u-50488 and Amnesia

The effects of systemic or intracerebroventricular injection of dynorphin A-(1-13), a kappa-selective opioid receptor agonist, on cycloheximide-induced amnesia were investigated by using a step-down-type passive avoidance task in mice. The intracerebroventricular injection of dynorphin A-(1-13) (0.3-3 micrograms) before training significantly prolonged step-down latency. The systemic administration of dynorphin A-(1-13) (1, 3 and/or 10 mg/kg, i.p.) before training or retention tests markedly inhibited the cycloheximide (30 mg/kg, s.c.)-induced shortening of step-down latency, indicating antiamnesic effects of dynorphin A-(1-13). One and 3 mg/kg doses of ((+/-)trans-3, 4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, methanesulfonate hydrate (U-50,488H), another kappa-selective opioid receptor agonist, significantly inhibited the shortening. The anti-amnesic effects of dynorphin A-(1-13) (3 and 10 mg/kg, i.p.) were almost completely antagonized by intracerebroventricular administration of the quaternary derivative of the opioid receptor antagonist naltrexone methobromide (0.3 microgram), but not by systemic administration of the opioid receptor antagonist (1 mg/kg, s.c.), demonstrating central mediation of the anti-amnesic effects of dynorphin A-(1-13). Furthermore, the kappa-selective opioid receptor antagonist, nor-binaltorphimine (2 mg/kg, s.c.), almost completely antagonized the effects of dynorphin A-(1-13) (3 and 10 mg/kg, i.p.). These results suggest that dynorphin A-(1-13) produces anti-amnesic effects through the blood-brain barrier.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Amnesia; Analgesics; Animals; Avoidance Learning; Cycloheximide; Dynorphins; Injections, Intraventricular; Male; Memory; Mice; Naltrexone; Narcotic Antagonists; Protein Synthesis Inhibitors; Pyrrolidines; Quaternary Ammonium Compounds; Receptors, Opioid, kappa

The effects of trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide methanesulfonate salt (U-50488H) on carbon monoxide (CO)-induced amnesia in mice were investigated using spontaneous alternation and step-down type passive avoidance tasks. The lower percentage alternation and shorter median step-down latency in the retention test of the CO-exposed group indicated that memory deficiency occurred in mice when behavioral testing commenced 5-7 days after CO exposure. Administration of U-50488H (0.21 and 0.64 mumol/kg s.c.) 25 min before spontaneous alternation performance or the first training session of the passive avoidance task improved the CO-induced impairment of alternation performance and passive avoidance tasks. To determine whether the effect of U-50488H was mediated via kappa-opioid receptors, we attempted to block its action using a selective kappa-opioid receptor antagonist (nor-binaltorphimine). Nor-binaltorphimine (5.44 nmol/mouse i.c.v.) blocked the effect of U-50488H on CO-induced delayed amnesia. Furthermore, a low dose of scopolamine (0.41 mumol/kg s.c.) also blocked the ameliorating effect of U-50488H. U-50488H (0.21-2.15 mumol/kg s.c.) did not facilitate the acquisition of memory in normal mice. These results suggest that U-50488H modulates the kappa-opioid receptor-mediated opioid neuronal system and activates the cholinergic neuronal system, and that it ameliorates the disruptive effect of CO on acquisition and/or consolidation of memory.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Amnesia; Analgesics; Animals; Avoidance Learning; Carbon Monoxide Poisoning; Electric Stimulation; Male; Mice; Naltrexone; Narcotic Antagonists; Pyrrolidines

Transient ischemia produced marked memory dysfunctions in mice on three different tasks, spontaneous alternation, elevated plus-maze and passive avoidance, as tested 1, 1-2, and 2-3 days after ischemic insult, respectively. U-50,488H, a kappa-opioid receptor agonist, administered 20 min before ischemic insult markedly prevented the impairment of spontaneous alternation, the prolongation of transfer latency in elevated-plus maze and the shortening of step-through latency in passive avoidance induced by transient ischemia. The protective effect of U-50,488H (30 mg/kg) on ischemia-induced memory dysfunctions observed in the three tasks was almost completely reversed by pretreatment with nor-binaltorphimine (4 micrograms, i.c.v.), a kappa-selective opioid antagonist. Although U-50,488H (30 mg/kg) did not affect body temperature in sham mice, it blocked hypothermia induced by ischemic insult. These results suggest that the protective effect of U-50,488H on memory dysfunctions in ischemic mice is associated with the activation of kappa-opioid receptors and is not based upon hypothermia.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Amnesia; Analgesics; Animals; Avoidance Learning; Body Temperature; Drug Interactions; Ischemic Attack, Transient; Learning; Male; Memory; Mice; Mice, Inbred Strains; Naltrexone; Pyrrolidines; Receptors, Opioid, kappa; Reperfusion; Time Factors