Effect of muscarinic ligands on the electrical activity recorded from the hippocampus: a quantitative approach. (73/85)

The electrical activity of the hippocampus was recorded from the CA 1 region in rats anaesthetized with halothane and the effects of compounds assessed following their intravenous injection. Quantification of the effects was achieved following on-line fast Fourier transformation of the signal. The electrical activity recorded from the hippocampus of the halothane-anaesthetized rat demonstrated identical characteristics to that recorded from the freely-moving animal. Three types of activity could be distinguished: rhythmical slow wave activity (RSA or theta); large amplitude slow wave activity (LIA); and small amplitude fast wave activity. Muscarinic agonists induced RSA with a consequent reduction in power. The effects were dose-dependent and were reversibly antagonized by scopolamine, but not methyl-scopolamine, indicating that the effects are mediated centrally by muscarinic receptors. The results show that, in halothane anaesthetized rats, a muscarinic RSA occurs which is unrelated to movement or behavioural arousal.  (+info)

The influence of cholinergic drugs on evoked field potentials in the gyrus dentatus of immobilized rats. (74/85)

We reported previously the elicitation of presumably monosynaptic evoked field potentials in the dentate gyrus of immobilized rats by stimulation of the medial septal nuclei. The septo-hippocampal pathway mediating this evoked potential (SHEP) is widely assumed to be cholinergic in nature. In order to further verify this assumption we studied the effects of muscarinic drugs on the SHEPs. Scopolamine as muscarinic cholinolytic and arecoline as muscarinic cholinergic agent influenced the SHEP in the expected manner. We conclude that the SHEP is elicited by cholinergic muscarinic activation.  (+info)

Characterization of muscarinic receptors mediating relaxation and contraction in the rat iris dilator muscle. (75/85)

1. The characteristics of muscarinic receptors mediating relaxation and/or contraction in the rat iris dilator muscle were examined. 2. Relaxation was induced in a dilator muscle by application of acetylcholine (ACh) at low doses (3 microM or less) and contraction was induced by high doses. Methacholine and carbachol also showed biphasic effects similar to those of ACh; in contrast, bethanechol, arecoline, pilocarpine and McN-A-343 induced mainly relaxation but no substantial contraction. 3. After parasympathetic denervation by ciliary ganglionectomy, the relaxant response to muscarinic agonists disappeared upon nerve stimulation. Application of McN-A-343 and pilocarpine induced only small contractions in denervated dilator muscles, indicating that these are partial agonists for contraction. 4. pA2 values of pirenzepine, methoctramine, AF-DX 116, himbacine, and 4-DAMP for antagonism to pilocarpine-induced relaxation in normal dilator muscles and those for antagonism to ACh-induced contraction in denervated dilator muscles were determined. The pA2 values for antagonism to relaxation of all these antagonists were most similar to those for M3-type muscarinic receptors. 5. Although pA2 values for contraction of these antagonists, except for methoctramine, were very close to those for relaxation, contraction was not significantly antagonized by methoctramine. Contraction might be mediated by M3-like receptors which have a very low affinity for methoctramine. 6. In conclusion, ACh-induced biphasic responses in rat iris dilator muscles were clearly distinguished from each other by specific muscarinic agonists and parasympathetic denervation, whereas muscarinic receptors could not be subclassified according to the pA2 values of 5 specific antagonists only.  (+info)

Potentiation by viral respiratory infection of ovalbumin-induced guinea-pig tracheal hyperresponsiveness: role for tachykinins. (76/85)

1. We investigated whether virus-induced airway hyperresponsiveness in guinea-pigs could be modulated by pretreatment with capsaicin and whether viral respiratory infections could potentiate ovalbumin-aerosol-induced tracheal hyperresponsiveness. 2. Animals were inoculated intratracheally with bovine parainfluenza-3 virus or control medium 7 days after treatment with capsaicin (50 mg kg-1, s.c.). Four days after inoculation, tracheal contractions were measured to increasing concentrations of substance P, histamine and the cholinoceptor agonist, arecoline. 3. In tracheae from virus-infected guinea-pigs, contractions in response to substance P, histamine and arecoline were significantly enhanced (P < 0.01) by 144%, 46% and 77%, respectively. Capsaicin pretreatment inhibited the hyperresponsiveness to substance P partly (62%) and to histamine and arecoline completely. 4. In another series of experiments animals were first sensitized with ovalbumin (20 mg kg-1, i.p.). After 14 days animals were exposed to either saline or ovalbumin aerosols for 8 days. After 4 aerosol exposures (4 days) animals were inoculated with either parainfluenza-3 virus or control medium. One day after the last ovalbumin aerosol, tracheal contraction in response to increasing concentrations of substance P, histamine and arecoline was measured. 5. Tracheae from ovalbumin-aerosol-exposed control inoculated animals showed a similar degree of airway hyperresponsiveness to saline-aerosol-exposed virus-treated guinea-pigs. Virus inoculation of ovalbumin-treated animals significantly potentiated the tracheal contractions to substance P compared to either of the treatments alone. The contractions in response to histamine and arecoline were only slightly enhanced. 6. In conclusion, sensory nerves and/or tachykinins are involved in virus-induced airway hyperresponsivenessin guinea-pigs and viral respiratory infections can potentiate the increase in tracheal responsiveness to bronchoconstrictor agonists after ovalbumin exposure.  (+info)

A centrally mediated prolonged hypotension produced by oxotremorine or pilocarpine. (77/85)

1 Oxotremorine, methyloxotremorine, pilocarpine or arecoline were given intravenously to anaesthetized cats, dogs or rats, and intraperitoneally to conscious normotensive and spontaneously hypertensive rats, pretreated with doses of methylatropine that completely blocked peripheral muscarinic receptors, to ascertain their effects on blood pressure and heart rate.2 Oxotremorine but not methyloxotremorine produced a prolonged hypotension in cats and dogs but not in rats. Heart rate was not changed. Pilocarpine, although less potent, produced an identical effect, whereas the effect of arecoline was short by comparison. The hypotensive effect of these drugs was reversed by atropine.3 In dogs, oxotremorine produced a prolonged hypotension with no change in heart rate or cardiac output.4 A decrease in spontaneous sympathetic nerve activity accompanied the hypotension in cats. Both effects were reversed by atropine but could be reinvoked by large doses of oxotremorine.5 The oxotremorine-induced hypotension in cats was not altered by decerebration but was abolished by high cervical spinal section.6 The results indicate that the prolonged hypotension elicited by oxotremorine is mediated by an action at muscarinic receptors in the brain stem resulting in a decrease in sympathetic nerve activity and peripheral resistance but not heart rate or cardiac output.  (+info)

Muscarinic excitatory and inhibitory mechanisms involved in afferent fibre-evoked depolarization of motoneurones in the neonatal rat spinal cord. (78/85)

1. The involvement of acetylcholine and muscarinic receptors in spinal synaptic responses evoked by electrical and noxious sensory stimuli was investigated in the neonatal rat spinal cord in vitro. 2. Potentials were recorded extracellularly from a ventral root (L3-L5) of the isolated spinal cord, spinal cord-cutaneous nerve, and spinal cord-skin preparations of 1- to 4-day-old rats. Spinal reflexes were elicited by electrical stimulation of the ipsilateral dorsal root or the cutaneous saphenous nerve, or by noxious skin stimulation. 3. Single shock stimulation of supramaximum intensity of a dorsal root induced a mono-synaptic reflex in the corresponding ventral root. Bath-application of the muscarinic agonists, muscarine (0.3-30 microM) and (+)-cis-dioxolane (0.1-100 microM), produced an inhibition of the mono-synaptic reflex and a depolarization of motoneurones. Other muscarinic agonists, arecoline (10 nM-10 microM) and oxotremorine (10 nM-1 microM), inhibited the mono-synaptic reflex with little or no depolarization of motoneurones. Repetitive stimulation of the saphenous nerve at C-fibre strength induced a slow depolarizing response lasting about 30 s of the L3 ventral root. This slow ventral root potential (VRP) was also inhibited by arecoline (10 nM-10 microM) and oxotremorine (10 nM-1 microM). 4. In the spinal cord-saphenous nerve-skin preparation, a slow VRP was evoked by application of capsaicin (0.5 microM), bradykinin (3 microM), or noxious heat (47 degrees C) to skin. This slow VRP was depressed by the muscarinic agonists, arecoline (3 microM) and oxotremorine (1 microM). 5. Of the (+)-cis-dioxolane-induced inhibition of mono-synaptic reflex and motoneurone depolarization, the M2 antagonists, AF-DX 116 (0.1-1 microM) and methoctramine (100-300 nM), preferentially blocked the former response, whereas the M3 antagonists, 4-DAMP (3-10 nM) and p-F-HHSiD (0.3-3 microM), preferentially blocked the latter response. AF-DX 116 (0.1-1 microM) and methoctramine (100-300 nM) also effectively antagonized the arecoline- and oxotremorine-induced inhibition of the slow VRP. The pA2 values of AF-DX 116 and methoctramine against the arecoline-induced inhibition of the mono-synaptic reflex were both 6.79, and that of 4-DAMP against the (+)-cis-dioxolane-induced motoneurone depolarization was 8.16. 6. In the spinal cord-cutaneous nerve preparation, the saphenous nerve-evoked slow VRP was augmented by the anticholinesterase, edrophonium (5 microM). AF-DX 116 (1 microM) and methoctramine (100 nM) also potentiated the slow VRP, whereas 4-DAMP (10 nM) depressed the response. 4-DAMP(5-10 nM) depressed the capsaicin-induced slow VRP in the spinal cord-skin preparation.7. Oxotremorine (0.3 microM) and arecoline (1 AM) markedly depressed the depolarization of motoneurones evoked by application of capsaicin (3 9AM) to the spinal cord, whereas they depressed only slightly the depolarization induced by substance P (10 nM).8. The present study suggests that both excitatory (via M3-type receptors) and inhibitory (via M2-type receptors) muscarinic mechanisms are involved in afferent fibre-evoked nociceptive transmissions in the neonatal rat spinal cord.  (+info)

Delayed emergence of effects of memory-enhancing drugs: implications for the dynamics of long-term memory. (79/85)

Many theories of memory postulate that processing of information outlasts the learning situation and involves several different physiological substrates. If such physiologically distinct mechanisms or stages of memory do in fact exist, they should be differentially affected by particular experimental manipulations. Accordingly, a selective improvement of the processes underlying short-term memory should be detectable only while the information is encoded in the short-term mode, and a selective influence on long-term memory should be detectable only from the moment when memory is based on the long-term trace. Our comparative study of the time course of the effects of the cholinergic agonist arecoline, the gamma-aminobutyric acid type B receptor antagonist CGP 36742, the angiotensin-converting enzyme inhibitor captopril, and the nootropic oxiracetam, four substances with completely different primary sites of action, show that the memory-enhancing effects consistently come into evidence no sooner than 16-24 h after the learning trial. On the one hand, this finding suggests that all these substances act by way of the same type of mechanism; on the other hand, it demonstrates that the substrate modulated by the compounds forms the basis of memory only after 16-24 h. From the observation that animals also show clear signs of retention during the first 16 h--i.e., before the effects of the substances are measurable--it can be inferred that retention during this time is mediated by other mechanisms that are not influenced by any of the substances.  (+info)

Phosphoinositide turnover imaging linked to muscarinic cholinergic receptor in the central nervous system by positron emission tomography. (80/85)

Receptor-mediated membrane processing plays an essential role in neural function in the synapses. In such neurotransmission process, the phosphoinositide (PI) response, an effector in the production of second-messengers, can be used to assess in vivo signal transduction. Using in vivo autoradiography and positron emission tomography (PET), we attempted to visualize the PI response to muscarinic cholinergic receptor (mAChR)-stimulation in rats and monkeys, which were administered 1,2-[11C]diacylglycerol (DAG) intravenously. Enhancement of 1,2-[11C]DAG incorporation was observed in the rat ipsilateral hippocampus and cortex in which mAChR-agonist was administered by local injection, but this was in contrast to spreading cortical depression in the ipsilateral cortex using KCl. In monkey PET studies, dynamic brain scanning revealed increase in activity over time for about 15 min after a bolus injection of 1,2-[11C]DAG in an awake state. The activity then remained at a constant level. This finding documented the theoretical "membrane-trapping" mechanism. The systemic mAChR-stimulation accelerated incorporation in the cerebral cortices of the same monkey brain. Radioactivity uptake did not differ significantly between the mAChR-stimulated and nonstimulated early scan images. This suggested that cerebral blood flow does not greatly affect DAG incorporation. In sequential membrane processes of PI turnover, diacylglycerol kinase rapidly metabolizes DAG, included in PI turnover. In conclusion 1,2-[11C]DAG incorporation was limited by receptor-mediated PI turnover, which can represent real synaptic transmission in neural networks.  (+info)