Involvement of sigma receptors in the modulation of the glutamatergic/NMDA neurotransmission in the dopaminergic systems.

Extracellular single-unit recordings and iontophoresis were used to examine the effects of different selective sigma 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) regions of the rat mesolimbic and nigrostriatal dopaminergic systems. The selective sigma1 receptor ligands 2-[4-(4-methoxy-benzyl)piperazin-1-yl-methyl]4-oxo[4H]-benzo-th iazolin-2-one (S-21377), systemically administered (1.2 mg/kg, i.v., cumulative dose), and 2[(4-benzyl piperazin-1-yl) mothyl] naphthalene, dichiorydrate (S-21378), iontophoretically applied, slightly increased the spontaneous firing rate and potentiated the NMDA-induced neuronal activation of dopaminergic neurons in the A9 and A10 regions. (+)N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethyl-butyl-2-N (JO-1784), another selective sigma1 receptor ligand produced no or little effect in these areas. The systemic administration of the selective sigma2 receptor ligand 1,4-bis-spiro[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 dopaminergic neurons, but significantly potentiated the NMDA-induced increase in firing activity of A10 dopaminergic neurons. None of the sigma receptor ligands tested had any effects on the dopamine-induced suppression of firing. In the nucleus accumbens, the systemic administration of (JO-1784), (40 microg/kg, i.v.), (+)-pentazocine (30 microg/kg, i.v.), another selective sigma1 receptor ligand, and of the non selective sigma1 receptor ligand di-tolyl-guanidine (DTG) (20 microg/i.v.) produced a significant increase of NMDA-induced neuronal activation. Microiontophoretic applications of JO-1784 also potentiated the NMDA response. They also increased significantly the suppressant effect of dopamine on NMDA and kainate-induced activations of accumbens neurons. In the caudate nucleus, (+)-pentazocine, but not JO-1784, potentiated slightly the neuronal response to NMDA. None of the sigma receptor ligands tested did modify significantly the responses of caudate and accumbens neurons to kainate. These findings suggest that at least two subtypes of sigma1 receptors may affect differentially the glutamate NMDA neurotransmission in the terminal and origin regions of the mesolimbic and nigrostriatal dopaminergic systems. These results also demonstrate the existence of a functional interaction between sigma2 and NMDA receptors in the A10 region.