Delta(9)-THC-induced cognitive deficits in mice are reversed by the GABA(A) antagonist bicuculline.
BACKGROUND
The results of recent in vitro studies have underscored the important role that activation of CB(1) receptors has on GABAergic activity in brain areas associated with memory.


OBJECTIVE
The primary purpose of this study was to test the hypothesis that the memory disruptive effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) in vivo are mediated through GABAergic systems. Conversely, we also evaluated whether blocking CB(1) receptor signaling would alter memory deficits elicited by GABA agonists.


METHODS
The GABA(A) antagonist bicuculline and GABA(B) antagonist CGP 36742 were evaluated for their ability to ameliorate Delta(9)-THC-induced deficits in a mouse working memory Morris water maze task. Mice were also assessed in a T-maze task, as well as non-cognitive behavioral assays. Additionally, the effects of GABA(A) and GABA(B) agonists were assessed in either CB(1) (-/-) mice or wild type mice treated with the CB(1) antagonist SR 141716.


RESULTS
Memory deficits resulting from 10 mg/kg Delta(9)-THC in the Morris water maze were completely reversed by bicuculline, though unaffected by CGP 36742. Bicuculline also blocked the disruptive effects of Delta(9)-THC in the T-maze, but failed to alter non-mnemonic effects of Delta(9)-THC. Although CB(1) (-/-) mice exhibited supersensitivity to muscimol-induced water maze deficits compared with wild type control mice, muscimol elicited virtually identical effects in SR 141716-treated and vehicle-treated wild type mice.


CONCLUSIONS
This is the first demonstration of which we are aware showing that GABA(A) receptors may play a necessary role in Delta(9)-THC-induced memory impairment in whole animals.
Department of Pharmacology, VCU, PO Box 980613, Richmond, VA 23298, USA. savarvel@vcu.edu
S A
SA
Varvel
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Anum
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Niyuhire
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Wise
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Lichtman
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects; D013759:Dronabinol / Q000633:toxicity*; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D008297:Male; D002189:Marijuana Abuse / Q000523:psychology*; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects; D011939:Mental Recall / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009118:Muscimol / Q000633:toxicity; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010641:Phenotype; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics
D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D009943:Organophosphorus Compounds; D043884:Receptor, Cannabinoid, CB1; C079148:(3-aminopropyl)(n-butyl)phosphinic acid; D009118:Muscimol; D013759:Dronabinol; D001418:Baclofen; D001640:Bicuculline