Localization and mechanisms of action of cannabinoid receptors at the glutamatergic synapses of the mouse nucleus accumbens.
Despite the role of excitatory transmission to the nucleus accumbens (NAc) in the actions of most drugs of abuse, the presence and functions of cannabinoid receptors (CB1) on the glutamatergic cortical afferents to the NAc have never been explored. Here, immunohistochemistry has been used to show the localization of CB1 receptors on axonal terminals making contacts with the NAc GABAergic neurons. Electrophysiological techniques in the NAc slice preparation revealed that cannabimimetics [WIN 55,212,2 (WIN-2) and CP55940] strongly inhibit stimulus-evoked glutamate-mediated transmission. The inhibitory actions of WIN-2 were dose-dependent (EC(50) of 293 +/- 13 nm) and reversed by the selective CB1 antagonist SR 141716A. In agreement with a presynaptic localization of CB1 receptors, WIN-2 increased paired-pulse facilitation, decreased miniature EPSC (mEPSC) frequency, and had no effect on the mEPSCs amplitude. Perfusion with the adenylate cyclase activator forskolin enhanced glutamatergic transmission but did not alter presynaptic CB1 actions, suggesting that cannabinoids inhibit glutamate release independently from the cAMP-PKA cascade. CB1 did not reduce evoked transmitter release by inhibiting presynaptic voltage-dependent Ca(2+) currents through N-, L-, or P/Q-type Ca(2+) channels, because CB1 inhibition persisted in the presence of omega-Conotoxin-GVIA, nimodipine, or omega-Agatoxin-IVA. The K(+) channel blockers 4-aminopyridine (100 micrometer) and BaCl(2) (300 micrometer) each reduced by 40-50% the inhibitory actions of WIN-2, and their effects were additive. These data suggest that CB1 receptors are located on the cortical afferents to the nucleus and can reduce glutamate synaptic transmission within the NAc by modulating K(+) channels activity.
Robbe
D
D
Centre National de la Recherche Scientifique Unité Propre de Recherche 9023 and Unité Mixte de Recherche 5101, 34094 Montpellier Cedex 05, France.
Alonso
G
G
Duchamp
F
F
Bockaert
J
J
Manzoni
O J
OJ
D000200:Action Potentials / Q000187:drug effects; D000344:Afferent Pathways / Q000166:cytology / Q000000981:diagnostic imaging* / Q000378:metabolism; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology; D002525:Cerebellar Cortex / Q000166:cytology / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers; D017729:Presynaptic Terminals / Q000378:metabolism; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D014463:Ultrasonography
D002121:Calcium Channel Blockers; D002186:Cannabinoids; D026902:Potassium Channel Blockers; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D017470:Receptors, Glutamate; D005576:Colforsin; D018698:Glutamic Acid; D011188:Potassium