Neuroprotective interaction effects of NMDA and AMPA receptor antagonists in an in vitro model of cerebral ischemia.

An in vitro model of ischemia was developed and characterized using the acute rat hippocampal slice preparation. Neuroprotective concentrations of several competitive and noncompetitive glutamate subtype-selective antagonists (CGS-19755, MK-801, YM90K and GYKI-52466) were initially determined in anoxia-enhanced agonist-induced excitotoxicity experiments. Concentrations which proved to be effective in these studies were subsequently tested for their effectiveness against an ischemic episode. Ischemia was defined as a 30-min exposure to aglycemic media ending in 5 min of concurrent anoxia, a protocol which was arrived at by empirically determining the effect of various hypoglycemic and anoxic insults on the ability of hippocampal slices to retain their electrophysiological viability. Exposure to such an ischemic episode resulted in a loss of viability by most slices, an effect which was strongly dependent on extracellular calcium. AMPA antagonists applied alone produced no neuroprotective effect in the present model of in vitro ischemia, while NMDA antagonists applied alone had a modest neuroprotective effect. In contrast, the coapplication of 10 microM MK-801 and 300 microM GYKI-52466, noncompetitive NMDA and AMPA receptor antagonists, respectively, resulted in almost complete neuroprotection. This protection was comparable to that obtained by withholding extracellular calcium, indicating that the toxic effects of glutamate receptor overstimulation can be accounted for solely by calcium influx. The effect of this combination treatment on the survival rate of hippocampal slices was synergistic, that is greater than the sum of the effects of the individual compounds. The results indicate that neuroprotection against acute ischemic insults may require a combination therapy approach.

Histamine in brain may have no role for histaminergic control of food-related drinking in the rat.

Adult male Sprague-Dawley rats surgically fitted with a cannula positioned in the third cerebral ventricle were tested for drinking after exogenous histamine or after eating with or without antagonism of H1 and/or H2 receptors for histamine using intracerebroventricular (ICV) dexbrompheniramine (DXB; 12.5-50 micrograms) or cimetidine (C; 25-100 micrograms). Histamine (0.06-16 micrograms) given ICV failed to elicit drinking. For rats drinking in response to subcutaneous (SC) histamine, ICV DXB alone did not affect drinking, whereas ICV DXB plus C, and ICV C given alone inhibited drinking. Such inhibition appeared to be relatively selective for drinking elicited by SC histamine, because ICV 50 micrograms DXB plus 100 micrograms C abolished drinking elicited by SC histamine, but failed to inhibit drinking after 12-hr water deprivation. When rats ate and drank after food deprivation, ICV DXB alone and ICV DXB plus C did not significantly inhibit food-related water intake. The inhibition of food-related drinking by ICV 100 micrograms C given alone was accompanied by inhibition of eating. In summary, histamine had unimpressive dipsogenic effects when given ICV, ICV DXB and C inhibited drinking elicited by SC histamine, but ICV DXB and C failed to inhibit food-related drinking in a manner parallel to the selective effects of intraperitoneal injection of these drugs on drinking elicited by eating. This suggests that it is histamine and histamine receptors in the periphery rather than in brain that have the predominant role for a histaminergic mechanism for drinking elicited by eating in the rat, but our findings do not rule out a role(s) for histamine in brain in the control of ingestive behavior.