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PloS One 2014Organophosphorus (OP) nerve agents are deadly chemical weapons that pose an alarming threat to military and civilian populations. The irreversible inhibition of the...
Organophosphorus (OP) nerve agents are deadly chemical weapons that pose an alarming threat to military and civilian populations. The irreversible inhibition of the critical cholinergic degradative enzyme acetylcholinesterase (AChE) by OP nerve agents leads to cholinergic crisis. Resulting excessive synaptic acetylcholine levels leads to status epilepticus that, in turn, results in brain damage. Current countermeasures are only modestly effective in protecting against OP-induced brain damage, supporting interest for evaluation of new ones. (-)-Phenserine is a reversible AChE inhibitor possessing neuroprotective and amyloid precursor protein lowering actions that reached Phase III clinical trials for Alzheimer's Disease where it exhibited a wide safety margin. This compound preferentially enters the CNS and has potential to impede soman binding to the active site of AChE to, thereby, serve in a protective capacity. Herein, we demonstrate that (-)-phenserine protects neurons against soman-induced neuronal cell death in rats when administered either as a pretreatment or post-treatment paradigm, improves motoric movement in soman-exposed animals and reduces mortality when given as a pretreatment. Gene expression analysis, undertaken to elucidate mechanism, showed that (-)-phenserine pretreatment increased select neuroprotective genes and reversed a Homer1 expression elevation induced by soman exposure. These studies suggest that (-)-phenserine warrants further evaluation as an OP nerve agent protective strategy.
Topics: Animals; Carrier Proteins; Chemical Warfare Agents; Cholinesterase Inhibitors; Gene Expression Regulation; Homer Scaffolding Proteins; Male; Physostigmine; Rats; Rats, Sprague-Dawley; Soman; Status Epilepticus
PubMed: 24955574
DOI: 10.1371/journal.pone.0099818 -
Pharmacological Reports : PR 2010The present study investigated the effects of subcutaneous (sc) and intracerebroventricular (icv) injections of physostigmine (a cholinesterase inhibitor), atropine (an...
The present study investigated the effects of subcutaneous (sc) and intracerebroventricular (icv) injections of physostigmine (a cholinesterase inhibitor), atropine (an antagonist of muscarinic cholinergic receptors) and hexamethonium (an antagonist of nicotinic cholinergic receptors) on the acute corneal nociception in rats. Local application of 5 M NaCl solution on the corneal surface of the eye produced a significant nociceptive behavior, characterized by eye wiping. The number of eye wipes was counted during the first 30 s. The sc (0.25, 0.5 and 1 mg/kg) and icv (1.25, 2.5, 5 and 10 μg) injections of physostigmine significantly (p < 0.05) decreased the number of eye wipes. Atropine and hexamethonium at (2 mg/kg, sc and 20 μg, icv) had no effects when used alone, however, atropine, but not hexamethonium prevented the antinociception induced by physostigmine (sc and icv). The results of this study indicate that the central muscarinic, but not nicotinic receptors might be involved in the antinociceptive effect of physostigmine in the acute corneal model of pain in rats.
Topics: Animals; Atropine; Cholinesterase Inhibitors; Cornea; Dose-Response Relationship, Drug; Hexamethonium; Injections, Intraventricular; Injections, Subcutaneous; Male; Muscarinic Antagonists; Nicotinic Antagonists; Pain; Pain Measurement; Physostigmine; Rats; Rats, Wistar; Sodium Chloride
PubMed: 21098868
DOI: 10.1016/s1734-1140(10)70345-5 -
British Journal of Clinical Pharmacology Jan 2022
Topics: Cholinesterase Inhibitors; Humans; Muscarinic Antagonists; Physostigmine
PubMed: 34784063
DOI: 10.1111/bcp.15121 -
The Journal of Pharmacology and... May 2023Optimization of effort-related choices is impaired in depressive disorders. Acetylcholine (ACh) and dopamine (DA) are linked to depressive disorders, and modulation of...
Optimization of effort-related choices is impaired in depressive disorders. Acetylcholine (ACh) and dopamine (DA) are linked to depressive disorders, and modulation of ACh tone in the ventral tegmental area (VTA) affects mood-related behavioral responses in rats. However, it is unknown if VTA ACh mediates effort-choice behaviors. Using a task of effort-choice, rats can choose to lever press on a fixed-ratio 5 (FR5) schedule for a more-preferred food or consume freely available, less-preferred food. VTA administration of physostigmine (1 μg and 2 μg/side), a cholinesterase inhibitor, reduced FR5 responding for the more-preferred food while leaving consumption of the less-preferred food intact. VTA infusion of the M5 muscarinic receptor negative allosteric modulator VU6000181 (3 μM, 10 μM, 30 μM/side) did not affect lever pressing or chow consumption. However, VU6000181 (30 μM/side) coadministration with physostigmine (2 μg/side) attenuated physostigmine-induced decrease in lever pressing in female and male rats and significantly elevated lever pressing above vehicle baseline levels in male rats. In in vivo voltammetry experiments, VTA infusion of combined physostigmine and VU6000181 did not significantly alter evoked phasic DA release in the nucleus accumbens core (NAc) in female rats. In male rats, combined VTA infusion of physostigmine and VU6000181 increased phasic evoked DA release in the NAc compared with vehicle, physostigmine, or VU6000181 infusion alone. These data indicate a critical role and potential sex differences of VTA M5 receptors in mediating VTA cholinergic effects on effort choice behavior and regulation of DA release. SIGNIFICANCE STATEMENT: Effort-choice impairments are observed in depressive disorders, which are often treatment resistant to currently available thymoleptics. The role of ventral tegmental area (VTA) acetylcholine muscarinic M5 receptors, in a preclinical model of effort-choice behavior, is examined. Using the selective negative allosteric modulator of the M5 receptor VU6000181, we show the role of VTA M5 receptors on effort-choice and regulation of dopamine release in the nucleus accumbens core. This study supports M5 receptors as therapeutic targets for depression.
Topics: Female; Rats; Male; Animals; Ventral Tegmental Area; Nucleus Accumbens; Dopamine; Receptor, Muscarinic M5; Acetylcholine; Physostigmine; Rats, Sprague-Dawley
PubMed: 36828630
DOI: 10.1124/jpet.122.001438 -
PloS One 2022Estrogens are thought to contribute to cognitive function in part by promoting the function of basal forebrain cholinergic neurons that project to the hippocampus and...
Estrogens are thought to contribute to cognitive function in part by promoting the function of basal forebrain cholinergic neurons that project to the hippocampus and cortical regions including the entorhinal cortex. Reductions in estrogens may alter cognition by reducing the function of cholinergic inputs to both the hippocampus and entorhinal cortex. In the present study, we assessed the effects of ovariectomy on proteins associated with cholinergic synapses in the entorhinal cortex. Ovariectomy was conducted at PD63, and tissue was obtained on PD84 to 89 to quantify changes in the degradative enzyme acetylcholinesterase, the vesicular acetylcholine transporter, and muscarinic M1 receptor protein. Although the vesicular acetylcholine transporter was unaffected, ovariectomy reduced both acetylcholinesterase and M1 receptor protein, and these reductions were prevented by chronic replacement of 17β-estradiol following ovariectomy. We also assessed the effects of ovariectomy on the cholinergic modulation of excitatory transmission, by comparing the effects of the acetylcholinesterase inhibitor eserine on evoked excitatory synaptic field potentials in brain slices obtained from intact rats, and from ovariectomized rats with or without 17β-estradiol replacement. Eserine is known to prolong the effects of endogenously released acetylcholine, resulting in an M1-like mediated reduction of glutamate release at excitatory synapses. The reduction in excitatory synaptic potentials in layer II of the entorhinal cortex induced by 15-min application of 10 μM eserine was greatly reduced in slices from ovariectomized rats as compared to intact rats and ovariectomized rats with replacement of 17β-estradiol. The reduced modulatory effect of eserine is consistent with the observed changes in cholinergic proteins, and suggests that reductions in 17β-estradiol following ovariectomy lead to impaired cholinergic function within the entorhinal cortex.
Topics: Acetylcholinesterase; Animals; Cholinergic Agents; Entorhinal Cortex; Estradiol; Estrogens; Excitatory Postsynaptic Potentials; Female; Humans; Ovariectomy; Physostigmine; Rats; Receptor, Muscarinic M1; Synaptic Transmission; Vesicular Acetylcholine Transport Proteins
PubMed: 35939438
DOI: 10.1371/journal.pone.0271131 -
Sleep Jun 2020The synaptic homeostasis theory of sleep proposes that low neurotransmitter activity in sleep optimizes memory consolidation. We tested this theory by asking whether...
The synaptic homeostasis theory of sleep proposes that low neurotransmitter activity in sleep optimizes memory consolidation. We tested this theory by asking whether increasing acetylcholine levels during early sleep would weaken motor memory consolidation. We trained separate groups of adult mice on the rotarod walking task and the single pellet reaching task, and after training, administered physostigmine, an acetylcholinesterase inhibitor, to increase cholinergic tone in subsequent sleep. Post-sleep testing showed that physostigmine impaired motor skill acquisition of both tasks. Home-cage video monitoring and electrophysiology revealed that physostigmine disrupted sleep structure, delayed non-rapid-eye-movement sleep onset, and reduced slow-wave power in the hippocampus and cortex. Additional experiments showed that: (1) the impaired performance associated with physostigmine was not due to its effects on sleep structure, as 1 h of sleep deprivation after training did not impair rotarod performance, (2) a reduction in cholinergic tone by inactivation of cholinergic neurons during early sleep did not affect rotarod performance, and (3) stimulating or blocking muscarinic and nicotinic acetylcholine receptors did not impair rotarod performance. Taken together, the experiments suggest that the increased slow wave activity and inactivation of both muscarinic and nicotinic receptors during early sleep due to reduced acetylcholine contribute to motor memory consolidation.
Topics: Acetylcholine; Animals; Memory Consolidation; Mice; Physostigmine; Sleep; Sleep Deprivation
PubMed: 31825510
DOI: 10.1093/sleep/zsz297 -
The Journal of Physiology Mar 19821. Cholinergic drugs were infused into the retinal circulation of the rabbit while we analysed the receptive field properties of directionally sensitive retinal ganglion...
1. Cholinergic drugs were infused into the retinal circulation of the rabbit while we analysed the receptive field properties of directionally sensitive retinal ganglion cells. Physostigmine eliminated the trigger feature, directional specificity, of both types (on-centre and on-off) of these cells. In this respect the action of physostigmine (an ACh potentiator) was very like that of picrotoxin (a GABA antagonist). Therefore, a detailed analysis of the receptive field properties of directionally sensitive ganglion cells was made to analyse the effects of physostigmine and picrotoxin.2. Size specificity and radial grating inhibition were not abolished by physostigmine, but were often affected by picrotoxin. The optimal velocity in the preferred direction (as measured by maximum firing frequency) was not much changed by physostigmine, but was higher during infusion of picrotoxin. Infusion of nicotine, a depolarizing ACh agonist which increases the activity of retinal ganglion cells, revealed the presence of inhibition to movement in the null direction. The null direction response during picrotoxin started slightly later than this inhibition. The null direction response during physostigmine was weaker and started later still. Mecamylamine and dihydro-beta-erythroidine, nicrotinic receptor antagonists, totally blocked the effect of physostigmine and reduced the control light response by about half.3. From this analysis, it appears that on-off ACh release onto directionally sensitive cells provides a substantial excitation which, when potentiated by physostigmine, overcomes or outlasts the null direction GABA inhibition within the receptive field. The spatial extent of GABA inhibition is asymmetric to and larger than the spatial extent of ACh excitation. Similar pathways appear to be involved in both the on-centre and on-off directionally sensitive ganglion cells, yet the on-centre cell pathway may receive an additional input which suppresses the ACh excitation at light offset. Possible schemes for the cellular mechanism of directional sensitivity are discussed in light of these results and recent anatomical and pharmacological findings.
Topics: Acetylcholine; Action Potentials; Animals; Neurons; Photic Stimulation; Physostigmine; Picrotoxin; Rabbits; Retina; gamma-Aminobutyric Acid
PubMed: 7097594
DOI: 10.1113/jphysiol.1982.sp014105 -
Journal of Neurophysiology Apr 2013Hippocampal theta and gamma oscillations coordinate the timing of multiple inputs to hippocampal neurons and have been linked to information processing and the dynamics...
Hippocampal theta and gamma oscillations coordinate the timing of multiple inputs to hippocampal neurons and have been linked to information processing and the dynamics of encoding and retrieval. One major influence on hippocampal rhythmicity is from cholinergic afferents. In both humans and rodents, aging is linked to impairments in hippocampus-dependent function along with degradation of cholinergic function. Cholinomimetics can reverse some age-related memory impairments and modulate oscillations in the hippocampus. Therefore, one would expect corresponding changes in these oscillations and possible rescue with the cholinomimetic physostigmine. Hippocampal activity was recorded while animals explored a familiar or a novel maze configuration. Reexposure to a familiar situation resulted in minimal aging effects or changes in theta or gamma oscillations. In contrast, exploration of a novel maze configuration increased theta power; this was greater in adult than old animals, although the deficit was reversed with physostigmine. In contrast to the theta results, the effects of novelty, age, and/or physostigmine on gamma were relatively weak. Unrelated to the behavioral situation were an age-related decrease in the degree of theta-gamma coupling and the fact that physostigmine lowered the frequency of theta in both adult and old animals. The results indicate that age-related changes in gamma and theta modulation of gamma, while reflecting aging changes in hippocampal circuitry, seem less related to aging changes in information processing. In contrast, the data support a role for theta and the cholinergic system in encoding and that hippocampal aging is related to impaired encoding of new information.
Topics: Aging; Animals; Brain Waves; Cholinesterase Inhibitors; Exploratory Behavior; Hippocampus; Male; Maze Learning; Physostigmine; Rats; Rats, Inbred F344; Theta Rhythm
PubMed: 23303862
DOI: 10.1152/jn.00409.2012 -
Psychopharmacology Sep 2015Bipolar disorder (BD) is a disabling and life-threatening disease characterized by states of depression and mania. New and efficacious treatments have not been...
RATIONALE
Bipolar disorder (BD) is a disabling and life-threatening disease characterized by states of depression and mania. New and efficacious treatments have not been forthcoming partly due to a lack of well-validated models representing both facets of BD.
OBJECTIVES
We hypothesized that cholinergic- and dopaminergic-pharmacological manipulations would model depression and mania respectively, each attenuated by lithium treatment.
METHODS
C57BL/6 J mice received the acetylcholinesterase inhibitor physostigmine or saline before testing for "behavioral despair" (immobility) in the tail suspension test (TST) and forced swim test (FST). Physostigmine effects on exploration and sensorimotor gating were assessed using the cross-species behavioral pattern monitor (BPM) and prepulse inhibition (PPI) paradigms. Other C57BL/6 J mice received chronic lithium drinking water (300, 600, or 1200 mg/l) before assessing their effects alone in the BPM or with physostigmine on FST performance. Another group was tested with acute GBR12909 (dopamine transporter inhibitor) and chronic lithium (1000 mg/l) in the BPM.
RESULTS
Physostigmine (0.03 mg/kg) increased immobility in the TST and FST without affecting activity, exploration, or PPI. Lithium (600 mg/l) resulted in low therapeutic serum concentrations and normalized the physostigmine-increased immobility in the FST. GBR12909 induced mania-like behavior in the BPM of which hyper-exploration was attenuated, though not reversed, after chronic lithium (1000 mg/ml).
CONCLUSIONS
Increased cholinergic levels induced depression-like behavior and hyperdopaminergia induced mania-like behavior in mice, while chronic lithium treated some, but not all, facets of these effects. These data support a cholinergic-monoaminergic mechanism for modeling BD aspects and provide a way to assess novel therapeutics.
Topics: Acetylcholine; Animals; Antimanic Agents; Behavior, Animal; Bipolar Disorder; Cholinesterase Inhibitors; Depression; Disease Models, Animal; Dopamine; Dopamine Uptake Inhibitors; Exploratory Behavior; Female; Hindlimb Suspension; Lithium Compounds; Male; Mice; Mice, Inbred C57BL; Physostigmine; Piperazines; Prepulse Inhibition; Sensory Gating; Swimming
PubMed: 26141192
DOI: 10.1007/s00213-015-4000-4 -
Current Alzheimer Research Feb 2009
Topics: Alzheimer Disease; Animals; Biomedical Research; Clinical Trials as Topic; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Drug Evaluation; Drug Industry; Humans; Observer Variation; Physostigmine; Selection Bias
PubMed: 19199878
DOI: 10.2174/156720509787313871