Synergistic activity between the delta-opioid agonist SNC80 and amphetamine occurs via a glutamatergic NMDA-receptor dependent mechanism

NEUROPHARMACOLOGY

卷:77

Article

Bosse, Kelly E.¹  Jutkiewicz, Emily M.¹  Schultz-Kuszak, Kristin N.²  Mabrouk, Omar S.²  Kennedy, Robert T.^1,2  Gnegy, Margaret E.¹  Traynor, John R.¹ 

[1] Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA

关键词: SNC80;    Amphetamine;    Delta opioid receptor;    Dopamine;    Glutamate;    GABA;   

DOI  :  10.1016/j.neuropharm.2013.08.027

来源: Elsevier

【 摘 要 】

Glutamate is known to cause the release of dopamine through a Ca2+-sensitive mechanism that involves activation of NMDA ionotropic glutamate receptors. In the current study, we tested the hypothesis that the delta opioid agonist SNC80 acts indirectly, via the glutamatergic system, to enhance both amphetamine-stimulated dopamine efflux from striatal preparations and amphetamine-stimulated locomotor activity. SNC80 increased extracellular glutamate content, which was accompanied by a concurrent decrease in GABA levels. Inhibition of NMDA signaling with the selective antagonist MK801 blocked the enhancement of both amphetamine-induced dopamine efflux and hyperlocomotion observed with SNC80 pretreatment. Addition of exogenous glutamate also potentiated amphetamine-stimulated dopamine efflux in a Mg2+- and MK801-sensitive manner. After removal of Mg2+ to relieve the ion conductance inhibition of NMDA receptors, SNC80 both elicited dopamine release alone and produced a greater enhancement of amphetamine-evoked dopamine efflux. The action of SNC80 to enhance amphetamine-evoked dopamine efflux was mimicked by the GABAB antagonist 2-hydroxysaclofen. These cumulative findings suggest SNC80 modulates amphetamine-stimulated dopamine efflux through an intra-striatal mechanism involving inhibition of GAB(A) transmission leading to the local release of glutamate followed by subsequent activation of NMDA receptors. (C) 2013 Published by Elsevier Ltd.

【 授权许可】

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