Involvement of sigma receptors in the modulation of the glutamatergic/NMDAneurotransmission in the dopaminergic systems

Extracellular single-unit recordings and iontophoresis were used to examine the effects of different selective a receptor ligands on dopaminergic and glutamatergic N-methyl-D-aspartate (NMDA) neurotransmissions both in origin (A10 and A9 areas) and terminal (nucleus accumbens and caudate nucleus) re gions of the rat mesolimbic and nigrostriatal. dopaminergic systems. The se lective a, receptor ligands 2-[4-(4-methoxy-benzyl)piperazin-1-yl-methyl]4- oxo[4H]-benzo-thiazolin-2-one (S-21377), systemically administered (1.2 mg/ kg, i.v., cumulative dose), and 2[(4-benzyl piperazin-l-yl) methyl] naphtha lene, dichiorydrate (S-21378), iontophoretically applied, slightly increase d the spontaneous firing rate and potentiated the NMDA-induced neuronal act ivation of dopaminergic neurons in the A9 and A10 regions. (+)N-cyclopropyl methyl-N-methyl-1,4-diphenyl-1-ethyl-butyl-2-N (JO-1784), another selective sigma(1) receptor ligand produced no or little effect in these areas. The systemic administration of the selective sigma(2) receptor ligand 1,4-bis-s piro[isobenzofuran-1(3H), 4'-piperidin-1'yl]butane (Lu 29-252) (2 mg/kg, i. v., cumulative dose) did not modify the firing activity of A9 and A10 dopam inergic neurons, but significantly potentiated the NMDA-induced increase in firing activity of A10 dopaminergic neurons. None of the a receptor ligand s tested had any effects on the dopamine-induced suppression of firing. In the nucleus accumbens, the systemic administration of (JO-1784), (40 mu g/k g, i.v.), (+)-pentazocine (30 mu g/kg, i.v.), another selective sigma(1) re ceptor ligand, and of the non selective sigma(1) receptor ligand di-tolyl-g uanidine (DTG) (20 mu g/i.v.) produced a significant increase of NMDA-induc ed neuronal activation. Microiontophoretic applications of JO-1784 also pot entiated the NMDA response. They also increased significantly the suppressa nt effect of dopamine on NMDA and kainate-induced activations of accumbens neurons. In the caudate nucleus, (+)-pentazocine, but not JO-1784, potentia ted slightly the neuronal response to NMDA. None of the sigma receptor liga nds tested did modify significantly the responses of caudate and accumbens neurons to kainate. These findings suggest that at least two subtypes of a, receptors may affect differentially the glutamate NMDA neurotransmission i n the terminal and origin regions of the mesolimbic and nigrostriatal dopam inergic systems. These results also demonstrate the existence of a function al interaction between sigma(2) and NMDA receptors in the A10 region. (C) 1 999 Elsevier Science B.V. All rights reserved.