norbinaltorphimine and Learning-Disabilities

We hypothesized that mice subjected to prolonged stress would demonstrate decreased performance in a learning and memory task attributable to the endogenous activation of the kappa opioid receptor (KOR). C57BL/6J mice were tested using the novel object recognition (NOR) assay at various time points after exposure to repeated forced swim stress (FSS). Unstressed mice demonstrated recognition of the novel object at the end of a procedure using three 10-min object interaction phases, with a recognition index (RI) for the novel object of 71.7+/-3.4%. However, 1 h after exposure to FSS, vehicle-pretreated mice displayed a significant deficit in performance (RI=58.2+/-4.1%) compared with unstressed animals. NOR was still significantly reduced 4 but not 24 h after FSS. Treatment with the KOR-selective antagonist norbinaltorphimine (10 mg/kg, i.p.) prevented the decline in learning and memory performance. Moreover, direct activation of the KOR induced performance deficits in NOR, as exogenous administration of the KOR agonist U50,488 [(+/-)-trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide] (0.3 mg/kg, i.p.) suppressed NOR (RI=56.0+/-3.9%). The effect of FSS on NOR performance was further examined in mice lacking the gene for the endogenous KOR agonist dynorphin (Dyn). Dyn gene-disrupted mice exposed to FSS did not show the subsequent learning and memory deficits (RI=66.8+/-3.8%) demonstrated by their wild-type littermates (RI=49.7+/-2.9%). Overall, these results suggest that stress-induced activation of the KOR may be both necessary and sufficient to produce subsequent deficits in novel object recognition.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Analysis of Variance; Animals; Behavior, Animal; Enkephalins; Gene Expression Regulation; Immobility Response, Tonic; Learning Disabilities; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Naltrexone; Narcotic Antagonists; Protein Precursors; Receptors, Opioid, kappa; Recognition, Psychology; Stress, Psychological; Swimming; Time Factors

Accumulating evidence indicates that the endogenous opioid peptides dynorphin A (1-17) and synthetic dynorphin A (1-13) interact not only with opioid receptors but also with as yet poorly characterized non-opioid binding sites. Dynorphin A (1-13) improved impairments of learning and memory via not only kappa-opioid receptor-mediated, but also 'non-opioid' mechanisms. In the present study, the effects of des-tyrosine(1) dynorphin A (2-13) as a non-opioid metabolite of dynorphin A, and dynorphin A (1-13) on mecamylamine-induced impairment of the acquisition of learning in rats were investigated using a step-through type passive avoidance task. Further, hippocampal acetylcholine release was examined using in vivo microdialysis. Mecamylamine significantly shortened the step-through latency when given 30 min before the acquisition trial. Not only dynorphin A (1-13) but also dynorphin A (2-13) attenuated the mecamylamine-induced impairment of the acquisition of learning. The effect of dynorphin A (2-13) was not blocked by pre-treatment with nor-binaltorphimine (nor-BNI), a selective kappa-opioid receptor antagonist. Dynorphin A (2-13) completely abolished the decrease in the extracellular acetylcholine concentration induced by mecamylamine and this effect was not blocked by nor-BNI. Taken together with our previous findings, the present results may indicate that dynorphin A (2-13) improves impairment of learning and/or memory in 'non-opioid' mechanisms and dynorphin A (1-13) ameliorates impairment of the acquisition of learning via not only kappa-opioid receptor-mediated mechanisms but also 'non-opioid' mechanisms, by regulating the release of extracellular acetylcholine.

Topics: Acetylcholine; Animals; Dynorphins; Functional Laterality; Hippocampus; Injections, Intraventricular; Learning; Learning Disabilities; Male; Mecamylamine; Microdialysis; Naltrexone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley

The effects of fmol doses of nociceptin/orphanin FQ on scopolamine-induced impairment of learning and/or memory were examined using spontaneous alternation of Y-maze and step-down type passive avoidance tasks. While fmol doses of nociceptin alone had no effect on spontaneous alternation or passive avoidance behavior in normal mice, administration of nociceptin (10 and/or 100 fmol/mouse) 30 min before spontaneous alternation performance or the training session of the passive avoidance task, significantly improved the scopolamine-induced impairment of spontaneous alternation and passive avoidance behavior. This ameliorating effect was not antagonized by nocistatin (0.5 and 5.0 nmol/mouse, i.c.v.), naloxone benzoylhydrazone (2.3, 11.2, and 56.1 micromol/kg, s.c.) or nor-binaltorphimine (4.9 nmol/mouse, i.c.v.). These results indicated that very low doses of nociceptin ameliorate impairments of spontaneous alternation and passive avoidance induced by scopolamine, and suggested that this peptide has bidirectional modulatory effects on learning and memory; impairment at high doses and amelioration at low doses.

Topics: Analgesics, Opioid; Animals; Avoidance Learning; Disease Models, Animal; Dizocilpine Maleate; Learning Disabilities; Male; Maze Learning; Memory Disorders; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Neuroprotective Agents; Nociceptin; Opioid Peptides; Psychomotor Performance; Rats; Scopolamine

The effects of intracerebroventricular administration of dynorphin A(1-13) on scopolamine- and pirenzepine-induced amnesia were investigated in mice by observing the step-down-type passive avoidance response and spontaneous alternation performance. The pre- or post-training, or preretention administration of dynorphin A(1-13) (0.3-10 micrograms) alone failed to affect the passive avoidance response, while scopolamine (1 mg/kg) significantly inhibited it. Dynorphin A(1-13) (1 microgram) given 15 min before training and retention tests, but not immediately after training, significantly improved the scopolamine (1 mg/kg)-induced impairment of passive avoidance response, indicating the anti-amnesic effects of dynorphin A(1-13). A lower dose (1 mg/kg) of the kappa-opioid receptor antagonist (-)-(1R,5R,9R)-5,9-diethyl-2-(3-furyl-methyl)-2'-hydroxy-6,7-benzomorpha n reversed the anti-amnesic effects of dynorphin A(1-13) (1 microgram). In contrast, although dynorphin A(1-13) (1, 3 and 10 micrograms) did not influence spontaneous alternation performance, scopolamine (1 mg/kg) and the muscarinic M1 receptor antagonist pirenzepine (3 micrograms) markedly decreased spontaneous alternation performance. Dynorphin A(1-13) (3, 5.6 and/or 10 micrograms) significantly improved the scopolamine (1 mg/kg)- and pirenzepine (3 micrograms)-induced impairment of spontaneous alternation performance. The improving effects of dynorphin A(1-13) (3 micrograms) were almost completely reversed by pretreatment with nor-binaltorphimine (4 micrograms), a kappa-selective opioid receptor antagonist. These results suggest that the stimulation of kappa-opioid receptors improves memory dysfunctions resulting from the blockade of muscarinic M1 receptors.

Topics: Analgesics, Opioid; Animals; Dynorphins; Injections, Intraventricular; Learning; Learning Disabilities; Male; Memory; Memory Disorders; Memory, Short-Term; Mice; Mice, Inbred Strains; Muscarinic Antagonists; Naltrexone; Narcotic Antagonists; Peptide Fragments; Pirenzepine; Receptors, Opioid, kappa; Scopolamine