Cannabinoids inhibit the formation of new synapses between hippocampal neurons in culture.
The principal psychoactive ingredient in marijuana, Delta(9)-tetrahydrocannabinol, has been shown to inhibit adenylyl cyclase activity in vitro and can lead to impairment of memory in vivo. cAMP-induced changes in synaptic plasticity are thought to underlie memory formation. We examined the effects of cannabinoid receptor agonists on forskolin-induced formation of new synapses between rat hippocampal neurons in culture. Functional synaptic boutons were identified with FM1-43-based digital imaging. Cannabimimetic drugs prevented the recruitment of new synapses by inhibiting the formation of cAMP. The inhibition produced by Win55212-2, a synthetic cannabinoid receptor agonist, was stereoselective and was reversed by a selective CB1 receptor antagonist. Both Delta(9)-tetrahydrocannabinol and the endogenous ligand, anandamide, inhibited the formation of new synapses. Win55212-2 blocked the formation of new synapses induced by forskolin, but not those evoked by a membrane permeant cAMP analog. Thus, activation of cannabinoid receptors can modulate synaptic plasticity independent of direct effects on neurotransmitter release. Preventing the formation of new synapses may contribute to the impairment of memory produced by cannabinoids.
Kim
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Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455-0217, USA.
Thayer
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SA
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D048588:Benzoxazines; D002186:Cannabinoids / Q000494:pharmacology*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D013759:Dronabinol / Q000494:pharmacology; D063388:Endocannabinoids; D005456:Fluorescent Dyes; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D017729:Presynaptic Terminals / Q000187:drug effects / Q000648:ultrastructure; D011720:Pyrazoles / Q000494:pharmacology; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; D051381:Rats; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000037:antagonists & inhibitors; D000077285:Rimonabant; D013569:Synapses / Q000187:drug effects* / Q000648:ultrastructure
D001095:Arachidonic Acids; D048588:Benzoxazines; D002186:Cannabinoids; D063388:Endocannabinoids; C073804:FM1 43; D005456:Fluorescent Dyes; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D005576:Colforsin; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; D000242:Cyclic AMP; D000077285:Rimonabant; C078814:anandamide