title: Role of the cyclic-AMP/PKA cascade and of P/Q-type Ca++ channels in endocannabinoid-mediated long-term depression in the nucleus accumbens.
abstract: Glutamate transmission between prefrontal cortex (PFC) and accumbens (NAc) plays a crucial role in the establishment and expression of addictive behaviors. At these synapses exogenous cannabinoid receptor 1 (CB1R) agonists reversibly inhibit excitatory transmission, and the sustained release of endogenous cannabinoids (eCB) following prolonged cortical stimulation leads to long-term depression (LTD). Activation of presynaptic K(+) channels mediates the effects of exocannabinoids, but the transduction pathway underlying the protracted phase of eCB-LTD is unknown. Here we report that the maintenance of eCB-LTD does not involve presynaptic K(+) channels: eCB-LTD was not affected by blockade of K(+) channels with 4-AP (100 microM) and BaCl(2) (300 microM) (fEPSP=78.9+/-5.4% of baseline 58-60 min after tetanus, compared to 78.9+/-5.9% in control slices). In contrast, eCB-LTD was blocked by treatment of the slices with the adenylyl cyclase (AC) activator forskolin (10 microM), and with the protein kinase A (PKA) inhibitor KT5720 (1 microM) (fEPSP=108.9+/-5.7% in forskolin and 110.5+/-7.7% in KT5720, compared to 80.6+/-3.9% in control conditions). Additionally, selective blockade of P/Q-type Ca(2+) channels with omega-agatoxin-IVA (200 nM) occluded the expression of eCB-LTD (fEPSP=113.4+/-15.9% compared to 78.6+/-4.4% in control slices), while blockade of N- with omega-conotoxin-GVIA (1 microM) or L-type Ca(2+) channels with nimodipine (1 microM), was without effect (fEPSP was 83.7+/-5.3% and 87+/-8.9% respectively). These data show that protracted inhibition of AC/PKA activity and P/Q-type Ca(2+) channels are necessary for expression of eCB-LTD at NAc synapses.
authors.affiliation: INSERM U862 Equipe Physiopathologie de la Plasticité Synaptique, 146 Rue Léo-Saignat, 33077 Bordeaux Cedex, France.
authors.forename: Susana
authors.initials: S
authors.lastname: Mato
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lafourcade
authors.forename: David
authors.initials: D
authors.lastname: Robbe
authors.forename: Yamina
authors.initials: Y
authors.lastname: Bakiri
authors.forename: Olivier J
authors.initials: OJ
authors.lastname: Manzoni
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D000818:Animals; D017609:Barium Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020865:Calcium Channels, P-Type / Q000502:physiology*; D063385:Cannabinoid Receptor Modulators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004558:Electric Stimulation / Q000379:methods; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D017609:Barium Compounds; D002121:Calcium Channel Blockers; D020865:Calcium Channels, P-Type; D063385:Cannabinoid Receptor Modulators; D002227:Carbazoles; D002712:Chlorides; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D007211:Indoles; D026902:Potassium Channel Blockers; D011758:Pyrroles; C024986:barium chloride; D005576:Colforsin; C057416:KT 5720; D015761:4-Aminopyridine; D000242:Cyclic AMP; D002118:Calcium