title: Cannabinoids depress inhibitory synaptic inputs received by layer 2/3 pyramidal neurons of the neocortex.
abstract: Using whole cell voltage-clamp recordings we investigated the effects of a synthetic cannabinoid (WIN55,212-2) on inhibitory inputs received by layer 2/3 pyramidal neurons in slices of the mouse auditory cortex. Activation of the type 1 cannabinoid receptor (CB1R) with WIN55,212-2 reliably reduced the amplitude of GABAergic inhibitory postsynaptic currents evoked by extracellular stimulation within layer 2/3. The suppression of this inhibition was blocked and reversed by the highly selective CB1R antagonist AM251, confirming a CB1R-mediated inhibition. Pairing evoked inhibitory postsynaptic currents (IPSCs) at short interstimulus intervals while applying WIN55,212-2 resulted in an increase in paired-pulse facilitation suggesting that the probability of GABA release was reduced. A presynaptic site of cannabinoid action was verified by an observed decrease in the frequency with no change in the amplitude or kinetics of action potential-independent postsynaptic currents (mIPSCs). When Cd(2+) was added or Ca(2+) was omitted from the recording solution, the remaining fraction of Ca(2+)-independent mIPSCs did not respond to WIN55,212-2. These data suggest that cannabinoids are capable of suppressing the inhibition of neocortical pyramidal neurons by depressing Ca(2+)-dependent GABA release from local interneurons.
authors.affiliation: Department of Pharmacology and Program in Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Trettel
authors.forename: Eric S
authors.initials: ES
authors.lastname: Levine
mesh_terms: D000818:Animals; D001303:Auditory Cortex / Q000502:physiology*; D048588:Benzoxazines; D002186:Cannabinoids / Q000494:pharmacology*; D004594:Electrophysiology; D066298:In Vitro Techniques; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D009433:Neural Inhibition / Q000187:drug effects*; D017966:Pyramidal Cells / Q000502:physiology*; D013569:Synapses / Q000187:drug effects* / Q000502:physiology*
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone