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1.
Neuropharmacology ; 77: 19-27, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24035916

RESUMO

Glutamate is known to cause the release of dopamine through a Ca(2+)-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 Mg(2+)- and MK801-sensitive manner. After removal of Mg(2+) 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 GABA(B) antagonist 2-hydroxysaclofen. These cumulative findings suggest SNC80 modulates amphetamine-stimulated dopamine efflux through an intra-striatal mechanism involving inhibition of GABA transmission leading to the local release of glutamate followed by subsequent activation of NMDA receptors.


Assuntos
Anfetamina/farmacologia , Analgésicos Opioides/farmacologia , Benzamidas/farmacologia , Corpo Estriado/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Piperazinas/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Opioides delta/agonistas , Animais , Corpo Estriado/metabolismo , Maleato de Dizocilpina/farmacologia , Dopamina/metabolismo , Sinergismo Farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Ácido gama-Aminobutírico/metabolismo
2.
Neuropsychopharmacology ; 38(9): 1770-9, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23542927

RESUMO

Kappa-opioid receptors (KORs) are important for motivation and other medial prefrontal cortex (mPFC)-dependent behaviors. Although KORs are present in the mPFC, their role in regulating transmission in this brain region and their contribution to KOR-mediated aversion are not known. Using in vivo microdialysis in rats and mice, we demonstrate that intra-mPFC administration of the selective KOR agonist U69,593 decreased local dopamine (DA) overflow, while reverse dialysis of the KOR antagonist nor-Binaltorphimine (nor-BNI) enhanced mPFC DA overflow. Extracellular amino-acid levels were also affected by KORs, as U69,593 reduced glutamate and GABA levels driven by the glutamate reuptake blocker, l-trans-pyrrolidine-2,4-dicarboxylate. Whole-cell recordings from mPFC layer V pyramidal neurons revealed that U69,593 decreased the frequency, but not amplitude, of glutamatergic mini EPSPs. To determine whether KOR regulation of mPFC DA overflow was mediated by KOR on DA terminals, we utilized a Cre recombinase-driven mouse line lacking KOR in DA neurons. In these mice, basal DA release or uptake was unaltered relative to controls, but attenuation of mPFC DA overflow by local U69,593 was not observed, indicating KOR acts directly on mPFC DA terminals to locally inhibit DA levels. Conditioning procedures were then used to determine whether mPFC KOR signaling was necessary for KOR-mediated aversion. U69,593-mediated conditioned place aversion was blocked by intra-mPFC nor-BNI microinjection. These findings demonstrate that mPFC KORs negatively regulate DA and amino-acid neurotransmission, and are necessary for KOR-mediated aversion.


Assuntos
Aprendizagem da Esquiva/fisiologia , Córtex Pré-Frontal/fisiologia , Receptores Opioides kappa/fisiologia , Transmissão Sináptica/fisiologia , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Benzenoacetamidas/administração & dosagem , Benzenoacetamidas/farmacologia , Ácidos Dicarboxílicos/antagonistas & inibidores , Ácidos Dicarboxílicos/farmacologia , Dopamina/metabolismo , Interações Medicamentosas , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Ácido Glutâmico/metabolismo , Ácido Glutâmico/farmacologia , Masculino , Camundongos , Camundongos Knockout , Microinjeções , Potenciais Pós-Sinápticos em Miniatura/efeitos dos fármacos , Naltrexona/administração & dosagem , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/farmacologia , Inibidores da Captação de Neurotransmissores/antagonistas & inibidores , Inibidores da Captação de Neurotransmissores/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Pirrolidinas/administração & dosagem , Pirrolidinas/antagonistas & inibidores , Pirrolidinas/farmacologia , Ratos , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides kappa/genética , Transmissão Sináptica/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo
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