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1.
Behav Neurosci ; 133(5): 527-536, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31246078

RESUMO

Recent research suggests that rats are capable of object categorization-like processes. To study whether mice possess similar abilities, we developed a spontaneous one-trial object category recognition (OCR) task. Based on the spontaneous object recognition paradigm, mice discriminated between two otherwise equally novel objects, one from a novel category and one from a studied category. During the sample phase, mice were exposed to two different exemplars from the same category. After a retention delay, they explored a third (i.e., novel) object from that sampled category and an object from a novel category in a choice phase. Mice preferentially explored the novel category object, taken as an index of category recognition, in this OCR task when a 30-min retention delay was used. Extensive preexposure to category exemplar objects also enhanced subsequent task performance across a longer (1-h) retention delay at which mice without preexposure did not demonstrate evidence for category recognition. Prechoice administration of the acetylcholine muscarinic receptor antagonist, scopolamine, disrupted OCR performance with or without preexposure, implicating acetylcholine in category recognition. The current study presents a valuable new rodent task for the study of the mechanistic basis of categorization-like processes and its potential relevance to common cognitive disorders. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Acetilcolina/farmacologia , Reconhecimento Visual de Modelos/fisiologia , Receptores Muscarínicos/metabolismo , Acetilcolina/metabolismo , Animais , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas Muscarínicos/farmacologia , Reconhecimento Visual de Modelos/efeitos dos fármacos , Receptores Muscarínicos/fisiologia , Escopolamina/farmacologia , Percepção Visual/efeitos dos fármacos
2.
Genetics ; 212(1): 231-243, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30898771

RESUMO

Precise signaling at the neuromuscular junction (NMJ) is essential for proper muscle contraction. In the Caenorhabditis elegans pharynx, acetylcholine (ACh) released from the MC and M4 motor neurons stimulates two different types of contractions in adjacent muscle cells, termed pumping and isthmus peristalsis. MC stimulates rapid pumping through the nicotinic ACh receptor EAT-2, which is tightly localized at the MC NMJ, and eat-2 mutants exhibit a slow pump rate. Surprisingly, we found that eat-2 mutants also hyperstimulated peristaltic contractions, and that they were characterized by increased and prolonged Ca2+ transients in the isthmus muscles. This hyperstimulation depends on cross talk with the GAR-3 muscarinic ACh receptor as gar-3 mutation specifically suppressed the prolonged contraction and increased Ca2+ observed in eat-2 mutant peristalses. Similar GAR-3-dependent hyperstimulation was also observed in mutants lacking the ace-3 acetylcholinesterase, and we suggest that NMJ defects in eat-2 and ace-3 mutants result in ACh stimulation of extrasynaptic GAR-3 receptors in isthmus muscles. gar-3 mutation also suppressed slow larval growth and prolonged life span phenotypes that result from dietary restriction in eat-2 mutants, indicating that cross talk with the GAR-3 receptor has a long-term impact on feeding behavior and eat-2 mutant phenotypes.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Contração Muscular , Músculos/metabolismo , Junção Neuromuscular/metabolismo , Receptores Muscarínicos/metabolismo , Receptores Nicotínicos/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/fisiologia , Neurônios Motores , Músculos/fisiologia , Faringe/metabolismo , Faringe/fisiologia , Receptores Muscarínicos/fisiologia , Receptores Nicotínicos/fisiologia , Transdução de Sinais
3.
Neurobiol Learn Mem ; 161: 26-36, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30851433

RESUMO

The association of a sensory cue and an aversive footshock that are separated in time, as in trace fear conditioning, requires persistent activity in prelimbic cortex during the cue-shock interval. The activation of muscarinic acetylcholine receptors has been shown to facilitate persistent firing of cortical cells in response to brief stimulation, and muscarinic antagonists in the prefrontal cortex impair working memory. It is unknown, however, if the acquisition of associative trace fear conditioning is dependent on muscarinic signaling in the prefrontal cortex. Here, we delivered the muscarinic receptor antagonist scopolamine to the prelimbic cortex of rats prior to trace fear conditioning and tested their memories of the cue and training context the following day. The effect of scopolamine on working memory performance was also tested using a spatial delayed non-match to sample task. Male and female subjects were included to examine potential sex differences in the modulation of memory formation, as we have previously observed for pituitary adenylate cyclase-activating polypeptide signaling in the prefrontal cortex (Kirry et al., 2018). We found that pre-training administration of intra-prelimbic scopolamine impaired the formation of cued and contextual fear memories in males, but not females at a dose that impairs spatial working memory in both sexes. Fear memory formation in females was impaired by a higher dose of scopolamine and this impairment was gated by estrous cycle stage: scopolamine failed to impair memory in rats in the diestrus or proestrus stages of the estrous cycle. These findings add to the growing body of evidence that the prefrontal cortex is sexually dimorphic in learning and memory and additionally suggest that males and females differentially engage prefrontal neuromodulatory systems in support of learning.


Assuntos
Condicionamento Clássico/efeitos dos fármacos , Ciclo Estral/fisiologia , Medo/fisiologia , Memória de Curto Prazo/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Receptores Muscarínicos/fisiologia , Escopolamina/farmacologia , Caracteres Sexuais , Memória Espacial/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Sinais (Psicologia) , Feminino , Masculino , Antagonistas Muscarínicos/administração & dosagem , Córtex Pré-Frontal , Ratos , Ratos Long-Evans , Receptores Muscarínicos/efeitos dos fármacos , Escopolamina/administração & dosagem
4.
Neuroscience ; 404: 39-47, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30708046

RESUMO

Hippocampal cholinergic activity enhances long-term potentiation (LTP) of synaptic transmission in intrahippocampal circuits and regulates cognitive function. We recently demonstrated intracellular distribution of functional M1-muscarinic acetylcholine receptors (mAChRs) and neuronal uptake of acetylcholine (ACh) in the central nervous system. Here we examined whether endogenous ACh acts on intracellular M1-mAChRs following its uptake and causes cholinergic facilitation of hippocampal LTP. ACh esterase (AChE) activities and [3H]ACh uptake was measured in rat hippocampal segments. LTP of evoked field excitatory postsynaptic potentials at CA1 synapses was induced by high frequency stimulation in hippocampal slices. Pretreatment with diisopropylfluorophosphate (DFP) irreversibly inhibited AChE, augmented ACh uptake, and significantly enhanced the LTP. This cholinergic facilitation was inhibited by pirenzepine, a membrane-permeable M1 antagonist, while only the early stage of cholinergic facilitation was inhibited by a membrane-impermeable M1 antagonist, muscarinic toxin 7. Tetraethylammonium (TEA) inhibited ACh uptake in hippocampal segments and selectively suppressed late stage cholinergic facilitation without changing the early stage. In contrast, LTP in DFP-untreated slices was not affected by the muscarinic antagonists and TEA. Carbachol (CCh; an AChE-resistant muscarinic agonist) competed with ACh for its uptake and produced cholinergic facilitation of LTP in DFP-untreated slices. The late stage of CCh-induced facilitation was also selectively inhibited by TEA. Our results suggest that when AChE is inactivated by inhibitors, LTP in hippocampal slices is significantly enhanced by endogenous ACh and that cholinergic facilitation is caused by direct activation of cell-surface M1-mAChRs and subsequent activation of intracellular M1-mAChRs after ACh uptake.


Assuntos
Acetilcolina/metabolismo , Inibidores da Colinesterase/farmacologia , Hipocampo/metabolismo , Potenciação de Longa Duração/fisiologia , Receptores Muscarínicos/fisiologia , Acetilcolinesterase/metabolismo , Animais , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar
5.
Front Neural Circuits ; 12: 67, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30210306

RESUMO

This review contrasts the neuromodulatory influences of acetylcholine (ACh) on the relatively conserved primary visual cortex (V1), compared to the newly evolved dorsolateral prefrontal association cortex (dlPFC). ACh is critical both for proper circuit development and organization, and for optimal functioning of mature systems in both cortical regions. ACh acts through both nicotinic and muscarinic receptors, which show very different expression profiles in V1 vs. dlPFC, and differing effects on neuronal firing. Cholinergic effects mediate attentional influences in V1, enhancing representation of incoming sensory stimuli. In dlPFC ACh plays a permissive role for network communication. ACh receptor expression and ACh actions in higher visual areas have an intermediate profile between V1 and dlPFC. This changing role of ACh modulation across association cortices may help to illuminate the particular susceptibility of PFC in cognitive disorders, and provide therapeutic targets to strengthen cognition.


Assuntos
Acetilcolina/fisiologia , Transtornos Mentais , Córtex Pré-Frontal/fisiologia , Receptores Muscarínicos/fisiologia , Receptores Nicotínicos/fisiologia , Córtex Visual/fisiologia , Acetilcolina/metabolismo , Animais , Humanos , Transtornos Mentais/metabolismo , Transtornos Mentais/fisiopatologia , Córtex Pré-Frontal/metabolismo , Receptores Muscarínicos/metabolismo , Receptores Nicotínicos/metabolismo , Córtex Visual/metabolismo
6.
J Vet Med Sci ; 80(9): 1407-1415, 2018 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-29973432

RESUMO

ML204, a potent transient receptor potential canonical 4 (TRPC4) channel blocker, is often used to elucidate the involvement of TRPC4 channels in receptor-operated signaling processes in visceral smooth muscles. In the present study, we investigated the possible antagonistic actions of ML204 on M2 and M3 muscarinic receptors, which mediate contractions in mouse ileal and detrusor smooth muscles. In ileal and detrusor smooth muscle preparations, ML204 (3 or 10 µM) significantly inhibited electrical field stimulation (EFS)-evoked cholinergic contractions. However, it did not significantly inhibit high K+-induced and EFS-evoked non-cholinergic contractions in the ileal preparations. When the muscarinic agonist, carbachol was cumulatively applied, ML204 (1, 3 and 10 µM) caused a rightward parallel shift of the concentration-response curves of carbachol. Additionally, ML204 (1, 3 and 10 µM) inhibited carbachol-induced negative chronotropic response in atrial preparations, which is mediated by M2 muscarinic receptors. Furthermore, ML204 significantly inhibited the contractions evoked by carbachol-induced intracellular Ca2+ release, which is mediated by M3 muscarinic receptors. These results suggested that ML204 might exhibit antagonistic actions on M2 and M3 muscarinic receptors; in addition, the inhibitory effects of ML204 against EFS-induced cholinergic contractions might be attributed to this receptor antagonism rather than inhibition of TRPC4 channel activity. Therefore, these effects should be considered when ML204 is used as a TRPC4 channel blocker.


Assuntos
Antagonistas Muscarínicos/farmacologia , Contração Muscular/fisiologia , Receptores Muscarínicos/fisiologia , Canais de Cátion TRPC/fisiologia , Animais , Fibrilação Atrial , Carbacol , Japão , Masculino , Camundongos , Músculo Liso/fisiologia , Miocárdio , Canais de Cátion TRPC/antagonistas & inibidores
7.
J Ethnopharmacol ; 224: 409-420, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-29913298

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Eruca sativa Mill., (Brassicaceae) is a popular remedy for the treatment of hypertension in Pakistan. However, direct effect of the extract and its fractions on blood pressure and vascular tone are unknown. AIM OF THE STUDY: This investigation was aimed to explore the pharmacological base for the traditional use of E. sativa in hypertension. MATERIALS AND METHODS: In-vivo blood pressure study was carried out using normotensive and high salt-induced hypertensive rats under anaesthesia. The cardiovascular mechanisms were explored using rat aorta and atria in-vitro. Preliminary phytochemical analysis, spectrophotometric detection of total phenols, flavonoids and HPLC analysis of crude extract were performed using quercetin and erucin as marker compounds. RESULTS: Intravenous injection of crude extract induced a fall in mean arterial pressure (MAP) in both normotensive (max fall: 41.79 ±â€¯1.55% mmHg) and hypertensive (max fall: 58.25 ±â€¯0.91% mmHg) rats. Atropine (1 mg/kg) pretreatment attenuated this effect significantly (p < 0.001), suggesting the involvement of muscarinic receptor in its antihypertensive effect. Fractions also induced atropine-sensitive antihypertensive effect. Similarly, oral administration of crude and aqueous extracts resulted a fall in MAP in the hypertensive rats. In isolated rat aortic rings from normotensive rats, crude extract and fractions induced an endothelium-dependent relaxation. This relaxation was partially inhibited with L-NAME and atropine pretreatment and with denudation of aortic rings, indicating involvement of muscarinic receptor-linked nitric oxide (NO). In aorta from the hypertensive rats, crude extract and fractions induced endothelium-independent relaxation. This relaxation was not affected by pretreatment with L-NAME or atropine. Crude extract and fractions also suppressed phenylephrine contractions in Ca+2 free/EGTA medium. In isolated rat atrial preparations, crude extract and fractions induced negative inotropic and chronotropic effects with a positive inotropic effect by the n-hexane fraction, which were not affected with atropine pretreatment. Phytochemical screening and spectrophotometric analysis indicated the presence of phenols and flavonoids, whereas HPLC analysis of crude extract revealed the presence of quercetin (flavonoid) and erucin (isothiocyanate). CONCLUSION: The results suggest that E. sativa is an antihypertensive remedy which is mainly due to its vasodilatory and partly cardiac effects. Muscarinic receptors-linked NO release and dual inhibitory effect on Ca+2 influx and release underlie the vasodilation. This finding provides pharmacological base to the traditional use of E. sativa in hypertension. The presence of quercetin and erucin further support this finding.


Assuntos
Anti-Hipertensivos/farmacologia , Brassicaceae , Cardiotônicos/farmacologia , Extratos Vegetais/farmacologia , Receptores Muscarínicos/fisiologia , Vasodilatadores/farmacologia , Animais , Anti-Hipertensivos/análise , Anti-Hipertensivos/uso terapêutico , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Função Atrial/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Cardiotônicos/análise , Cardiotônicos/uso terapêutico , Átrios do Coração/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Técnicas In Vitro , Metanol/química , Camundongos Endogâmicos BALB C , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Componentes Aéreos da Planta/química , Extratos Vegetais/análise , Extratos Vegetais/uso terapêutico , Ratos Sprague-Dawley , Solventes/química , Vasodilatação/efeitos dos fármacos , Vasodilatadores/análise , Vasodilatadores/uso terapêutico
8.
Neurosci Lett ; 681: 6-11, 2018 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-29775673

RESUMO

Stress induces retrograde amnesia in humans and rodents. Muscarinic antagonism under normal physiological conditions causes gender dependent impairment in episodic memory retrieval. We aimed to explore the gender dependent role of muscarinic receptors in memory retrieval under sub-chronic stress condition. Male and female mice were trained for Morris water maze test and contextual fear conditioning, followed by 3 h restraint stress per day for five days. Stress was either given alone or in combination with a daily subcutaneous injection of scopolamine (1 mg/kg) or donepezil (1 mg/kg). Control mice were given saline without any stress. Sub-chronic stress (induced for five days) impaired spatial memory retrieval in males (P < 0.005) but not in females (P > 0.05). Stress induced spatial memory recall deficit in male mice was independent of muscarinic receptor activity (P > 0.05). However, stress induced contextual fear memory recall impairment was reversed by donepezil treatment in male (P < 0.005) and female (P < 0.0001) mice. These findings suggest that differential role of muscarinic activity in retrieving different types of memories under stress depends on gender of subjects.


Assuntos
Memória/fisiologia , Receptores Muscarínicos/fisiologia , Caracteres Sexuais , Estresse Psicológico/psicologia , Animais , Medo/efeitos dos fármacos , Medo/fisiologia , Medo/psicologia , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Rememoração Mental/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Antagonistas Muscarínicos/farmacologia , Escopolamina/farmacologia
9.
Sheng Li Xue Bao ; 70(2): 123-131, 2018 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-29691576

RESUMO

Cholinergic receptor activation and intracellular current injection lead to the persistent activity (PA), which may be involved in inducing neural plasticity. Our previous study showed that PA is closely related to the activation of muscarinic acetylcholine receptors (mAChRs) in pyramidal neurons of mouse primary auditory cortex (AI). However, the subtypes of mAChRs involved in PA remain unclear. Thus, using whole-cell patch-clamp recording and pharmacological methods, we investigated the role of different mAChR subtypes in inducing PA in AI layer V pyramidal neurons of young mice. The results showed that activation of mAChRs with intracellular depolarizing current induced PA in layer V pyramidal neurons. Blockade of M1, M2 or M3 subtypes prevented the PA, whereas M4 receptor antagonists did not affect the production of PA. The results suggest that the PA may be induced through a mechanism involving M1, M2 and M3 muscarinic receptors, but not M4 subtype.


Assuntos
Córtex Auditivo/fisiologia , Células Piramidais/fisiologia , Receptores Muscarínicos/fisiologia , Acetilcolina , Animais , Camundongos , Técnicas de Patch-Clamp , Receptores Muscarínicos/classificação
10.
Neuron ; 97(2): 390-405.e3, 2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-29290549

RESUMO

Sensorimotor integration regulates goal-directed movements. We study the signaling mechanisms underlying sensorimotor integration in C. elegans during olfactory steering, when the sinusoidal movements of the worm generate an in-phase oscillation in the concentration of the sampled odorant. We show that cholinergic neurotransmission encodes the oscillatory sensory response and the motor state of head undulations by acting through an acetylcholine-gated channel and a muscarinic acetylcholine receptor, respectively. These signals converge on two axonal domains of an interneuron RIA, where the sensory-evoked signal suppresses the motor-encoding signal to transform the spatial information of the odorant into the asymmetry between the axonal activities. The asymmetric synaptic outputs of the RIA axonal domains generate a directional bias in the locomotory trajectory. Experience alters the sensorimotor integration to generate specific behavioral changes. Our study reveals how cholinergic neurotransmission, which can represent sensory and motor information in the mammalian brain, regulates sensorimotor integration during goal-directed locomotions.


Assuntos
Acetilcolina/fisiologia , Caenorhabditis elegans/fisiologia , Quimiotaxia/fisiologia , Neurônios Colinérgicos/fisiologia , Locomoção/fisiologia , Percepção Olfatória/fisiologia , Comportamento Espacial/fisiologia , Animais , Animais Geneticamente Modificados , Aprendizagem da Esquiva/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/fisiologia , Cálcio/análise , Canais de Cloreto/fisiologia , Movimentos da Cabeça/fisiologia , Interneurônios/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Odorantes , Receptores Muscarínicos/fisiologia , Proteínas Recombinantes de Fusão/efeitos da radiação , Transmissão Sináptica , Transgenes
11.
Appetite ; 122: 17-25, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-27988368

RESUMO

The elucidation of the behavioral, neurochemical, neuroanatomical and genetic substrates mediating the development of conditioned flavor preferences (CFP) is one of the multi-faceted scientific contributions that Dr. Anthony Sclafani has made to the study of food intake. This review summarizes the results of thirty-five publications over nearly twenty years of collaborations between the Sclafani and Bodnar laboratories. This includes the different approaches employed to study the orosensory (flavor-flavor) and post-ingestive (flavor-nutrient) processes underlying CFP including its acquisition (learning) and expression. It describes how CFP is elicited by different sugars (sucrose, glucose, fructose) and fats (corn oil) in rats, and how strain-specific CFP effects can be observed through the use of inbred mouse strains to evaluate genetic variance. The roles of pharmacological substrates (dopamine, glutamate, opioids, acetylcholine, GABA, cannabinoids) mediating sugar- and fat-CFP acquisition and expression are elucidated. Finally, neuroanatomical sites of action (nucleus accumbens, amygdala, medial prefrontal and orbital frontal cortices, lateral hypothalamus) are evaluated at which dopamine signaling mediates acquisition and expression of different forms of CFP.


Assuntos
Encéfalo/fisiologia , Preferências Alimentares/fisiologia , Variantes Farmacogenômicos , Paladar , Acetilcolina/farmacologia , Animais , Canabinoides/farmacologia , Gorduras na Dieta/administração & dosagem , Açúcares da Dieta/administração & dosagem , Dopamina/fisiologia , Camundongos , N-Metilaspartato/fisiologia , Quinina/farmacologia , Ratos , Receptor CB1 de Canabinoide/fisiologia , Receptores de GABA-B/fisiologia , Receptores Muscarínicos/fisiologia
12.
Pharm Biol ; 56(1): 559-566, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31070538

RESUMO

CONTEXT: Aquilariae Lignum Resinatum (ALR), the dry rhizome of Aquilaria agallocha R. (Thymelaeaeeae), has been widely used to treat emesis, stomachache and gastrointestinal dysfunction. OBJECTIVE: This study evaluates the effects of ALR methanol extract on gastrointestinal motility (GIM) and possible mechanisms of the action involved. MATERIALS AND METHODS: In vivo, the study evaluated the effects of ALR (200-800 mg/kg) on gastric emptying and small intestinal motility in normal and neostigmine-induced adult KM mice. The in vitro effects of ALR (0.2-1.6 mg/mL) on GIM were performed on isolated jejunum of Wistar rats, pretreated with acetylcholine (ACh), KCl, CaCl2, and pre-incubation with l-NAME (a selective inhibitor of the nitric oxide synthase). RESULTS: In vivo, ALR (800 mg/kg) decreased gastric emptying (70.82 ± 9.81%, p < 0.01, compared with neostigmine group 91.40 ± 7.81%), small intestinal transit (42.82 ± 3.82%, p < 0.01, compared with neostigmine group 85.53 ± 5.57%). In vitro, ALR concentration dependently decreased the contractions induced by ACh (10-5 M) and KCl (60 mM) with respective EC50 values of 0.35 and 0.32 mg/mL. The Ca2+ concentration-response curves were shifted by ALR to the right, similar to that caused by verapamil (the positive). The spasmolytic activity of ALR was inhibited by pre-incubation with l-NAME. DISCUSSION AND CONCLUSIONS: ALR played a spasmolytic role in GIM, which is probably mediated through inhibition of muscarinic receptors, blockade of Ca2+ influx and NO release. This is the first study presenting a comprehensive description of the effects of ALR on GIM.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Motilidade Gastrointestinal/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Óxido Nítrico/antagonistas & inibidores , Parassimpatolíticos/farmacologia , Extratos Vegetais/farmacologia , Thymelaeaceae , Animais , Bloqueadores dos Canais de Cálcio/isolamento & purificação , Canais de Cálcio/fisiologia , Relação Dose-Resposta a Droga , Esvaziamento Gástrico/efeitos dos fármacos , Esvaziamento Gástrico/fisiologia , Motilidade Gastrointestinal/fisiologia , Camundongos , Antagonistas Muscarínicos/isolamento & purificação , Óxido Nítrico/fisiologia , Técnicas de Cultura de Órgãos , Parassimpatolíticos/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Distribuição Aleatória , Ratos , Ratos Wistar , Receptores Muscarínicos/fisiologia
13.
Bull Exp Biol Med ; 164(2): 144-147, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29178050

RESUMO

We studied the effect of moderate heat stress (30oC) and muscarinic cholinergic receptor agonists arecoline and pilocarpine on sensitivity of the behavior of the nematode Caenorhabditis elegans of N2 line to the action of the agonist of nicotinic cholinergic receptor agonist levamisole. Heat stress and muscarinic cholinergic receptor agonists increased the sensitivity of swimming induced by mechanical stimulation to levamisole (32-64 µM), which manifested in dyscoordination of locomotor muscles during swimming and complete loss of ability to swim. Combined exposure to heat stress and muscarinic cholinergic receptor agonists revealed their synergism in the influence on sensitivity of swimming behavior to levamisole: heating to 30oC potentiated the effect of arecoline and arecoline potentiated the effect of heat stress. It is assumed, that the effect of heat stress on the sensitivity of nicotinic receptors is mediated by its effect on muscarinic receptors.


Assuntos
Arecolina/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Agonistas Colinérgicos/farmacologia , Levamisol/farmacologia , Atividade Motora/efeitos dos fármacos , Pilocarpina/farmacologia , Animais , Caenorhabditis elegans/fisiologia , Resposta ao Choque Térmico/efeitos dos fármacos , Temperatura Alta , Receptores Muscarínicos/fisiologia , Receptores Nicotínicos/fisiologia , Natação
14.
Neurobiol Learn Mem ; 145: 59-66, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28864239

RESUMO

Memory retrieval requires coordinated intra- and inter-regional activity in networks of brain structures. Dysfunction of these networks and memory impairment are seen in many psychiatric disorders, but relatively little is known about how memory retrieval and memory failure are represented at the level of local and regional oscillatory activity. To address this question, we measured local field potentials (LFPs) from mice as they explored a novel context, retrieved memories for contextual fear conditioning, and after administration of two amnestic agents: the NMDA receptor antagonist MK-801 and muscarinic acetylcholine receptor antagonist scopolamine (SCOP). LFPs were simultaneously recorded from retrosplenial cortex (RSC), dorsal hippocampus (DH), and anterior cingulate cortex (ACC), which are involved in processing contextual memories, and analyzed for changes in intra-regional power and inter-regional peak coherence of oscillations across multiple frequency bands. Context encoding and memory retrieval sessions yielded similar patterns of changes across all three structures, including decreased delta power and increased theta peak coherence. Baseline effects of MK-801 and SCOP were primarily targeted to gamma oscillations, but in opposite directions. Both drugs also blocked memory retrieval, as indicated by reduced freezing when mice were returned to the conditioning context, but this common behavioral impairment was only associated with power and peak coherence disruptions after MK-801 treatment. These findings point to neural signatures for memory impairment, whose underlying mechanisms may serve as therapeutic targets for related psychiatric disorders.


Assuntos
Acetilcolina/fisiologia , Encéfalo/fisiologia , Ácido Glutâmico/fisiologia , Rememoração Mental/fisiologia , Transmissão Sináptica , Animais , Encéfalo/efeitos dos fármacos , Antagonistas Colinérgicos/administração & dosagem , Condicionamento Clássico , Maleato de Dizocilpina/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Medo , Masculino , Camundongos Endogâmicos C57BL , Vias Neurais/fisiologia , Receptores Muscarínicos/fisiologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , Escopolamina/administração & dosagem
15.
Pharmacol Biochem Behav ; 160: 39-46, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28807620

RESUMO

Background and Aim The cholinergic system can affect drug reward. The present study aimed to examine the roles of muscarinic acetylcholine receptor (mAChR) and nicotinic acetylcholine receptor (nAChR) in morphine-induced behavioral sensitization. METHODS: To analyze the roles of mAChR and nAChR in behavioral sensitization induced by morphine (5mg/kg), seven experiments were designed. Experiments 1 and 2 examined the effects of 3, 1, and 0.3 mg/kg scopolamine and 0.2, 0.1, and 0.05mg/kg scopolamine, respectively, on the locomotor activity when administered alone. Experiments 3 and 4 explored the effect of scopolamine on morphine-induced behavioral sensitization. Experiment 5 studied the effect of mecamylamine on morphine-induced behavioral sensitization. Experiments 6 and 7 investigated the effects of scopolamine+huperzine A and mecamylamine+huperzine A, respectively, on morphine-induced behavioral sensitization. RESULTS: The results revealed that 3mg/kg scopolamine, which significantly enhanced locomotor activity when administered alone, inhibited the acquisition of morphine-induced sensitization. However, mecamylamine (0.5, 1, 2mg/kg) did not have these effects. The co-administration of scopolamine (0.05 mg/kg)+huperzine A (0.4mg/kg) or mecamylamine (1mg/kg)+huperzine A (0.4mg/kg) did not affect the acquisition of morphine-induced behavioral sensitization. Scopolamine (0.05mg/kg) which did not affect the locomotor activity when administered alone, but not mecamylamine (1mg/kg), reversed the acute attenuation effect of huperzine A (0.4mg/kg) on morphine-induced locomotor activity at the acquisition stage and reversed the inhibition of huperzine A on the expression of morphine-induced sensitization. CONCLUSION: The mAChR might play a more important role in morphine-induced locomotor activity and the expression of morphine-induced behavioral sensitization. The mechanisms of mAChR and nAChR were relatively separate in morphine-induced sensitization.


Assuntos
Comportamento Animal/efeitos dos fármacos , Morfina/farmacologia , Receptores Muscarínicos/fisiologia , Alcaloides/farmacologia , Animais , Relação Dose-Resposta a Droga , Locomoção/efeitos dos fármacos , Masculino , Mecamilamina/farmacologia , Ratos , Ratos Wistar , Receptores Nicotínicos/fisiologia , Escopolamina/farmacologia , Sesquiterpenos/farmacologia
16.
Nitric Oxide ; 70: 51-58, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28847570

RESUMO

The aim of this study was to investigate the possible interaction of l-cysteine/H2S pathway and muscarinic acetylcholine receptors (mAChRs) in the mouse corpus cavernosum (CC). l-cysteine (endogenous H2S substrate; 10-6-10-3 M), sodium hydrogen sulfide (NaHS; exogenous H2S; 10-6-10-3 M) and acetylcholine (10-9-10-4 M) produced concentration-dependent relaxation in isolated mouse CC tissues. Relaxations to endogenous and exogenous H2S were reduced by non-selective mAChR antagonist atropine (5 × 10-5 M), selective M1 mAChR antagonist pirenzepine (5 × 10-5 M) and selective M3 mAChR antagonist 4-DAMP (10-7 M) but not by selective M2 mAChR antagonist AF-DX 116 (10-6 M). Also, acetylcholine-induced relaxations were reduced by atropine, pirenzepine, 4-DAMP and AF-DX 116, confirming the selective effects of mAChR antagonists. Furthermore, acetylcholine-induced relaxations were attenuated by cystathionine-gamma-lyase (CSE) inhibitor d,l-propargylglycine (PAG, 10-2 M) and cystathionine-ß-synthase inhibitor (CBS) aminooxyacetic acid (AOAA, 10-3 M). l-nitroarginine, nitric oxide synthase inhibitor, augmented the inhibitory effects of mAChR antagonists and H2S enzyme inhibitors on acetylcholine-induced relaxations. In addition, the existence and localization of CSE, CBS and 3-MST were demonstrated in mouse CC. Furthermore, tissue acetylcholine release was significantly increased by l-cysteine but not by exogenous H2S. The increase in acetylcholine level was completely inhibited by AOAA and PAG. These results suggest that M1 and M3 mAChRs contributes to relaxant effect mediated by endogenous H2S but at same time l-cysteine triggers acetylcholine release from cavernosal tissue. Also, the role of NO in the interaction of l-cysteine/H2S pathway and muscarinic acetylcholine receptors (mAChRs) could not be excluded.


Assuntos
Cisteína/fisiologia , Sulfeto de Hidrogênio/metabolismo , Pênis/fisiologia , Receptores Muscarínicos/fisiologia , Acetilcolina/metabolismo , Alquinos/farmacologia , Ácido Amino-Oxiacético/farmacologia , Animais , Cistationina beta-Sintase/antagonistas & inibidores , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/antagonistas & inibidores , Cistationina gama-Liase/metabolismo , Glicina/análogos & derivados , Glicina/farmacologia , Masculino , Camundongos , Antagonistas Muscarínicos/farmacologia , Relaxamento Muscular/fisiologia , Nitroarginina/farmacologia , Pênis/metabolismo , Receptores Muscarínicos/metabolismo , Transdução de Sinais/fisiologia , Sulfurtransferases/metabolismo
17.
J Physiol ; 595(17): 5875-5893, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28714121

RESUMO

KEY POINTS: The ascending brainstem transmitter acetylcholine depolarizes thalamocortical relay neurons while it induces hyperpolarization in local circuit inhibitory interneurons. Sustained K+ currents are modulated in thalamic neurons to control their activity modes; for the interneurons the molecular nature of the underlying ion channels is as yet unknown. Activation of TASK-1 K+ channels results in hyperpolarization of interneurons and suppression of their action potential firing. The modulation cascade involves a non-receptor tyrosine kinase, c-Src. The present study identifies a novel pathway for the activation of TASK-1 channels in CNS neurons that resembles cholinergic signalling and TASK-1 current modulation during hypoxia in smooth muscle cells. ABSTRACT: The dorsal part of the lateral geniculate nucleus (dLGN) is the main thalamic site for state-dependent transmission of visual information. Non-retinal inputs from the ascending arousal system and inhibition provided by γ-aminobutyric acid (GABA)ergic local circuit interneurons (INs) control neuronal activity within the dLGN. In particular, acetylcholine (ACh) depolarizes thalamocortical relay neurons by inhibiting two-pore domain potassium (K2P ) channels. Conversely, ACh also hyperpolarizes INs via an as-yet-unknown mechanism. By using whole cell patch-clamp recordings in brain slices and appropriate pharmacological tools we here report that stimulation of type 2 muscarinic ACh receptors induces IN hyperpolarization by recruiting the G-protein ßγ subunit (Gßγ), class-1A phosphatidylinositol-4,5-bisphosphate 3-kinase, and cellular and sarcoma (c-Src) tyrosine kinase, leading to activation of two-pore domain weakly inwardly rectifying K+ channel (TWIK)-related acid-sensitive K+ (TASK)-1 channels. The latter was confirmed by the use of TASK-1-deficient mice. Furthermore inhibition of phospholipase Cß as well as an increase in the intracellular level of phosphatidylinositol-3,4,5-trisphosphate facilitated the muscarinic effect. Our results have uncovered a previously unknown role of c-Src tyrosine kinase in regulating IN function in the brain and identified a novel mechanism by which TASK-1 channels are activated in neurons.


Assuntos
Acetilcolina/fisiologia , Interneurônios/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Canais de Potássio de Domínios Poros em Tandem/fisiologia , Tálamo/fisiologia , Quinases da Família src/fisiologia , Animais , Feminino , Subunidades beta da Proteína de Ligação ao GTP/fisiologia , Subunidades gama da Proteína de Ligação ao GTP/fisiologia , Masculino , Camundongos Transgênicos , Agonistas Muscarínicos/farmacologia , Proteínas do Tecido Nervoso/genética , Oxotremorina/análogos & derivados , Oxotremorina/farmacologia , Técnicas de Patch-Clamp , Fosfatidilinositol 3-Quinases/fisiologia , Canais de Potássio de Domínios Poros em Tandem/genética , Receptores Muscarínicos/fisiologia , Transdução de Sinais , Regulação para Cima
18.
Br J Pharmacol ; 174(19): 3173-3190, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28667666

RESUMO

The presence and severity of cognitive symptoms, including working memory, executive dysfunction and attentional impairment, contributes materially to functional impairment in schizophrenia. Cognitive symptoms have proved to be resistant to both first- and second-generation antipsychotic drugs. Efforts to develop a consensus set of cognitive domains that are both disrupted in schizophrenia and are amenable to cross-species validation (e.g. the National Institute of Mental Health Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia and Research Domain Criteria initiatives) are an important step towards standardization of outcome measures that can be used in preclinical testing of new drugs. While causative genetic mutations have not been identified, new technologies have identified novel genes as well as hitherto candidate genes previously implicated in the pathophysiology of schizophrenia and/or mechanisms of antipsychotic efficacy. This review comprises a selective summary of these developments, particularly phenotypic data arising from preclinical genetic models for cognitive dysfunction in schizophrenia, with the aim of indicating potential new directions for pro-cognitive therapeutics. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Animais , Antipsicóticos/uso terapêutico , Cognição/fisiologia , Disfunção Cognitiva/fisiopatologia , Predisposição Genética para Doença , Humanos , Receptores Dopaminérgicos/fisiologia , Receptores de Glutamato/fisiologia , Receptores Muscarínicos/fisiologia , Esquizofrenia/fisiopatologia
19.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 46(1): 15-21, 2017 Jan 25.
Artigo em Chinês | MEDLINE | ID: mdl-28436626

RESUMO

Epilepsy is a chronic neurological disorder, which is not only related to the imbalance between excitatory glutamic neurons and inhibitory GABAergic neurons, but also related to abnormal central cholinergic regulation. This article summarizes the scientific background and experimental data about cholinergic dysfunction in epilepsy from both cellular and network levels, further discusses the exact role of cholinergic system in epilepsy. In the cellular level, several types of epilepsy are believed to be associated with aberrant metabotropic muscarinic receptors in several different brain areas, while the mutations of ionotropic nicotinic receptors have been reported to result in a specific type of epilepsy-autosomal dominant nocturnal frontal lobe epilepsy. In the network level, cholinergic projection neurons as well as their interaction with other neurons may regulate the development of epilepsy, especially the cholinergic circuit from basal forebrain to hippocampus, while cholinergic local interneurons have not been reported to be associated with epilepsy. With the development of optogenetics and other techniques, dissect and regulate cholinergic related epilepsy circuit has become a hotspot of epilepsy research.


Assuntos
Neurônios Colinérgicos/química , Neurônios Colinérgicos/patologia , Neurônios Colinérgicos/fisiologia , Epilepsia/genética , Epilepsia/patologia , Epilepsia/fisiopatologia , Sistema Colinérgico não Neuronal/fisiologia , Acetilcolina/fisiologia , Prosencéfalo Basal/patologia , Química Encefálica/genética , Química Encefálica/fisiologia , Neurônios Colinérgicos/classificação , Epilepsia do Lobo Frontal/genética , Neurônios GABAérgicos/fisiologia , Hipocampo/patologia , Humanos , Mutação/genética , Mutação/fisiologia , Neurônios , Sistema Colinérgico não Neuronal/genética , Receptores Muscarínicos/genética , Receptores Muscarínicos/fisiologia , Receptores Nicotínicos/genética , Receptores Nicotínicos/fisiologia , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia
20.
Neurosci Lett ; 649: 62-69, 2017 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-28408330

RESUMO

Muscarinic cholinoreceptors regulate the neurosecretion process in vertebrate neuromuscular junctions. The diversity of muscarinic effects on acetylcholine (ACh) secretion may be attributed to the different muscarinic subtypes involved in this process. In the present study, the location of five muscarinic receptor subtypes (M1, M2, M3, M4 and M5) on the motor nerve terminals of frog cutaneous pectoris muscle was shown using specific polyclonal antibodies. The modulatory roles of these receptors were investigated via assessment of the effects of muscarine and specific muscarinic antagonists on the quantal content of endplate currents (EPCs) and the time course of secretion, which was estimated from the distribution of "real" synaptic delays of EPCs recorded in a low Ca2+/high Mg2+ solution. The agonist muscarine decreased the EPC quantal content and synchronized the release process. The depressing action of muscarine on the EPC quantal content was abolished only by pretreatment of the preparation with the M3 blockers 4-DAMP (1,1-Dimethyl-4-diphenylacetoxypiperidinium iodide) and J 104129 fumarate ((αR)-α-Cyclopentyl-α-hydroxy-N-[1-(4-methyl-3-pentenyl)-4-piperidinyl]benzeneacetamide fumarate). Moreover, antagonists of the M1, M2, M3 and M4 receptors per se diminished the intensity of secretion, which suggests a putative up-regulation of the release by endogenous ACh.


Assuntos
Acetilcolina/metabolismo , Placa Motora/metabolismo , Receptores Muscarínicos/fisiologia , Animais , Feminino , Masculino , Placa Motora/fisiologia , Rana ridibunda , Receptor Muscarínico M1/fisiologia , Receptor Muscarínico M2/fisiologia , Receptor Muscarínico M3/fisiologia , Receptor Muscarínico M4/fisiologia
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