Transmission In Rats Research Articles

Endogenous GABA released into the fourth ventricle of the rat brain in vivo is enhanced by noxious stimuli

In vivo release of endogenous γ-aminobutyric acid (GABA) and glutamic acid into the 4th ventricle of the rat brain in response to noxious stimuli was examined. Both these compounds were dansylated and the concentrations determined, using high-performance liquid chromatography (HPLC) combined with an UV detector. Following noxious stimuli (subcutaneous injection of diluted formalin into the hind-paw or noxious pinch of the hind-paws), there was a remarkable release of GABA, but not of glutamic acid. Basal on our heretofore obtained data that bicuculline methiodide, a GABA A antagonist, produces a potent analgesia in mice, the present results suggest that the GABAergic system in the brain stem may promote nociceptive transmission in rats

A further study of the neuromuscular effects of vesamicol (AH5183) and of its enantiomer specificity.

1. The effects of vesamicol (2-(4-phenylpiperidino) cyclohexanol), an inhibitor of acetylcholine storage, and its two optical isomers have been studied on neuromuscular transmission in rat and frog muscle, and on nerve conduction in frog nerve. 2. Racemic vesamicol produced a pre-block augmentation of twitch tension that also occurred in directly-stimulated muscle. This effect is thus at least partially due to an increase in muscle contractility. 3. (-)-Vesamicol was approximately 20 times more potent than (+)-vesamicol in blocking twitches elicited at 1 Hz. This degree of stereoselectivity is similar to that measured for inhibition of acetylcholine uptake by isolated synaptic vesicles. Both enantiomers were equally weak in reducing nerve action potential amplitude in frog nerve. 4. Further studies with the active isomer, (-)-vesamicol, showed that, like that produced by racemic vesamicol, the neuromuscular block was highly frequency-dependent. The block was not reversed by choline or neostigmine, but was partially reversed by 4- or 3,4-aminopyridine. 5. Preliminary electrophysiological studies showed that vesamicol reduced miniature endplate potential amplitude in rapidly-stimulated frog nerve-muscle preparations. Addition of lanthanum ions increased the frequency of miniature endplate potentials and led to the appearance of apparently normal-sized potentials amongst those of reduced amplitude. 6. The results show the close agreement between pharmacological and biochemical observations indicating the suitability of the rat diaphragm as a test model for substances of this nature. The degree of reversibility of the vesamicol-induced neuromuscular block by aminopyridines was unexpected, and it is suggested that in the presence of a drug which greatly increases release, a pool of acetylcholine is capable of being released which is not normally releasable after block of storage by vesamicol. It is also considered possible that the results from the intracellular recording studies may be explained in these terms.

Early enhancement of monosynaptic transmission in rat spinal motoneurons by conduction block of the peripheral nerve

Early enhancement of monosynaptic transmission in rat spinal motoneurons by conduction block of the peripheral nerve

P-112 - Pre- and postjunctional actions of neuropeptide Y on sympathetic transmission in rat perfused mesenteric arterial beds

P-112 - Pre- and postjunctional actions of neuropeptide Y on sympathetic transmission in rat perfused mesenteric arterial beds

Blockade and recovery of cholinergic transmission in rats treated with hemicholinium 3

Nerve-induced responses of parotid gland and gastrocnemius muscle were reduced by HC-3 (1 mg kg −1) in proportion to the number of stimuli. Contractions by somatic muscle at 100 Hz were abolished after 6.0 × 10 3 stimuli while 14 × 10 3 were applied at 20 Hz before secretion was blocked. As stimulus rate was decreased, blockade of secretion resulted from fewer stimuli but no difference in ACh content was found between stimulated and unstimulated glands. When stimuli were withheld for 1.5 h transmission recovered temporarily; initial secretory flow rate was only 50% of that in untreated controls when stimulation resumed. In both organs, the time during which responses were sustained, however, was much shorter than when the preparations were stimulated initially. After choline, recovery of transmission was dose-dependent: 150 mg kg −1 were required to restore responsiveness to the muscle and the gland comparable to that in HC-3-treated rats stimulated for the first time. Resting recovery, when stimuli are withheld, probably depends upon stored transmitter becoming mobilized rather than on de novo transmitter synthesis because the endogenous choline in plasma is only 1/1000 of that following exegenous choline.

Behavioural and ECoG spectrum power effects after intraventricular injection of drugs altering dopaminergic transmission in rats

In rats with cannulae permanently implanted into the third cerebral ventricle, the effects of different pharmacological manipulations affecting dopaminergic mechanisms, were studied on behaviour and electrocorticographic (ECoG) activity, continuously quantified in its spectrum power. The intraventricular injection (0.1–1 nmol) of ( − )3PPP[3-(3-hydroxyphenyl) N- n-propylpiperidine], a specific agonist at dopamine (DA) autoreceptors, produced dose-dependent behavioural sedation or sleep and an increase in ECoG spectrum power, with a predominant increase in the lower frequency bands. Short episodes of stereotyped movements, wet-dog syndrome, penile grooming and erection were also observed. Similar behavioural and ECoG effects were elicited by the intraventricular injection of R-( + )-8-chloro-2, 3,4,5-tetrohydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol (SCH 23390), a selective antagonist at D 1 postsynaptic receptors, although these were preceded by a short period of behavioural and sexual stimulation. In addition, the intraventricular administration of some neuroleptics, chloropromazine and haloperidol, produced behavioural and ECoG slow wave sleep. No significant changes were observed with a neuroleptic drug, 1-sulpiride, which is reputed to act selectively as an antagonist at dopamine D 2 receptors. In conclusion, the present experiments add new evidence in favour of the idea that dopaminergic mechanisms are involved in mammalian species in the control of arousal and that both post-synaptic D 1 and D 2 receptors may take part in such a control.

Cyclic adenosine 3′,5′‐monophosphate and β‐effects in rat isolated superior cervical ganglia

Isoprenaline (0.01-1 microM) increased the amount of cyclic adenosine 3',5'-monophosphate (cyclic AMP) in rat isolated superior cervical ganglia by up to 10 times after 10 min application. Cyclic AMP levels returned to control values after 20 min washing. Salbutamol, in concentrations (1-100 microM) that depolarized the ganglion and facilitated submaximal transmission, did not significantly raise ganglionic cyclic AMP levels. The action of isoprenaline was antagonized by butoxamine (apparent KI approximately equal to 0.14 microM) and weakly by practolol (apparent KI approximately equal to 9.1 microM). The effect of 0.1 microM isoprenaline was also inhibited 94% by 100 microM of the adenylate cyclase inhibitor, 9-(tetrahydro-2-furyl)adenine (SQ 22,536). Exogenous dibutyryl cyclic AMP did not replicate the effects of isoprenaline on ganglionic d.c. potentials or submaximal transmission. The phosphodiesterase inhibitors theophylline, isobutylmethylxanthine or 4-(3,4-dibutoxybenzyl)-2-imidazolidinone (Ro 20-1724) did not potentiate these electrical responses to isoprenaline. The adenylate cyclase inhibitor, SQ 22,536, did not inhibit the electrical responses to isoprenaline. It is concluded that available evidence does not support the view that the ganglion depolarization or facilitation of submaximal transmission in rat isolated ganglia produced by isoprenaline are likely to be mediated by cyclic AMP.

Modulation of transmission in rat sympathetic ganglia by activation of presynaptic alpha- and beta-adrenoceptors.

1 Conditions under which transmission in rat isolated superior cervical ganglia may be affected by activation of presynaptic alpha- and beta-adrenoceptors have been investigated by means of an extracellular recording method. 2 Clonidine caused a small hyperpolarization of the ganglia (mean EC50 approximately 2 nM) in unstimulated preparations; with continuous preganglionic stimulation at 0.2 Hz, clonidine markedly decreased the height of the compound action potential (mean EC50 approximately 18 nM). 3 Phentolamine (0.1-3 microM) per se increased the height of the compound action potential by up to 15%, and antagonized the inhibitory effects of adrenaline and clonidine. 4 Using a higher frequency of stimulation (0.5 Hz), the effect of phentolamine (1 microM) was unchanged, whereas the inhibitory effectiveness of adrenaline on the height of the compound action potential was reduced. 5 (+/-)-Propranolol (0.1 microM) did not affect the height of the compound action potential, whereas the inhibitory effects of high concentrations of adrenaline were enhanced. 6 During an infusion of clonidine (1 microM), adrenaline (1-100 microM) and, less effectively, noradrenaline (10-100 microM) increased the height of the compound action potential by up to 14%; these effects were antagonized by propranolol (0.1 microM). 7 In the presence of noradrenaline (10 and 30 microM) adrenaline (100 microM) caused a small (up to 5%) enhancement of the height of the compound action potential. 8 The results obtained are consistent with the existence of presynaptic alpha- and beta-adrenoceptors on preganglionic terminals. The alpha-adrenoceptor may be part of a trans-synaptic inhibitory feedback. mechanism; however the functional role of the facilitatory beta-adrenoceptor is not clear.

Axonal transport of noradrenaline and noradrenergic transmission in rats with streptozotocin-induced diabetes.

The accumulation of noradrenaline in constricted sciatic nerves was measured in 6 month diabetic rats (streptozotocin 35 mg/kg) and 4 day diabetic rats (streptozotocin 70 mg/kg) together with two groups of age-matched control animals. There was no alteration in the amount of noradrenaline accumulated in the nerves of the diabetic animals when compared with the controls. The vasa deferentia of the long-term diabetic animals showed an impaired response to stimulation of their noradrenergic nerves and a hypersensitivity to exogenous noradrenaline. These vasa were not wasted and showed a normal contractility in response to potassium chloride. Vasa deferentia from the short-term diabetic rats showed no abnormalities of function. Vasa deferentia from all groups of rats were also examined at the ultrastructural level. Specimens from all the chronically diabetic animals contained many abnormal nerve terminals. These lesions were not seen in vasa from the short-term diabetic rats. Taken together these findings indicate that rats with chronic streptozotocin-induced diabetes exhibit pathological changes in the noradrenergic nerves supplying the vas deferens. These animals do not, however, show an impairment of the axonal transport of noradrenaline.

Mechanisms of disturbance in neuromuscular transmission in rats with alloxan diabetes.

1. Considerable impairment of neuromuscular synaptic transmission, wholly due to a decrease in the excitatory capacity of the presynaptic formations, is observed in rats with mild alloxan diabetes of short duration. 2. The presynaptic mechanism of the deterioration in neuromuscular transmission is expressed in a reduction of the frequency of the MEPP and in a decrease in the quantum composition of the EPP, which leads to reduction of the amplitude of the rhythmical EPP of the skeletal muscles of animals with diabetes. 3. The progressive depression of the amplitude of the EPP of muscle fibers of rats with diabetes is due to a deficiency in the fraction of mediator ready for use as a result of insufficient synthesis of AC.

Ethanol effects on dopaminergic function: Modulation by the endogenous opioid system

Different behavioral and biochemical data suggest that ethanol has different effects on central dopaminergic transmission in rat and mouse. We found that ethanol induces an increase of striatal dopamine turnover which does not persist after chronic drinking. Following chronic ethanol treatment, we observed the development of supersensitivity of the striatal dopamine (DA) recognition sites, in terms of an enhanced affinity. We investigated various experimental models to clarify the existence of an enkephalinergic modulation of ethanol effects on the dopaminergic system. We found that in the rat, a pretreatment with naloxone abolishes the striatal DA turnover increase observed after ethanol. DBA 2J mice, which differ from C57 BL/6J and Swiss Albino, by genetically lacking enkephalinergic modulation on dopaminergic activity in the striatum, do not show any change of DA metabolism after acute ethanol. In the rat retina, where we hypothesized a less operant regulation of dopaminergic activity by enkephalins, tolerance does not develop after chronic drinking to the increase in DA turnover as it did in striatum. Our results confirm the importance of the endogenous opioid system in the regulation of the ethanol induced neurochemical and behavioral effects.

State of neuromuscular transmission in rats with experimental hypoparathyroidism

Experiments on albino rats with hypoparathyrosis demonstrated disturbances of the neuro-muscular transmission characterized by a decrease of the liminal strength of irritation in case of indirect stimulation, reduced amplitude of the muscle action potential, diminished latent period of response and absolute and relative refracterity phases and the character of muscular retention as well in indirect rhythmic stimulation. The investigated parameters displayed the same indices as in the control experiments following intravenous injection of proserine. Disturbances of the neuro-muscular transmission proved to be related to the presynaptic defect and could play a definite role in the development of the motor failure under conditions of hypoparathyrosis.

Inhibition of amine uptake by 4-phenyl-bicyclo(2,2,2)octan-1-amine hydrochloride monohydrate (EXP 561) in rats

SR58611A is a selective β3-adrenoceptor (Adrb3) agonist which has demonstrated antidepressant and anxiolytic properties in rodents. The present study confirmed the detection of Adrb3 mRNA transcript in rodent brain sub-regions and evaluated the effect of SR58611A on serotonergic and noradrenergic transmission in rats and mice in an attempt to elucidate the mechanism(s) underlying these properties.SR58611A (3 and 10 mg/kg, p.o.) increased the synthesis of 5-HT and tryptophan (Trp) levels in several rodent brain areas (cortex, hippocampus, hypothalamus, striatum). Moreover, SR58611A (10 mg/kg, p.o.) increased the release of 5-HT assessed by in vivo microdialysis in rat prefrontal cortex. Systemic (3 mg/kg, i.v.) or chronic administration of SR58611A (10 mg/kg, p.o.), in contrast to fluoxetine (15 mg/kg, p.o.), did not modify the activity of serotonergic neurons in the rat dorsal raphe nucleus. The increase in 5-HT synthesis induced by SR58611A was not observed in Adrb3s knockout mice, suggesting a selective involvement of Adrb3s in this effect.SR58611A (3 and 10 mg/kg, p.o.) did not modify norepinephrine synthesis and metabolism but increased its release in rat brain. Repeated administration of SR58611A (10 mg/kg, p.o.) did not modify basal norepinephrine release in rat prefrontal cortex whereas it prevented its tail-pinch stress-induced enhancement similarly to reboxetine (15 mg/kg, p.o.). Finally SR58611A increased the firing rate of noradrenergic neurons in the rat locus coeruleus following systemic (3 mg/kg, i.v.) or local (0.01 and 1 μM) but not chronic (10 mg/kg, p.o.) administration.These results suggest that the anxiolytic- and antidepressant-like activities of SR58611A involve an increase of brain serotonergic and noradrenergic neurotransmissions, triggered by activation of Adrb3s.

Pathological mechanisms in experimental autoimmune myasthenia gravis. I. Immunogenicity of syngeneic muscle acetylcholine receptor and quantitative extraction of receptor and antibody-receptor complexes from muscles of rats with experimental automimmune myasthenia gravis.

Immunization of Lewis rats with acetylcholine receptor (AChR) purified from either Electrophorus electricus electric organ or syngeneic rat muscle induced experimental autoimmune myasthenia gravis (EAMG). This was demonstrated by clinical signs of weakness and by electromyographic evidence of imparied neuromuscular transmission. The amount of rat AChR required to induce an autoimmune response was comparable to the amount of eel AChR required. In vitro complexing of rat AChrR with antibody reduced its immunogenicity. Autoantibody to muscle AChR was present in serum and complexed with AChR in muscle. Antibody was not bound to the ACh binding site of AChR, since antibody-AChR complexes extracted from muscle could still bind 125I-alpha-bungarotoxin. The amount of AChR extracted from muscle of rats with EAMG was diminished. The amount of AChR and antibody-AChR complexes in muscle was measured at intervals after immunization with eel AChR. The amount of AChR decreased in rats with acute EAMG, then transiently increased to more than normal amounts during remission, and finally decreased to only about 20% of normal in rats with chronic EAMG. At least half of the AChR remaining in animals with chronic EAMG was complexed with antibody. Thus, both a decrease in amount of AChR and the formation of antibody-AChR complexes contribute to impairment of neuromuscular transmission in rats with EAMG. The possible mechanisms involved in the changes in AChR content are discussed.

238) - Sympathetic inhibition on the intramural ganglionic transmission in rat isolated stomach

238) - Sympathetic inhibition on the intramural ganglionic transmission in rat isolated stomach

Effects of thalamic midline nuclei stimulation upon lateral geniculate transmission in rats: inhibition of principal cells and excitation of internuncial cells.

Effects of low-frequency stimulation of thalamic midline nuclei (MID) upon unitary activities of principal (P) and internuncial (I) cells of the lateral geniculate body were examined in urethane-anesthetized rats. P-cells responsed to single shocks to the optic tract (OT) with single spikes at short latencies (initial spike, IS), followed by a phase of inhibition which lasted for more than 150 msec and ended with a burst of grouped discharges (late discharge, LD). Excitability of P-cells, assessed with the response probability of IS to testing OT shocks, was reduced for about 300 msec after single shock stimulation of MID. Usually this excitability depression became evident about 20 msec after MID shocks and was maximum from 50 to 100 msec. LDs were made more vigorous when MID shocks were given almost simultaneously with testing OT shocks. This was interpreted that MID stimulation induced an inhibition in P-cells and it summed with that induced by OT stimulation. That the MID-induced inhibition of P-cells was due to IPSPs was proved by the quasi-intracellular recording. I-cells, the units fired repetitively by single OT shocks and have been presumed to be inhibitory neurons acting upon P-cells, were found to receive from MID stimulation an excitatory effect followed by an inhibitory one of long duration. It was suggested that the primary inhibition of P-cells by low-frequency stimulation of MID would be a direct consequence of the primary excitation of I-cells.

Inhibition of post-ganglionic motor transmission in vas deferens by indirectly acting sympathomimetic drugs.

1. Using field stimulation with short trains of pulses (< 10 per train), the post-ganglionic motor transmission in the mammalian vas deferens has been further analysed pharmacologically.2. In preparations taken from guinea-pigs, rats and rabbits the effects of the indirectly sympathomimetic drugs, tyramine and cocaine, could be explained entirely on the basis of the actions of released, endogenous noradrenaline.3. Tyramine produced a contraction in vasa taken from normal rats but not from normal guinea-pigs. The tyramine contraction was due to release of endogenous noradrenaline because it was not seen in preparations taken from reserpinized rats and because it was abolished in normal vasa by phenoxybenzamine or phentolamine, thus denying the supposed inaccessibility, to alpha-blockers, of the motor alpha-adrenoceptors activated by endogenous noradrenaline.4. Phenoxybenzamine or phentolamine failed to block post-ganglionic motor transmission in rat and in guinea-pig vasa.5. Tyramine strongly inhibited motor transmission in vasa taken from normal but not from reserpinized guinea-pigs.6. Tyramine produced inhibition of motor transmission in phenoxybenzamine-treated preparations taken from normal but not from reserpinized rats.7. Cocaine inhibited motor transmission in guinea-pig and in rat vasa. This effect was not due to a local anaesthetic or to a smooth-muscle depressant action because it did not occur in preparations taken from reserpinized animals.8. The inhibitory effect of tyramine or cocaine was not abolished by beta-adrenoceptor blockade with propranolol.9. Whereas reserpinization abolished the tyramine- and cocaine-inhibitions, it did not affect the inhibitory actions of noradrenaline or of PGE(2).10. Indomethacin and sodium meclofenamate, which suppress prostaglandin synthesis, did not affect the twitch-inhibiting actions of noradrenaline, tyramine or cocaine.11. These results provide further support for the conclusion that post-ganglionic motor transmission to the vas deferens is non-adrenergic in these species and assign to endogenously released noradrenaline an inhibitory role upon motor transmission.

Activation and transmission in rats of infection with Pneumocystis.

Corticosteroid-treated rats develop an overt infection with Pneumocystis and provide a ready source of organisms for study. A system of cortisonizing animals by the oral route was developed, utilizing daily provision of 200 ml of water containing 0.2 mg of dexamethasone and 100 mg of tetracycline to pairs of 200-g rats. The intensity of infection with Pneumocystis was related to length of time on treatment. Overt infection with Pneumocystis did not develop in a strain of pathogen-free rats in barrier cages while on the corticosteroid treatment schedule. However, transmission of the organism to pathogen-free treated animals was accomplished on contact exposure to infected rats.

Placental barrier to the fetal transfer of maternal chloroleukemia in rats.

SummaryI. No leukemia developed in a total of 84 offspring of a group of female rats with either active or latent Shay chloroleukemia followed for periods up to 2 years. None of 22 F2 generation offspring followed for a similar period developed leukemia. II. These data indicate efficient transplacental inhibition of Shay chloroleukemia transmission in rats. Although transplacental passage of inadequate numbers of leukemic cells may account for this result there is some evidence that either the placenta or some humoral placental factor may be responsible.