Enaminones and norepinephrine employ convergent mechanisms to depress excitatory synaptic transmission in the rat nucleus accumbens in vitro.
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.
Kombian
Samuel B
SB
Department of Applied Therapeutics, Faculty of Pharmacy, Health Sciences Centre, Kuwait University, PO Box 24923, Safat 13110, Kuwait. kombian@hsc.edu.kw
Ananthalakshmi
Kethireddy V V
KV
Edafiogho
Ivan O
IO
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
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