Ethanol effects of NMDA-stimulated levels of extracellular neurotransmitters by in vivo microdialysis.

To determine whether the inhibition of NMDA receptor function by ethanol observed in vitro may be reflected in vivo, we measured the effects of ethanol administration on levels of extracellular dopamine (DA) using a microdialysis method. Rats were implanted with a guide cannula under anesthesia one week prior to placement of a microdialysis probe into the striatum. At a perfusion rate of 2 microliters/min recovery of DA from a standard solution was typically 20-25%. Basal levels of dialysate DA were approximately 0.5 pg/microliter. NMDA infusion into the striatum of an awake rat caused a concentration-dependent stimulation of extracellular DA levels. A one hour infusion of NMDA caused increases in dialysate DA from 2.3-50 fold over basal at concentrations from 0.3-10 mM. MK-801 (25 microM), AP-5 (10 microM), and DNQX (10 microM) significantly inhibited the stimulation of extracellular DA levels by 1 mM NMDA for 10 minutes. This suggests complex regulation of extracellular DA levels in the striatum by NMDA. Ethanol (0.5-3 g/kg, i.p.) did not alter the extracellular DA levels in the striatum. Furthermore, ethanol administration had no significant effects on DA levels in striatal dialysates when stimulated by infusion of 1 mM NMDA for 10 minutes. Our results suggest that ethanol's actions on extracellular DA levels in vivo in the striatum may not be predicted from a single effect of ethanol on one transmitter receptor system but depend on the integration of multiple signals in this brain region.

Cholinergic modulation of N-methyl-D-aspartate-evoked [3H]norepinephrine release from rat cortical slices.

Previous work has shown that N-methyl-D-aspartate (NMDA) receptor activation inhibits muscarinic receptor-mediated phosphoinositide hydrolysis in brain slices. To further explore the potential interactions between NMDA receptors and cholinergic receptors, the effects of cholinergic agonists and NMDA on [3H]norepinephrine (NE) release from rat cortical slices were determined. Slices were labeled with [3H]NE, washed and treated with various agonists by transferring the slices through a series of vials at 1-min intervals. Radioactivity remaining in the medium was then quantitated to determine the fractional release of [3H]NE from the slices. Carbachol (30-3000 microM) slightly stimulated [3H]NE release from a basal level of 0.10 to approximately 0.35 fractional release by itself and significantly enhanced the effect of 250 microM NMDA (3.6 fractional release for NMDA and 5.3 for carbachol + NMDA) in a concentration-dependent manner. Carbachol (1 mM) increased the maximal response but had no effect on the EC50 of NMDA. Atropine (1 microM) significantly attenuated the effect of carbachol alone and the potentiation of NMDA-evoked [3H]NE release by carbachol, whereas d-tubocurarine (10 microM) inhibited the effect of carbachol alone but had no effect on the enhancement of the NMDA response by carbachol. Mecamylamine (100 microM) inhibited the effect of carbachol alone, but also inhibited the NMDA-evoked response with an IC50 of 16 microM. The nicotinic agonist, dimethylphenylpiperazinium (DMPP) stimulated [3H]NE release (approximately 0.4 fractional release at 30 microM) and also potentiated NMDA-stimulated [3H]NE release (2.0 above NMDA alone). d-Tubocurarine, but not atropine, partially inhibited DMPP-stimulated [3H]NE release, but neither antagonist altered the enhancement of NMDA-stimulated [3H]NE release by DMPP.(ABSTRACT TRUNCATED AT 250 WORDS)