Cholinergic modulation of experience-dependent plasticity in human auditory cortex.
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The factors that influence experience-dependent plasticity in the human brain are unknown. We used event-related functional magnetic resonance imaging (fMRI) and a pharmacological manipulation to measure cholinergic modulation of experience-dependent plasticity in human auditory cortex. In a differential aversive conditioning paradigm, subjects were presented with high (1600 Hz) and low tones (400 Hz), one of which was conditioned by pairing with an electrical shock. Prior to presentation, subjects were given either a placebo or an anticholinergic drug (0.4 mg iv scopolamine). Experience-dependent plasticity, expressed as a conditioning-specific enhanced BOLD response, was evident in auditory cortex in the placebo group, but not with scopolamine. This study provides in vivo evidence that experience-dependent plasticity, evident in hemodynamic changes in human auditory cortex, is modulated by acetylcholine. (+info)
Cholinergic and nitrergic regulation of in vivo giant migrating contractions in rat colon.
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The aim of this study was to characterize in vivo rat colonic motor activity in normal and inflamed states and determine its neural regulation. Circular muscle contractions were recorded by surgically implanted strain-gauge transducers. The rat colon exhibited predominantly giant migrating contractions (GMCs) whose frequency decreased distally. Only a small percentage of these GMCs propagated in the distal direction; the rest occurred randomly. Phasic contractions were present, but their amplitude was very small compared with that of GMCs. Inflammation induced by oral administration of dextran sodium sulfate suppressed the frequency of GMCs in the proximal and middle but not in the distal colon. Frequency of GMCs was suppressed by intraperitoneally administered atropine and 4-diphenylacetoxy-N-methyl-piperidine methiodide and was enhanced by N(w)-nitro-L-arginine methyl ester. Serotonin, tachykinin, and calcitonin gene-related peptide receptor or receptor subtype antagonists as well as guanethidine and suramin had no significant effect on the frequency of GMCs. Verapamil transiently suppressed the GMCs. In conclusion, unlike the canine and human colons, the rat colon exhibits frequent GMCs and their frequency is suppressed in inflammation. In vivo GMCs are stimulated by neural release of acetylcholine that acts on M3 receptors. Constitutive release of nitric oxide may partially suppress their frequency. (+info)
Botulinum neurotoxin A blocks cholinergic ganglionic neurotransmission in the dog heart.
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There is no data about whether botulinum neurotoxin inhibits the parasympathetic ganglionic neurotransmission in the heart, although botulinum toxin as a clinical drug inhibits the release of acetylcholine at the neuromuscular junction. Therefore, we investigated whether botulinum toxin (type A) injected into the sinoatrial (SA) fat pad inhibits decreases in heart rate induced by stimulation of the preganglionic parasympathetic nerves in the heart of the anesthetized dog. Stimulation of the parasympathetic nerves in the SA fat pad (SAP stimulation) prolonged the atrial interval but not the atrioventricular (AV) interval, and cervical vagus nerve stimulation (CV stimulation) prolonged both atrial and AV intervals. After botulinum toxin (20 or 25 mouse units) was injected into the SA fat pad, it gradually inhibited the prolongation of the atrial interval evoked by SAP and CV stimulations but not the prolongation of the AV interval evoked by CV stimulation. Conditioning successive stimulation of the cervical vagus nerves accelerated the inhibition by botulinum toxin of the chronotropic response to CV stimulation. These results indicate that selective injection of botulinum toxin into the SA fat pad blocks bradycardia mediated by parasympathetic ganglionic activation in the dog heart. (+info)
Adenosine induces inositol 1,4,5-trisphosphate receptor-mediated mobilization of intracellular calcium stores in basal forebrain cholinergic neurons.
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In the cholinergic basal forebrain, we found previously that the extracellular adenosine concentration increase that accompanies sleep deprivation, acting via the A1 receptor, led to activation of the transcription factor nuclear factor-kappaB and to the upregulation of A1 adenosine receptor mRNA. We thus began to examine intracellular signaling mechanisms. We report here that adenosine, acting in a dose-dependent manner and predominantly via A1 receptors, stimulated IP3 receptor-regulated calcium release from intracellular stores. To the best of our knowledge, this calcium signaling pathway effect is a novel action of the G(i)-coupled A1 adenosine receptor in neurons. Moreover, this calcium mobilization was not seen at all in noncholinergic neurons but was present in a large proportion of cholinergic neurons. These data suggest a potential role for a calcium-signaling pathway in adenosine-induced long-term effects of sleep deprivation and a key role for cholinergic neurons in this process. (+info)
Agrin plays an organizing role in the formation of sympathetic synapses.
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Agrin is a nerve-derived factor that directs neuromuscular synapse formation, however its role in regulating interneuronal synaptogenesis is less clear. Here, we examine agrin's role in synapse formation between cholinergic preganglionic axons and sympathetic neurons in the superior cervical ganglion (SCG) using agrin-deficient mice. In dissociated cultures of SCG neurons, we found a significant decrease in the number of synapses with aggregates of presynaptic synaptophysin and postsynaptic neuronal acetylcholine receptor among agrin-deficient neurons as compared to wild-type neurons. Moreover, the levels of pre- and postsynaptic markers at the residual synapses in agrin-deficient SCG cultures were also reduced, and these defects were rescued by adding recombinant neural agrin to the cultures. Similarly, we observed a decreased matching of pre- and postsynaptic markers in SCG of agrin-deficient embryos, reflecting a decrease in the number of differentiated synapses in vivo. Finally, in electrophysiological experiments, we found that paired-pulse depression was more pronounced and posttetanic potentiation was significantly greater in agrin-deficient ganglia, indicating that synaptic transmission is also defective. Together, these findings indicate that neural agrin plays an organizing role in the formation and/or differentiation of interneuronal, cholinergic synapses. (+info)
Purines and pyrimidines are not involved in NANC relaxant responses in the rabbit vaginal wall.
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1. Non-adrenergic non-cholinergic (NANC) relaxant responses were elicited by electrical field stimulation (EFS) in rabbit vaginal wall strips after treatment with guanethidine and scopolamine and raising smooth muscle tone with phenylephrine. Under these conditions treatment with NOS inhibitors revealed a non-nitrergic NANC relaxant response. The possible role of purines and pyrimidines in these non-nitrergic NANC responses was investigated. 2. Exogenous application of ATP, ADP, adenosine, UTP, or UDP (all at 0.03-10 mM) induced concentration-dependent relaxant responses. 3. Responses to exogenous application of ATP were reduced by the general P2 antagonist cibacron blue (500 micro M), but not by suramin (100 micro M) and were unaffected by L-NAME (500 micro M), omega-conotoxin GVIA (omega-CTX, 500 nM) or tetrodotoxin (TTX, 1 micro M). 4. Responses to exogenous application of adenosine were reduced by the A(2A) antagonist ZM-241385 (30 micro M). 5. ATP- and ADP-induced responses were unaffected by the G-protein inhibitor pertussis toxin (100 ng ml(-1)), whilst ADP- but not ATP-induced responses were reduced by GDPbetaS (100 micro M), which stabilizes G-proteins in their inactive state. 6. EFS-induced non-nitrergic NANC relaxant responses were unaffected by suramin, cibacron blue, ZM-241385, pertussis toxin or GDPbetaS, but were completely inhibited by TTX. 7. Exogenous application of ATP (10 mM) and adenosine (10 mM) increased intracellular cyclic adenosine-3', 5'-monophosphate (cAMP). However, non-nitrergic NANC responses were not associated with increased cAMP. Neither non-nitrergic NANC responses nor responses to ATP or adenosine were associated with increased intracellular cyclic guanosine-3', 5'-monophosphate (cGMP) concentrations. 8. These results suggest that adenosine A(2A) receptors and P2 receptors are present in the rabbit vaginal wall, but that they are not involved in non-nitrergic NANC relaxant responses. (+info)
Reversal of akinesia in experimental parkinsonism by GABA antagonist microinjections in the pedunculopontine nucleus.
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Recent studies, mainly in animals, have shown that the pedunculopontine nucleus (PPN) in the upper brainstem has extensive connections with several motor centres in the CNS. This structure has also been implicated in the akinesia seen in patients with Parkinson's disease. Here we demonstrate that microinjection of gamma-aminobutyric acid (GABA) receptor A antagonist substance, bicuculline, into the PPN of non-human primates (n = 2) rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results in significant improvement of akinesia. The effect of bicuculline microinjection in the PPN matches that of oral administration of L-dopa. This finding opens up new possibilities in the management of akinesia, the most intractable symptom of advanced Parkinson's disease. (+info)
Acetylcholine released from cholinergic nerves contributes to cutaneous vasodilation during heat stress.
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Nitric oxide (NO) contributes to active cutaneous vasodilation during a heat stress in humans. Given that acetylcholine is released from cholinergic nerves during whole body heating, coupled with evidence that acetylcholine causes vasodilation via NO mechanisms, it is possible that release of acetylcholine in the dermal space contributes to cutaneous vasodilation during a heat stress. To test this hypothesis, in seven subjects skin blood flow (SkBF) and sweat rate were simultaneously monitored over three microdialysis membranes placed in the dermal space of dorsal forearm skin. One membrane was perfused with the acetylcholinesterase inhibitor neostigmine (10 microM), the second membrane was perfused with the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME; 10 mM) dissolved in the aforementioned neostigmine solution (l-NAME(Neo)), and the third membrane was perfused with Ringer solution as a control site. Each subject was exposed to approximately 20 min of whole body heating via a water-perfused suit, which increased mean body temperature from 36.4 +/- 0.1 to 37.5 +/- 0.1 degrees C (P < 0.05). After the heat stress, SkBF at each site was normalized to its maximum value, identified by administration of 28 mM sodium nitroprusside. Mean body temperature threshold for cutaneous vasodilation was significantly lower at the neostigmine-treated site relative to the other sites (neostigmine: 36.6 +/- 0.1 degrees C, l-NAME(Neo): 37.1 +/- 0.1 degrees C, control: 36.9 +/- 0.1 degrees C), whereas no significant threshold difference was observed between the l-NAME(Neo)-treated and control sites. At the end of the heat stress, SkBF was not different between the neostigmine-treated and control sites, whereas SkBF at the l-NAME(Neo)-treated site was significantly lower than the other sites. These results suggest that acetylcholine released from cholinergic nerves is capable of modulating cutaneous vasodilation via NO synthase mechanisms early in the heat stress but not after substantial cutaneous vasodilation. (+info)