title: Enaminones and norepinephrine employ convergent mechanisms to depress excitatory synaptic transmission in the rat nucleus accumbens in vitro.
abstract: We recently reported that anticonvulsant anilino enaminones depress excitatory postsynaptic currents (EPSCs) in the nucleus accumbens (NAc) indirectly via gamma-aminobutyric acid (GABA) acting on GABA(B) receptors [S.B. Kombian et al. (2005)Br. J. Pharmacol., 145, 945-953]. Norepinephrine (NE) and dopamine (DA), both known to be involved in seizure disorders, also depress EPSCs in this nucleus. The current study explored a possible interaction between enaminones and adrenergic and/or dopaminergic mechanisms that may contribute to their synaptic depression and anticonvulsant effect. Using whole-cell recording in rat forebrain slices containing the NAc, we show that NE-induced, but not DA-induced, EPSC depression occludes E139-induced EPSC depressant effect. UK14,304, a selective alpha(2) receptor agonist, mimicked the synaptic effect of NE and also occluded E139 effects. Phentolamine, a non-selective alpha-adrenergic antagonist that blocked NE-induced EPSC depression, also blocked the E139-induced EPSC depression. Furthermore, yohimbine, an alpha(2)-adrenoceptor antagonist, also blocked the E139-induced EPSC depression, while prazosin, a selective alpha(1)-adrenergic antagonist, and propranolol, a non-selective beta-adrenoceptor antagonist, did not block the E139 effect. Similar to the E139-induced EPSC depression, the NE-induced EPSC depression was also blocked by the GABA(B) receptor antagonist, CGP55845. By contrast, however, neither SCH23390 nor sulpiride, D1-like and D2-like DA receptor antagonists, respectively, blocked the E139-induced synaptic depression. These results suggest that NE and E139, but not DA, employ a similar mechanism to depress EPSCs in the NAc, and support the hypothesis that E139, like NE, may act on alpha(2)-adrenoceptors to cause the release of GABA, which then mediates synaptic depression via GABA(B) receptors.
authors.affiliation: Department of Applied Therapeutics, Faculty of Pharmacy, Health Sciences Centre, Kuwait University, PO Box 24923, Safat 13110, Kuwait. kombian@hsc.edu.kw
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Kombian
authors.forename: Kethireddy V V
authors.initials: KV
authors.lastname: Ananthalakshmi
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Edafiogho
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000068438:Brimonidine Tartrate; D003510:Cyclohexanes / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D018756:GABA Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D009638:Norepinephrine / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000166:cytology* / Q000187:drug effects / Q000528:radiation effects; D010721:Phosphinic Acids / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects* / Q000528:radiation effects
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D003510:Cyclohexanes; C482385:E139 compound; D018756:GABA Antagonists; D010721:Phosphinic Acids; D011412:Propanolamines; D011810:Quinoxalines; C085075:CGP 55845A; D000068438:Brimonidine Tartrate; D004298:Dopamine; D009638:Norepinephrine; D011224:Prazosin