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.

Norepinephrine and E139 Interactions on Epileptiform Activity in the Rat Hippocampus in vitro

“…Our data on fieldrecorded PS whereby both NE and E139 suppressed the amplitude that mutually occluded each other are consistent with our previous finding in single-cell studies [6] . Analyses of the synaptic component (initial rising phase) of the PS indicate that suppression of this phase contributed the most to the entire PS suppression since for both NE and E139, the latter suppression was not significantly different from the suppression of the initial rising phase.…”

“…By recording whole-cell currents from single cells, we recently reported that NE-induced depression of excitatory synaptic transmission occluded that induced by E139 [6] suggesting that E139 may employ mechanisms similar to NE to produce its reported in vivo anticonvulsant effects. In a recent study, we also showed that E139 suppresses electrically and chemically induced epileptiform activity recorded in rat hippocampal slices [5] .…”

Anti-tussive and bronchodilator mechanisms of action for the enaminone E121

“…Some analogs were found to be protective against generalized tonic-clonic and complex partial seizures in rats and mice Scott et al, 1995). These anticonvulsant effects may be through GABAergic (Kombian et al, 2005), adrenergic Kombian et al, 2006;Kombian et al, 2008) or sodium channel blocking mechanisms . Based on these central effects, some of which have been previously linked to antitussive effects (Callaway and King, 1992;Bolser et al, 1994), we hypothesized that enaminones may be good therapeutic agents for the treatment of cough.…”

Direct intra-accumbal infusion of a beta-adrenergic receptor antagonist abolishes WIN 55,212-2-induced aversion

“…β1-AR is a G-protein coupled receptor that stimulates Gs, and whose activation can increase glutamate-mediated excitation of medium spiny neurons (MSN) in the Acb [9]. It is hypothesized that activation of MSN can trigger the development of aversive responses while inactivation of MSN can trigger reward responses [2].…”