Reversal Of Scopolamine-induced Amnesia Research Articles

Metanicotine: A nicotinic agonist with central nervous system selectivity?in vitro and in vivo characterization

A growing body of evidence suggests that disruption of nicotinic cholinergic systems may be an important factor in the etiology of a number of different diseases, ranging from neurodegenerative diseases, such as Alzheimer's and Parkinson's, to ulcerative colitis. The mechanistic basis for such diverse nicotinic effects is likely to lie in the ever growing number of potential receptor subtypes. Therefore, the development of receptor subtype-selective probes is essential to understand the emerging complexity of nicotinic cholinergic systems and the mechanisms underlying diseases that may involve these systems. Toward this end, we have evaluated the nicotinic agonist metanicotine, (E)-N-methyl-4-(3-pyridinyl)-3-butene-1-amine, using the following in vitro and in vivo methods: 1) receptor binding and up-regulation, 2) neurotransmitter release and ion flux in synaptosomes/cells, 3) in vivo microdialysis in rats, 4) reversal of scopolamine-induced amnesia in a step-through passive-avoidance paradigm, 5) water maze performance in mice, 6) radial-arm maze performance in brain-lesioned rats, 7) changes in heart rate and blood pressure, and 8) physiological depression of body temperature, locomotor activity, acoustic startle, and respiration rate. Our in vitro results indicate that metanicotine binds with high affinity to the major receptor subtype in brain (α4β2), evokes dopamine release from striatal synaptosomes and Rb+ efflux from thalamic synaptosomes, but does not activate ganglionic, muscle, or other peripheral type nicotinic receptors. These results suggest that metanicotine is selective for α4-containing central nervous system (CNS) nicotinic receptors and has reduced selectivity for peripheral nervous system (PNS) receptor subtypes. These conclusions are further supported by in vivo studies with metanicotine showing enhanced cognitive effects and significantly lower peripheral effects. Our in vivo results indicate that metanicotine increases the release of acetylcholine, norepinephrine, dopamine, and serotonin in cortex and is equal to or better than nicotine on measures of cognitive enhancement. By comparison, metanicotine is significantly less potent than nicotine in increasing heart rate and blood pressure and in causing physiological depression. These results are consistent with in vitro data indicating metanicotine's CNS receptor selectivity, and they suggest that this ligand may be a suitable tool for probing the relationships that underlie the complex central and peripheral pharmacology of nicotinic cholinergic systems. Furthermore, metanicotine may be a good lead candidate for developing nicotinic agonists as CNS therapeutics with reduced peripheral side effects. Drug Dev. Res. 38:169–176 © 1996 Wiley-Liss, Inc.

BR-16A restricts development of electroconvulsive shock-induced retrograde amnesia

Forty nine adult male Sprague Dawley rats were selected for rapid learning in a T-maze to study the effects of BR-16A, a herbal preparation on ECS-induced retrograde amnesia. Half the rats received 200 mg/kg BR-16A and the other half received vehicle alone. The rats were trained to run into the enclosed chamber of either the left or the right arm on a T-maze; a food pellet served as a reward in the correct arm. Satisfactory learning was defined as 9 correct arm entries over 10 consecutive trials on the maze. On the 5 th day, the rats in both the groups were randomised to receive true or sham ECS. The post-ECS data revealed that the number of trials to satisfactory learning and the number of trials with wrong arm entries were large in the ECS-vehicle group, which suggests that BR-16A prevented the development of amnesia. Cholinergic facilitation may be involved, as evidenced by the reversal of scopolamine-induced amnesia and it may also influence opioid neurotransmission. Since ECT-induced retrograde amnesia is a particularly distressing adverse consequence of the treatment, it is hoped that BR-16A will offer a viable solution to the problem of memory deficits following ECT.

Reversal of scopolamine-induced amnesia by the GABA B receptor antagonist CGP 35348 in the mouse

We studied the effects of CGP 35348, a centrally active blocker of GABA B receptors, on scopolamine-induced amnesia for a passive avoidance response in the mouse. Both pre-training or post-training intraperitoneal administration of the GABA B antagonist (75, 150 and 300 mg/kg i.p.) significantly reduces the amnesic effect of scopolamine (1.0 mg/kg i.p.). Our results are in agreement with previous observations indicating a role for the GABA B receptors in the modulation of memory function, and suggest a possible role of GABA B receptor antagonists as nootropic drugs.

Central muscarinic activities of an M1-selective agonist: preferential effect on reversal of amnesia

Effects of FKS-508 (AF102B; cis-2-methylspiro (1,3-oxathiolane-5,3′)-quinuclide), a novel M1-selective agonist, on central muscarinic responses in mice were examined in comparison with oxotremorine. FKS-508 was slightly less potent (6 times) in reversal of scopolamine-induced amnesia (passive avoidance failure), but far less potent (260 and 55 times) in producing hypothermia and tremor than oxotremorine. These results show that the selective M1 agonist FKS-508 differentiates highly between the central muscarinic effects.

Reversal of scopolamine-induced amnesia and alterations in energy metabolism by the nootropic piracetam: implications regarding identification of brain structures involved in consolidation of memory traces

Pretreatment with scopolamine, 3 mg/kg, prevented the acquisition of a passive avoidance task in rats. These amnesic effects of scopolamine could largely be treatment with 100 mg/kg of the nootropic drug piracetam. In order to identify the brain structures involved, the effects of these drugs on regional energy metabolism were measured throughout the brain, utilizing Sokoloff's 2-deoxyglucose autoradiographic procedures. Scopolamine, 3 mg/kg, reduced glucose utilization in several areas of the cerebral cortex. These effects were largest in the parietal and temporal cortices. Other areas affected included the sensorimotor and cingulate cortices, the ventral and lateral thalamus, and the dendritic neuropil of the CA 1, CA 2, and CA 3 regions of the hippocampus. The regional depressions in glucose metabolism observed following scopolamine treatment in the rat had some resemblance to depression in glucose metabolism reported for Alzheimer's disease patients in positron emission tomography studies. Piracetam, 100 mg/kg, did not alter the energy metabolism of any of the 41 brain regions examined. However, this dose of piracetam completely reversed the scopolamine-induced depressions in the hippocampus. Piracetam partially but significantly reversed the scopolamine effects in the the cingulate cortex. It is concluded that the data provide support for the hippocampal-cholinergic theory of memory as originally formulated by Meyers and Domino in 1964 and give insight into the mechanisms by which nootropics work.

Reversal of scopolamine-induced amnesia by phosphatidylserine in rats.

Scopolamine (2 mg/kg IP) and propranolol (55 mg/kg IP), given before a single learning trial, reduce retention of a passive avoidance response in rats. Phosphatidylserine, 30-60 mg/kg IP, antagonizes the amnesic effect of scopolamine but not that of propranolol. The retention of the passive avoidance response is not affected by phosphatidylserine given alone. The results indicate that this phospholipid selectively counteracts the action of scopolamine on passive avoidance acquisition, probably via a cholinergic mechanism.

Reversal of scopolamine-induced amnesia of passive avoidance by pre- and post-training naloxone.

In a series of five experiments, the modulating role of naloxone on a scopolamine-induced retention deficit in a passive avoidance paradigm was investigated in mice. Scopolamine, but not methyl scopolamine (1 and 3 mg/kg), induced an amnesia as measured by latency and duration parameters. Naloxone (0.3, 1, 3, and 10 mg/kg) injected prior to training attenuated the retention deficit with a peak of activity at 3 mg/kg. The effect of naloxone could be antagonized with morphine (1, 3, and 10 mg/kg), demonstrating the opioid specificity of the naloxone effect. Post-training administration of naloxone (3 mg/kg) as a single or as a split dose also attenuated the scopolamine-induced amnesia. Control experiments indicated that neither an increase in pain sensitivity (pre-training naloxone) nor an induced aversive state (post-training naloxone) appear to be responsible for the influence of naloxone on the scopolamine-induced retention deficit. These results extend previous findings implicating a cholinergic-opioid interaction in memory processes. A possible mechanism for this interaction involving the septo-hippocampal cholinergic pathway is discussed.