransmission on brain reward function using the rate-frequency curve shift paradigm of intracranial self-stimulation (ICSS).


METHODS
Animals were implanted with electrodes into the medial forebrain bundle (MFB). After brain stimulation reward thresholds stabilized, rats received intraperitoneal injections of the fatty acid amide hydrolase (FAAH) inhibitors phenylmethylsulfonyl fluoride (PMSF) (0, 15, 30, and 60 mg/kg) and URB-597 (0, 0.3, 1, and 3 mg/kg) and the selective anandamide reuptake inhibitor OMDM-2 (0, 3, 10, and 30 mg/kg).


RESULTS
The highest dose of URB-597 and OMDM-2 significantly increased the threshold frequency required for MFB ICSS, while PMSF increased the threshold frequency in all doses tested. The cannabinoid 1 (CB1) receptor antagonist SR141716A reversed the actions of URB-597 and OMDM-2, but not PMSF, without affecting reward thresholds by itself.


CONCLUSIONS
These results indicate that under the present experimental conditions endocannabinoid modulators do not exhibit reinforcing properties, but rather have inhibitory influence on reward processes. The anhedonic effects of URB-597 and OMDM-2, but not PMSF, observed at the highest doses in this study are probably mediated through direct CB1 receptor stimulation.
Vlachou
Styliani
S
Laboratory of Behavioral Neuroscience, Department of Psychology, School of Social Sciences, University of Crete, 74100 Rethymnon, Crete, Greece.
Nomikos
George G
GG
Panagis
George
G
D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D063385:Cannabinoid Receptor Modulators / Q000502:physiology; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D063388:Endocannabinoids; D007274:Injections, Intraperitoneal; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects / Q000502:physiology; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000037:antagonists & inhibitors / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000502:physiology; D012055:Reinforcement Schedule; D012201:Reward; D000077285:Rimonabant; D012653:Self Stimulation / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D001593:Benzyl Compounds; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D063388:Endocannabinoids; D010664:Phenylmethylsulfonyl Fluoride; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011480:Protease Inhibitors; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant; D000099252:Fatty Acid Amide Hydrolases; C474343:OMDM-2 cpd; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C078814:anandamide