Acetylcholine (ACh) is an important neuromodulator in various cognitive functions. However, it is unclear how ACh influences neural circuit dynamics by altering cellular properties. Here, we investigated how ACh influences reverberatory activity in cultured neuronal networks. We found that ACh suppressed the occurrence of evoked reverberation at low to moderate doses, but to a much lesser extent at high doses. Moreover, high doses of ACh caused a longer duration of evoked reverberation, and a higher occurrence of spontaneous activity. With whole-cell recording from single neurons, we found that ACh inhibited excitatory postsynaptic currents (EPSCs) while elevating neuronal firing in a dose-dependent manner. Furthermore, all ACh-induced cellular and network changes were blocked by muscarinic, but not nicotinic receptor antagonists. With computational modeling, we found that simulated changes in EPSCs and the excitability of single cells mimicking the effects of ACh indeed modulated the evoked network reverberation similar to experimental observations. Thus, ACh modulates network dynamics in a biphasic fashion, probably by inhibiting excitatory synaptic transmission and facilitating neuronal excitability through muscarinic signaling pathways.
Cholinergic Agents/pharmacology* ; Acetylcholine/metabolism* ; Neurons/metabolism* ; Synaptic Transmission/physiology*

Cardiovascular diseases are life-threatening illnesses with high morbidity and mortality. Suppressed vagal (parasympathetic) activity and increased sympathetic activity are involved in these diseases. Currently, pharmacological interventions primarily aim to inhibit over-excitation of sympathetic nerves, while vagal modulation has been largely neglected. Many studies have demonstrated that increased vagal activity reduces cardiovascular risk factors in both animal models and human patients. Therefore, the improvement of vagal activity may be an alternate approach for the treatment of cardiovascular diseases. However, drugs used for vagus nerve activation in cardiovascular diseases are limited in the clinic. In this review, we provide an overview of the potential drug targets for modulating vagal nerve activation, including muscarinic, and β-adrenergic receptors. In addition, vagomimetic drugs (such as choline, acetylcholine, and pyridostigmine) and the mechanism underlying their cardiovascular protective effects are also discussed.
Acetylcholine ; pharmacology ; Animals ; Cardiovascular Diseases ; drug therapy ; Cholinergic Agents ; therapeutic use ; Humans ; Receptors, Muscarinic ; drug effects ; Sympathetic Nervous System ; drug effects ; physiopathology ; Vagus Nerve ; drug effects ; physiopathology

Artemisia capillaris Thunberg is a medicinal plant used as a traditional medicine in many cultures. It is an effective remedy for liver problems including hepatitis. Recent pharmacological reports have indicated that Artemisia species can exert various neurological effects. Previously, we reported a memory-enhancing effect of Artemisia species. However, the mechanisms underlying the neuroprotective effect of A. capillaris (AC) are still unknown. In the present study, we investigated the effect of an ethanol extract of AC on ischemic brain injury in a mouse model of transient forebrain ischemia. The mice were treated with AC for seven days, beginning one day before induction of transient forebrain ischemia. Behavioral deficits were investigated using the Y-maze. Nissl and Fluoro-jade B staining were used to indicate the site of injury. To determine the underlying mechanisms for the drug, we measured acetylcholinesterase activity. AC (200 mg·kg) treatment reduced transient forebrain ischemia-induced neuronal cell death in the hippocampal CA1 region. The AC-treated group also showed significant amelioration in the spontaneous alternation of the Y-maze test performance, compared to that in the untreated transient forebrain ischemia group. Moreover, AC treatment showed a concentration-dependent inhibitory effect on acetylcholinesterase activity in vitro. Finally, the effect of AC on forebrain ischemia was blocked by mecamylamine, a nonselective nicotinic acetylcholine receptor antagonist. Our results suggested that in a model of forebrain ischemia, AC protected against neuronal death through the activation of nicotinic acetylcholine receptors.
Acetylcholinesterase ; metabolism ; Animals ; Artemisia ; Cell Death ; drug effects ; Cholinergic Antagonists ; pharmacology ; Disease Models, Animal ; Ethanol ; chemistry ; Hippocampus ; pathology ; physiopathology ; Ischemic Attack, Transient ; drug therapy ; pathology ; physiopathology ; Male ; Mecamylamine ; pharmacology ; Memory ; drug effects ; Mice ; Mice, Inbred C57BL ; Models, Neurological ; Neuroprotective Agents ; administration & dosage ; pharmacology ; Phytotherapy ; Plant Components, Aerial ; chemistry ; Plant Extracts ; administration & dosage ; pharmacology ; Receptors, Cholinergic ; metabolism

PURPOSE: Reduced brain glucose metabolism and basal forebrain cholinergic neuron degeneration are common features of Alzheimer's disease and have been correlated with memory function. Although regions representing glucose hypometabolism in patients with Alzheimer's disease are targets of cholinergic basal forebrain neurons, the interaction between cholinergic denervation and glucose hypometabolism is still unclear. The aim of the present study was to evaluate glucose metabolism changes caused by cholinergic deficits. MATERIALS AND METHODS: We lesioned basal forebrain cholinergic neurons in rats using 192 immunoglobulin G-saporin. After 3 weeks, lesioned animals underwent water maze testing or were analyzed by 18F-2-fluoro-2-deoxyglucose positron emission tomography. RESULTS: During water maze probe testing, performance of the lesioned group decreased with respect to time spent in the target quadrant and platform zone. Cingulate cortex glucose metabolism in the lesioned group decreased, compared with the normal group. Additionally, acetylcholinesterase activity and glutamate decarboxylase 65/67 expression declined in the cingulate cortex. CONCLUSION: Our results reveal that spatial memory impairment in animals with selective basal forebrain cholinergic neuron damage is associated with a functional decline in the GABAergic and cholinergic system associated with cingulate cortex glucose hypometabolism.
Acetylcholine/metabolism ; Alzheimer Disease ; Animals ; Antibodies, Monoclonal/*pharmacology ; Basal Forebrain/*drug effects/metabolism ; Cholinergic Agents/administration & dosage/*pharmacology ; Cholinergic Neurons/*drug effects/metabolism ; Fluorodeoxyglucose F18 ; GABAergic Neurons/*drug effects/metabolism ; Glucose/*metabolism ; Gyrus Cinguli/*drug effects/metabolism ; Humans ; Injections ; Maze Learning ; Motor Activity/physiology ; Positron-Emission Tomography ; Rats ; Ribosome Inactivating Proteins, Type 1/*pharmacology

BACKGROUND/AIMS: Urocortin 1, a corticotropin-releasing factor related peptide, increases colonic motility under stressful conditions. We investigated the effect of urocortin 1 on colonic motility using an experimental model with isolated rat colon in which the blood flow and intestinal nerves were preserved. Furthermore, we assessed whether this effect was mediated by adrenergic or cholinergic nerves. METHODS: Colonic motility was measured in the proximal and distal parts of resected rat colon. The colon resected from the peritoneum was stabilized, and then urocortin 1 (13.8, 138, 277, and 1,388 pM) was administered via a blood vessel. Motility index was measured in the last 5 min of the 15 min administration of urocortin 1 and expressed as percentage change from baseline. Subsequently, the change in motility was measured by perfusing urocortin 1 in colons pretreated with phentolamine, propranolol, hexamethonium, atropine, or tetrodotoxin. RESULTS: At concentrations of 13.8, 138, 277, and 1,388 pM, urocortin 1 increased the motility of proximal colon (20.4+/-7.2%, 48.4+/-20.9%, 67.0+/-25.8%, and 64.2+/-20.9%, respectively) and the motility of distal colon (3.3+/-3.3%, 7.8+/-7.8%, 71.1+/-28.6%, and 87.4+/-32.5%, respectively). The motility induced by urocortin 1 was significantly decreased by atropine to 2.4+/-2.4% in proximal colon and 3.4+/-3.4% in distal colon (p<0.05). However, tetrodotoxin, propranolol, phentolamine, and hexamethonium did not inhibit motility. CONCLUSIONS: Urocortin 1 increased colonic motility and it is considered that this effect was directly mediated by local muscarinic cholinergic receptors.
Animals ; Colon/*drug effects/physiology ; Injections, Intravenous ; Male ; Muscle Contraction/drug effects ; Neurotransmitter Agents/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Cholinergic/chemistry/metabolism ; Urocortins/isolation & purification/*pharmacology

OBJECTIVETo investigate the changes of cholinergic nerves in doxorubicin (DOX)-induced rat failing heart and tumor necrosis factor-α (TNF-α) in the heart tissue and serum.

METHODSAdult Sprague-Dawley rats were randomized into control (n=10) and DOX-induced chronic heart failure (CHF) groups (n=15), and in the latter group, the rats were given intraperitoneal injections of 2.5 mg/kg DOX once a week for 6 weeks, with a total cumulative dose of 15 mg/kg. The control rats were injected with normal saline (1 ml/week). Karnovsky-Roots histochemical staining combined with point counting was used to demonstrate the distribution of cholinergic nerves in the heart. The expression levels of TNF-α in the heart tissue and serum were determined with ELISA.

RESULTSPositively stained cholinergic nerves were found in all the rat hearts in the two groups, but in CHF group, the point counts of cholinergic nerves were significantly lower than that of the control group (P<0.01). Compared with the control rats, those with DOX-induced CHF showed elevated levels of TNF-α both in the heart tissue and in the serum (P<0.01).

CONCLUSIONIn rats with DOX-induced CHF, the parasympathetic nervous system is down-regulated in the failing heart, and the diminished cholinergic anti-inflammatory pathway may play an important role in the progression of CHF.

Animals ; Cholinergic Agents ; pharmacology ; Cholinergic Fibers ; drug effects ; Doxorubicin ; pharmacology ; Heart ; drug effects ; innervation ; Heart Failure ; chemically induced ; metabolism ; Male ; Myocardium ; metabolism ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha ; metabolism

This article summarizes the progress of the application of functional magnetic resonance image (fMRI) on neuropharmacology. Cholinergic drugs are types of neurotransmitters which are usually used to treat neurological disorders. fMRI is widely used in the research of evaluation of cholinergic drugs. This article systematically summerizes the research of drug evaluation on memory, attention, emotion and vision by fMRI using the cholinergic drugs for example. Combined with the charactors and disciplines of traditional Chinese medicine (TCM), this article also makes a prospect of the application of fMRI on traditional Chinese medicine evaluation, especially the drugs on brain disease and emotional modulation.
Animals ; Cholinergic Agents ; pharmacology ; Drug Evaluation ; methods ; Humans ; Magnetic Resonance Imaging ; methods ; Medicine, Chinese Traditional ; Neurotransmitter Agents ; pharmacology

Based on the report of previous clinical study which showed cholinergic receptor antagonist scopolamine had antidepressant activity, this study was to investigate the antidepressant activity of scopolamine and explore its effective dose in mice, and to evaluate the effect of scopolamine on the central nervous system and learning/memory ability at its antidepressant effective dose. Tail suspension test, forced swimming test, step-down passive avoidance test and open field test were used to evaluate its effects on mice. Compared with the vehicle control group, single-dose administration of scopolamine (0.1-0.4 mg x kg(-1), ip) significantly decreased the immobility time (P < 0.01 or P < 0.001) in tail suspension test, and significantly decreased the immobility time (P < 0.001) in forced swimming test, but had no effect on the step-down latency and errors in step-down passive avoidance test. Scopolamine (0.1 and 0.2 mg x kg(-1), ip) had no influence on the locomotor activity in open field test, while at dose of 0.4 mg x kg(-1) significantly increase the locomotor activity. These results showed that scopolamine produced reliable antidepressant effect at doses of 0.1 and 0.2 mg x kg(-1), without impairment on learning and memory, as well as excitory or inhibitory effect on central nervous system in mice.
Animals ; Antidepressive Agents ; administration & dosage ; pharmacology ; Avoidance Learning ; drug effects ; Behavior, Animal ; drug effects ; Cholinergic Antagonists ; administration & dosage ; pharmacology ; Depression ; physiopathology ; prevention & control ; Hindlimb Suspension ; Male ; Memory ; drug effects ; Mice ; Mice, Inbred ICR ; Motor Activity ; drug effects ; Random Allocation ; Scopolamine Hydrobromide ; administration & dosage ; pharmacology ; Swimming

This study was aimed to investigate the protective effect of Liu Wei Dihuang (LWDH) against D-galactose (D-gal)-induced brain injury in rats and the existence of sex-dependent differences in LWDH protection. Sixty-four rats evenly composed of males and females were randomly assigned into 4 groups (n = 8): normal saline (NS) + NS (N + N), NS + LWDH (N + L), D-gal + NS (D + N) and D-gal + LWDH (D + L) groups. Rats in D + N and D + L groups received daily injection of D-gal (100 mg/kg, s.c.) for six weeks to establish the aging model, while rats in N + N and N + L groups were injected with the same volume of NS. From the third week, rats in N + L and D + L groups were orally administered with a decoction of LWDH for subsequent six weeks. Rats in N + N and D + N groups were orally administered just with the same volume of NS simultaneously. Morris water maze test was employed to evaluate the ability of learning and memory of the rats in all the groups. Acetylcholine (ACh) content, activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in visual cortex were assayed. Hematoxylin and eosin (HE) staining were used to observe the morphologic injury in hippocampus and visual cortex, and immunohistochemistry was performed to evaluate ChAT and AChE expression levels in the visual cortex. The results showed that the rats in D + N groups exhibited a longer escape latency to platform, lower swimming speed, less percent of target quadrant search time and platform crossings, compared with N + N groups, suggesting the establishment of aging model, while LWDH improved these indexes in D-gal-treated rats. Compared with D + N groups, LWDH increased ACh content and ChAT activity, and decreased AChE activity in visual cortex. Remarkable loss of neurons was found in hippocampus and visual cortex of aging rats, and the injury was significantly attenuated by LWDH. Immunohistochemistry showed D-gal-induced decreases of ChAT and AChE expressions were restored by LWDH. Furthermore, under the neural protection of LWDH, the improvement on platform crossings in male aging rats was better than that in female ones, while in ChAT expression and neuron density in visual cortex, female aging rats obtained more amelioration. These results suggest LWDH can markedly reverse the D-gal-induced cognitive impairments and neuronal damage in both hippocampus and visual cortex, which are achieved at least partly through restoring cholinergic system in central nervous system. Moreover, there is some sex difference in protective effects of LWDH against D-gal-induced impairment.
Animals ; Brain ; metabolism ; pathology ; Cholinergic Fibers ; drug effects ; pathology ; Cognition Disorders ; prevention & control ; Drugs, Chinese Herbal ; pharmacology ; Female ; Galactose ; toxicity ; Hippocampus ; metabolism ; pathology ; Male ; Neurons ; pathology ; Neuroprotective Agents ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Visual Cortex ; metabolism ; pathology

AIM AND METHODSIn the present study, we investigated the TH immunoreactivity and the expression of angiotensin AT1 receptor in locus coeruleus after intracerebroventricular (i. c. v.) injection of carbachol in conscious SD rats with immunohistochemistry. Meanwhile the effects of blocking AT1 receptor were also observed.

RESULTSBoth mean optical density and number of TH and AT1 immunoreactive positive neurons were markedly increased in locus coeruleus after 40 minutes of i.c.v. injection of carbachol (0.5 microg). The enhancement was significantly reduced by i. c. v. injection of losartan.

CONCLUSIONThe results above suggest that i. c. v. injection of cholinergic agonist carbachol can enhance the activity of adrenergic neurons and the expression of AT1 receptor in locus coeruleus. The blockade of AT1 receptor may down regulate the above action induced by carbachol in locus coeruleus.

Animals ; Brain ; Carbachol ; pharmacology ; Cholinergic Agents ; pharmacology ; Injections, Intraventricular ; Locus Coeruleus ; drug effects ; metabolism ; Losartan ; pharmacology ; Male ; Neurons ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, Angiotensin, Type 1 ; metabolism ; Tyrosine 3-Monooxygenase