dynorphins and Learning-Disabilities

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 role of kappa opioid receptor agonists in learning and memory is controversial. In the present study, the effects of U-50,488H on scopolamine-, mecamylamine- and dizocilpine-induced learning and memory impairments in rats were investigated. Scopolamine (3.3 mumol/kg s.c.), a muscarinic cholinergic antagonist, and mecamylamine (40 mumol/kg s.c.), a nicotinic cholinergic antagonist, significantly impaired learning and memory in rats in a step-through type passive avoidance test. Administration of U-50,488H (0.17 or 0.51 mumol/kg s.c.) 25 min before the acquisition trial reversed the impairment of learning and memory induced by scopolamine and mecamylamine. Although low doses of scopolamine (0.17 mumol/kg) and mecamylamine (12 mumol/kg) had no effect, concurrent administration of both antagonists induced impairment of learning and memory. Scopolamine significantly increased acetylcholine release in the hippocampus as determined by in vivo brain microdialysis. On the other hand, mecamylamine significantly decreased acetylcholine release. U-50,488H completely blocked the decrease in acetylcholine release induced by mecamylamine, whereas it only partially blocked the increase of acetylcholine induced by scopolamine. On the other hand, an endogenous kappa opioid receptor agonist, dynorphin A (1-13), did not block the increase in acetylcholine release induced by scopolamine. The antagonistic effect of U-50,488H was abolished by pretreatment with nor-binaltorphimine (4.9 nmol/rat i.c.v.), a selective kappa opioid receptor antagonist. U-50,488H did not affect the impairment of learning and memory induced by the blockade of NMDA receptors by dizocilpine ((+)-MK-801). These results suggest that U-50,488H reverses the impairment of learning and memory induced by the blockade of cholinergic transmission and abolishes the decrease of acetylcholine release induced by mecamylamine via the kappa receptor-mediated opioid neuronal system.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acetylcholine; Animals; Dizocilpine Maleate; Dynorphins; Learning Disabilities; Male; Mecamylamine; Memory Disorders; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Scopolamine

1. We investigated whether carbachol, a muscarinic receptor agonist, induces learning and memory impairment, and if so, dynorphin A (1-13), an endogenous kappa-opioid receptor agonist, ameliorates the impairment of learning and memory induced by carbachol, by use of a step-through type passive avoidance task. 2. Carbachol induced a dose-related dual response. Carbachol (1.66 pmol per rat) administered directly into the hippocampus significantly shortened the step-through latency, while lower (0.166 pmol per rat) and higher (16.6 pmol per rat) doses of carbachol did not induce learning or memory impairment. 3. Dynorphin A (1-13) (0.5 nmol per rat, i.c.v.) administered 5 min after carbachol injection significantly reversed carbachol-induced impairment of learning and memory. 4. Perfusion with carbachol (3 x 10(-4) M) significantly decreased acetylcholine release in the hippocampus during perfusion as determined by in vivo brain microdialysis. This decrease in acetylcholine release was suppressed by co-perfusion with a low dose of atropine (10(-7) M). 5. Dynorphin A (1-13) (0.5 nmol per rat, i.c.v.) immediately before carbachol perfusion completely blocked this decrease in extracellular acetylcholine concentration induced by carbachol. 6. These antagonistic effects of dynorphin A (1-13) were abolished by treatment with norbinaltorphimine (5.44 nmol per rat, i.c.v.), a selective kappa-opioid receptor antagonist, 5 min before dynorphin A (1-13) treatment. 7. These results suggest that the neuropeptide dynorphin A (1-13) ameliorates the carbachol-induced impairment of learning and memory, accompanied by attenuation of the reductions in acetylcholine release which may be associated with dysfunction of presynaptic cholinergic neurones via kappa-opioid receptors.

Topics: Acetylcholine; Animals; Atropine; Carbachol; Dynorphins; Extracellular Space; Learning Disabilities; Male; Memory Disorders; Muscarinic Agonists; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa

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

1. Human galanin (0.32 nmol per rat, i.c.v.), an endogenous neuropeptide, administered 30 min before acquisition or retention trials, significantly impaired the acquisition of learning and recall of memory in a step-through type passive avoidance performance. 2. The role of dynorphin A (1-13) in learning and memory is controversial. Dynorphin A (1-13) (0.5 nmol per rat, i.c.v.) administered 5 min before galanin injection, completely antagonized these impairments. 3. Galanin significantly decreased acetylcholine release in the hippocampus 40 to 120 min after injection as determined by in vivo brain microdialysis. This peptide also decreased acetylcholine release, albeit to a lesser extent, from the frontal cortex. 4. Dynorphin A (1-13) (0.5 nmol per rat, i.c.v.) 5 min before galanin injection, completely blocked the decrease in extracellular acetylcholine concentration induced by galanin. 5. These antagonistic effects of dynorphin A (1-13) were abolished by treatment with norbinaltorphimine (5.44 nmol per rat, i.c.v.), a selective kappa-opioid receptor antagonist, 5 min before dynorphin A (1-13). 6. Dynorphin A (1-13) (0.5 nmol) itself had no effect on learning and memory and on the acetylcholine concentration in the hippocampus or the frontal cortex in normal rats. 7. These results suggest that the neuropeptide dynorphin A (1-13) ameliorates the galanin-induced impairment of learning and memory accompanied by abolition of reductions in acetylcholine release via kappa-opioid receptors.

Topics: Acetylcholine; Animals; Dynorphins; Galanin; Hippocampus; Learning Disabilities; Male; Memory Disorders; Microdialysis; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Cholinergic; Receptors, Opioid, kappa; Synaptic Transmission

The effects of aging on extracellular glutamate and tissue dynorphin content in the hippocampus were examined in Fischer-344 rats. Young adult (4-month-old) and aged (24-month-old) rats were trained to find a hidden platform in the Morris water task. Aged rats were unable to acquire the spatial learning task as rapidly as young controls. Following behavioral testing, an in vivo microdialysis perfusion method was used to determine extracellular glutamate levels in the hippocampus. There was a 25-35% reduction in extracellular glutamate concentration in both dorsal and ventral hippocampus of aged rats compared to young rats, in the absence of any change in tissue glutamate levels. Radioimmunoassay showed an increase in dynorphin A(1-8)-like immunoreactivity [DYN-A(1-8)LI] in both dorsal and ventral hippocampus, but not striatum, of aged rats. Immunocytochemistry indicated that this increase was localized to the dentate granule cells and mossy fibers. Furthermore, among the aged rats the increase in DYN-A(1-8)LI was inversely correlated with the decrease in extracellular glutamate. These results suggest that the disregulation of dynorphin observed in cognitively impaired aged rats is related to reduced excitatory transmission within the hippocampal formation.

Topics: Aging; Animals; Axons; Dynorphins; Glutamates; Glutamic Acid; Hippocampus; Learning Disabilities; Male; Microdialysis; Peptide Fragments; Radioimmunoassay; Rats; Rats, Inbred F344; Spatial Behavior; Synaptic Transmission