title: Pharmacological elevation of anandamide impairs short-term memory by altering the neurophysiology in the hippocampus.
abstract: In rodents, many exogenous cannabinoid agonists including Δ(9)-THC and WIN55,212-2 (WIN-2) have been shown to impair short-term memory (STM) by inhibition of hippocampal neuronal assemblies. However, the mechanisms by which endocannabinoids such as anandamide and 2-arachidonyl glycerol (2-AG) modulate STM processes are not well understood. Here the effects of anandamide on performance of a Delayed-Non-Match-to-Sample (DNMS) task (i.e. STM task) and concomitant hippocampal ensemble activity were assessed following administration of either URB597 (0.3, 3.0 mg/kg), an inhibitor of the Fatty Acid Amide Hydrolase (FAAH), AM404 (1.5, 10.0 mg/kg), a putative anandamide uptake/FAAH inhibitor, or R-methanandamide (3.0, 10.0 mg/kg), a stable analog of anandamide. Principal cells from hippocampal CA3/CA1 were recorded extracellularly by multi-electrode arrays in Long-Evans rats during DNMS task (1-30 s delays) performance and tracked throughout drug administration and recovery. Both R-methanandamide and URB597 caused dose- and delay-dependent deficits in DNMS performance with suppression of hippocampal ensemble activity during the encoding (sample) phase. R-methanandamide-induced effects were not reversed by capsaicin excluding a contribution of TRPV-1 receptors. AM404 produced subtle deficits at longer delay intervals but did not alter hippocampal neuronal activity during task-specific events. Collectively, these data indicate that endocannabinoid levels affect performance in a STM task and their pharmacological elevation beyond normal concentrations is detrimental also for the underlying physiological responses. They also highlight a specific window of memory processing, i.e. encoding, which is sensitive to cannabinoid modulation.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 271157-1083, USA.
authors.forename: Anushka V
authors.initials: AV
authors.lastname: Goonawardena
authors.forename: John
authors.initials: J
authors.lastname: Sesay
authors.forename: Cheryl Ann
authors.initials: CA
authors.lastname: Sexton
authors.forename: Gernot
authors.initials: G
authors.lastname: Riedel
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hampson
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000502:physiology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D055724:Electrophysiological Phenomena / Q000187:drug effects / Q000502:physiology; D063388:Endocannabinoids; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D058990:Molecular Targeted Therapy; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D053284:Polyunsaturated Alkamides / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide; C107594:N-(4-hydroxyphenyl)arachidonylamide