Group II Metabotropic Glutamate Receptors Modulate Extracellular Glutamate in the Nucleus Accumbens

Abstract

The regulation of extracellular glutamate in the nucleus accumbens by group II metabotropic glutamate receptors (mGluR2/3) was examined in vivo. Stimulation of mGluR2/3 with 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC) or N-acetylaspartylglutamate reduced extracellular glutamate levels. Conversely, blockade of mGluR2/3 by LY143495 or (RS)-1-amino-5-phosphonoindan-1-carboxylic acid (APICA) increased extracellular glutamate, an effect antagonized by the coadministration of APDC. These effects likely involve both vesicular and nonvesicular glutamate, because the increase in glutamate by APICA or the decrease by APDC was prevented by blocking N-type calcium channels and the release of glutamate after potassium-induced membrane depolarization was antagonized by APDC. In addition, blockade of the cystine-glutamate exchange, a major nonvesicular source of extracellular glutamate, by (S)-4-carboxyphenylglycine blocked the effects induced by either APDC or APICA. However, blockade of Na ϩ channels by tetrodotoxin or Na ϩ -dependent glutamate transporters by DL-threo-␤-benzyloxyaspartate failed to affect the alterations in extracellular glutamate by APICA or APDC, respectively. Group II mGluRs are G i -coupled and coperfusion with the cAMP-dependent protein kinase (PKA) activator Sp-cAMPS blocked the reduction in glutamate by APDC and the PKA inhibitor Rp-cAMPS prevented the elevation in glutamate by APICA. Taken together, these data support three conclusions: 1) group II mGluRs regulate both vesicular and nonvesicular release of glutamate in the nucleus accumbens, 2) there is tonic in vivo stimulation of mGluR2/3 by endogenous glutamate, and 3) modulation of group II mGluRs of extracellular glutamate is Ca 2ϩ -and PKAdependent.

Toluene-Induced Locomotor Activity is Blocked by 6-Hydroxydopamine Lesions of the Nucleus Accumbens and the mGluR2/3 Agonist LY379268

“…The present finding that LY379268, a selective mGlu2/3 agonist, attenuated toluene-induced activity further suggests that mGlu receptors (mGluRs) may be recruited subsequent to the toluene-induced increase in DA neurotransmission (Cartmell and Schoepp, 2000;Xi et al, 2002). Typically inactive, mGluRs function as autoreceptors during elevated neuronal activity to attenuate DA, GABA, glutamate, and acetylcholine release (Cartmell and Schoepp, 2000).…”

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

“…It is synthesized enzymatically from NAA and glutamate (Arun et al, 2006;Boltshauser et al, 2004;Cangro et al, 1987;Gehl et al, 2004) and is localized in specific types of neurons throughout the CNS (Anderson et al, 1987;Moffett et al, 1993;Moffett and Namboodiri, 1995;Tieman et al, 1991;Tieman and Tieman, 1996). NAAG is released from synapses in a calcium dependent manner (Williamson et al, 1991), and acts through presynaptic metabotropic glutamate receptors to modulate the release of classical neurotransmitters (Xi et al, 2002;Zhao et al, 2001). NAAG biosynthesis has been studied for over three decades, but the biosynthetic and regulatory mechanisms involved remain poorly understood.…”

Contribution of Cystine–Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

“…Studies utilizing microdialysis in the nucleus accumbens or electrophysiological recordings from acute prefrontal cortical or nucleus accumbens tissue slices indicate that nonvesicular glutamate release from cystineglutamate exchange stimulates extrasynaptic group II metabotropic glutamate receptors (mGluR) (Baker et al, 2002;Xi et al, 2002a;Moran et al, 2005). Because group II mGluRs function as autoreceptors (Baskys and Malenka, 1991;Cochilla and Alford, 1998;Hu et al, 1999b;Schoepp, 2001;Valenti et al, 2002;Xi et al, 2002b), extrasynaptic glutamate maintained by cystine-glutamate exchange negatively modulates synaptic release of glutamate (Moran et al, 2005).…”