Neurokinin 3 Receptor Effects on Cognitive Behaviour in a Rat Model of Alzheimer's Disease

Alzheimer's disease (AD) is accepted as a form of progressive and irreversible dementia. It is known that cholinergic systems are commonly affected in AD. Neurokinin 3 receptor (NK3R) is involved in learning and memory related processes. Activation of NK3R is known to facilitate the release of many neurotransmitters such as acetylcholine (Ach), dopamine (DA), noradrenaline (NA). Based on this information, hypothesis of the study that NK3R agonism can have positive effects on behavioral and learning parameters through cholinergic and catecholaminergic mechanisms. The aim of this study was to investigate the effects of NK3R agonist senktide on cognitive and neurobehavioral mechanisms in model of AD.50 adult male Wistar albino rats were obtained; Control, AD, Control+NK3R agonist, AD+NK3R agonist, AD+NK3R agonist+antagonist groups. AD model was established by administering Aβ1-42 intracerebroventricularly. Following NK3R agonist+antagonist injections, open field (OF) and Morris water maze (MWM) were applied for behavioral and learning parameters. Hippocampus and cortex tissues were extracted. Analysis of cholinergic mechanisms from these tissues were performed by ELISA method.Group-time effect was significant in OF (p<0.05). Distance moved parameter was significant between groups in MWM (p<0.05). There was a significant difference between groups in AChE and ChAT levels (p<0.05). DA concentrations of brainstem samples were significant (p<0.05). There was no significant difference in NA concentration (p>0.05). NK3R agonists were found to be effective in improving cognitive functions in rats with AD pathology. It has been observed that positive effects on learning and memory performances can be mediated by cholinergic mechanisms.

Autonomic and cholinergic mechanisms mediating cardiovascular and temperature effects of donepezil in conscious mice

Donepezil is a centrally-acting acetylcholinesterase (AChE) inhibitor with therapeutic potential in inflammatory diseases; however, the underlying autonomic and cholinergic mechanisms remain unclear. Here, we assessed effects of donepezil on mean arterial pressure (MAP), heart rate (HR), HR variability, and body temperature in conscious adult male C57BL/6 mice to investigate the autonomic pathways involved. Central vs. peripheral cholinergic effects of donepezil were assessed using pharmacological approaches including comparison with the peripherally-acting AChE inhibitor, neostigmine. Drug treatments included donepezil (2.5 or 5 mg/kg s.c.), neostigmine methyl sulfate (80 or 240 μg/kg i.p.), atropine sulfate (5 mg/kg i.p.), atropine methyl bromide (5 mg/kg i.p.), or saline. Donepezil, at 2.5 and 5 mg/kg, decreased HR by 36±4 and 44±3% compared to saline (n=10, P<0.001). Donepezil, at 2.5 and 5 mg/kg, decreased temperature by 13±2 and 22±2% compared to saline (n=6, P<0.001). Modest (P<0.001) increases in MAP were observed with donepezil after peak bradycardia occurred. Atropine sulfate and atropine methyl bromide blocked bradycardic responses to donepezil, but only atropine sulfate attenuated hypothermia. The pressor response to donepezil was similar in mice co-administered atropine sulfate; however, co-administration of atropine methyl bromide potentiated the increase in MAP. Neostigmine did not alter HR or temperature but did result in early increases in MAP. Despite the marked bradycardia, donepezil did not increase normalized high frequency HR variability. We conclude that donepezil causes marked bradycardia and hypothermia in conscious mice via activation of muscarinic receptors while concurrently increasing MAP via autonomic and cholinergic pathways that remain to be elucidated.

Opposite Pathways of Cholinergic Mechanisms of Hypoxic Preconditioning in the Hippocampus: Participation of Nicotinic α7 Receptors and Their Association with the Baseline Level of Startle Prepulse Inhibition

(1) Background. A one-time moderate hypobaric hypoxia (HBH) has a preconditioning effect whose neuronal mechanisms are not studied well. Previously, we found a stable correlation between the HBH efficiency and acoustic startle prepulse inhibition (PPI). This makes it possible to predict the individual efficiency of HBH in animals and to study its potential adaptive mechanisms. We revealed a bi-directional action of nicotinic α7 receptor agonist PNU-282987 and its solvent dimethyl sulfoxide on HBH efficiency with the level of PPI > or < 40%. (2) The aim of the present study was to estimate cholinergic mechanisms of HBH effects in different brain regions. (3) Methods: in rats pretested for PPI, we evaluated the activity of synaptic membrane-bound and water-soluble choline acetyltransferase (ChAT) in the sub-fractions of ‘light’ and ‘heavy’ synaptosomes of the neocortex, hippocampus and caudal brainstem in the intact brain and after HBH. We tested the dose-dependent influence of PNU-282987 on the HBH efficiency. (4) Results: PPI level and ChAT activity correlated negatively in all brain structures of the intact animals, so that the values of the latter were higher in rats with PPI < 40% compared to those with PPI > 40%. After HBH, this ChAT activity difference was leveled in the neocortex and caudal brainstem, while for membrane-bound ChAT in the ‘light’ synaptosomal fraction of hippocampus, it was reversed to the opposite. In addition, a pharmacological study revealed that PNU-282987 in all used doses and its solvent displayed corresponding opposite effects on HBH efficiency in rats with different levels of PPI. (5) Conclusion: We substantiate that in rats with low and high PPI two opposite hippocampal cholinergic mechanisms are involved in hypoxic preconditioning, and both are implemented by forebrain projections via nicotinic α7 receptors. Possible causes of association between general protective adaptation, HBH, PPI, forebrain cholinergic system and hippocampus are discussed.

Carbachol and Nicotine in Prefrontal Cortex Have Differential Effects on Sleep-Wake States

The role of the brainstem cholinergic system in the regulation of sleep-wake states has been studied extensively but relatively little is known about the role of cholinergic mechanisms in prefrontal cortex in the regulation of sleep-wake states. In a recent study, we showed that prefrontal cholinergic stimulation in anesthetized rat can reverse the traits associated with anesthesia and restore a wake-like state, thereby providing evidence for a causal role for prefrontal cholinergic mechanisms in modulating level of arousal. However, the effect of increase in prefrontal cholinergic tone on spontaneous sleep-wake states has yet to be demonstrated. Therefore, in this study, we tested the hypothesis that delivery of cholinergic agonists – carbachol or nicotine – into prefrontal cortex of rat during slow wave sleep (SWS) would produce behavioral arousal and increase the time spent in wake state. We show that unilateral microinjection (200 nL) of carbachol (1 mM) or nicotine (100 mM) into prefrontal cortex during SWS decreased the latency to the onset of wake state (p = 0.03 for carbachol, p = 0.03 for nicotine) and increased the latency to the onset of rapid eye movement sleep (p = 0.008 for carbachol, p = 0.006 for nicotine). Although the infusion of 1 mM carbachol increased the time spent in wake state (p = 0.01) and decreased the time spent in SWS (p = 0.01), infusion of 10 or 100 mM nicotine did not produce any statistically significant change in sleep-wake architecture. These data demonstrate a differential role of prefrontal cholinergic receptors in modulating spontaneous sleep-wake states.

The influence of cholinergic drugs on electroencephalogram of the gonadectomized female rabbits

The results of investigation has shown, that after the gonadectomy of the rabbits-females the general power of EEG spectrum (GPS of EEG) changed under influence of cholinergic drugs. The sterilizathion of the animals leads to disorders of interaction between M- and N-cholinergic mechanisms in the brain. In particular, blockade of M-cholinoreceptors by metamizyl in intact and ovariectomized rabbits increased the GPS of EEG. The simultaneous administration of metamizyl with galantamine to intact females led to even greater increase of GPS of EEG, whereas the sterilized rabbits demonstrated its reduction. On the contrary, the application of the N-cholinoreceptors inhibitor gangleron with inhibitor of acetylcholinesterase (AChE) galantamine reduced the GPS of EEG in intact animals and increased it in gonadectomized rabbits in comparison with gangleron alone. Thus, the effect of M,N-cholinoblockators in combination with AChE inhibitor in sterilized rabbits changed the EEG spectrum to opposite in comparison with intact females.