Myoclonic and tonic seizures elicited by microinjection of cholinergic drugs into the inferior colliculus.

The inferior colliculus (IC) is the initiation site in the neuronal network for the epileptic audiogenic seizure (AGS). The present study investigates the effects of alteration of IC cholinergic transmission on the elicitation of epileptic seizures. Unilateral microinjections of carbachol (3 and 6 micrograms/0.2 microliter) into the IC elicited intense locomotor activity, contraversive rotations and myoclonic seizures. This result indicates that the IC is the initiation site for the induction of myoclonic seizures and suggests that these myoclonic seizures may result from activation of m1 muscarinic receptors. Microinjections of the nicotinic-muscarinic antagonist, gallamine (2 and 6 micrograms/0.2 microliter), into the IC induced AGS susceptibility. However, microinjections of muscarinic antagonists, atropine (15 micrograms/0.2 microliter) and scopolamine (12 and 20 micrograms/0.2 microliter), or the nicotinic antagonist, hexamethonium (12 and 20 micrograms/0.2 microliter), into the IC have no effect. Gallamine-induced AGS susceptibility may result from a selective blockade of m2 muscarinic receptors.

The inhibitory effect of the neuromuscular blocking agent, gallamine triethiodide, on camel retina acetylcholinesterase activity.

The present investigation addresses the mode of inhibition of the camel retinal acetylcholinesterase (AChE) activity by gallamine triethiodide, which is known to be a specific non-depolarizing neuromuscular blocking agent and polar cholinergic antagonist. This study gave the following results: it was found that gallamine (GA) reversibly inhibited the AChE activity in a concentration dependent manner, the IC50 being about 0.633 mM. The Km for the hydrolysis of acetylthiocholine iodide by AChE was found to be 0.0803 mM in the control system, and the value increased by 19-463% in the GA (0.125-1.0 mM) treated systems. The Vmax was 0.649 micromol/min per mg protein for the control as well as GA treated systems. Dixon as well as Lineweaver-Burk plots and their secondary replots indicated that the nature of the inhibition is of the reversible competitive type. The Ki value was estimated as 0.160 mM. The Ki value increased with an increase in substrate concentration. The turnover number (Kcat) and specificity constant (Ksp) were 62.1 min(-1) and 7.73 x 10(5) (M x min)(-1) in the control system while the value for one parameter (Ksp) was decreased by 25-83% in the GA (0.125-1.0 mM) treated systems.

Dysfunction of muscarinic M2 receptors after the early allergic reaction: possible contribution to bronchial hyperresponsiveness in allergic guinea-pigs.

1. Using a guinea-pig model of allergic asthma, in which the animals display early (0-5 h) and late phase (8-23 h after antigen challenge) bronchoconstrictor reactions, the function of prejunctional inhibitory M2 and postjunctional M3 receptors in isolated tracheal preparations have been investigated. In addition, cardiac M2 receptor function in vitro and bronchial responsiveness to histamine in vivo were evaluated. 2. Sensitivity to inhaled histamine was increased 3.1 fold and 1.6 fold after the early and late allergic reactions (i.e. at 5 h and 23 h after a single ovalbumin challenge), respectively. At 23 h after the last of four allergen challenges, executed on four consecutive days, bronchial hyperresponsiveness to histamine was diminished to 1.3 fold. 3. After the early response, there was no change in cardiac muscarinic M2 receptor function, since in left atria pD2 (-log EC50) and Emax values of pilocarpine and pKB values of AQ-RA 741, a selective M2 receptor antagonist, were not significantly different from controls (unchallenged sensitized animals), and this also applied to methacholine pD2 values for muscarinic M3 receptors in tracheal smooth muscle. 4. Prejunctional inhibitory muscarinic M2 autoreceptors in airway smooth muscle were markedly dysfunctional after the early allergic response, since potentiation of electrically evoked twitch contractions of tracheal preparations by low concentrations of the M2-selective muscarinic receptor antagonists, gallamine, methoctramine, AQ-RA 741 and AF-DX 116, which is the result of M2 receptor blockade, was clearly and significantly diminished compared to controls. However, after the late response, both in single and repeatedly challenged animals, twitch potentiation was not significantly different from and similar to controls, indicating restoration of M2 receptor function during the late allergic reaction.5. It is concluded that dysfunction of muscarinic M2 autoreceptors in the airways of sensitized and challenged guinea-pigs is already present after the early allergic reaction, and that it has recovered after the late response. Since histamine-induced bronchoconstriction involves vagal pathways, the present results suggest that bronchial hyperresponsiveness to histamine is partly due to M2 auto receptor dysfunction, leading to increased release of acetylcholine.

Ranitidine reverses gallamine paralysis in rats.

The effect of ranitidine on gallamine-induced depression of twitch tension was evaluated in urethane-anaesthetized and mechanically ventilated male Sprague-Dawley rats. Gallamine was administered as an intravenous (IV) bolus and constant rate infusion in 15 rats to maintain 89 +/- 7% (SE) depression of twitch tension induced by electrical stimulation of a sciatic nerve. Ranitidine, IV at either 0.5, 1, 2.5, 5, or 10 mg/kg, was then administered into groups of three rats. Ranitidine produced an immediate dose- and serum concentration-dependent reversal (antagonism) of the twitch tension depression induced with gallamine. The reversal was observed within approximately 30 s and was maintained for 3-26 (12 +/- 2) min. The dose of ranitidine that produced 50% reversal was 2.9 +/- 0.1 mg/kg, and this reversal was associated with a ranitidine serum concentration of 5.2 +/- 0.3 micrograms/mL. Ranitidine administered alone (and without gallamine) did not alter twitch tension at either 2.5 or 20 mg/kg. In addition, ranitidine did not alter either the gallamine neuromuscular blocking concentration in serum or the serum clearance of gallamine. Ranitidine reverses the neuromuscular action of gallamine, and this effect of ranitidine is not due to a pharmacokinetic interaction between ranitidine and gallamine.

Myoclonus in the decerebrate cat produced by gallamine.

After intravenous infusion maintaining a neuromuscular blocking concentration very little gallamine enters the cerebrospinal fluid (CSF) of the intact anesthetized cat even after several days. After a similar intravenous infusion in the decerebrate cat gallamine enters the CSF slowly over 4 days eventually reaching a concentration similar to that in the plasma. This procedure is accompanied by very strong twitching in many muscles and the occurrence of slow waves in the inferior olive in synchrony with the twitches. A large dose (4 mg) of gallamine triethiodide injected directly into the cisterna magna of an intact anesthetized cat produced twitching within 1 min and slow waves in the inferior olive in good synchrony with the twitches; the effects lasted at least 43 h. Injection of a quantity of gallamine triethiodide (about 130 micrograms) sufficient to mimic the concentration in the CSF obtained after 3-4 days of neuromuscular block in the decerebrate cat (50-120 micrograms/ml gallamine) had extremely weak effects lasting for at most 1 h. However, this weak effect is probably due to the anesthetic because injection of a similar quantity into an (unanesthetized) decerebrate cat at any time after decerebration had strong effects. After intracisternal injection of gallamine the concentration in the CSF reaches very low levels within 12 h but twitching and activity in the inferior olive persists for 1-2 days. The reasons for this prolonged action are now being investigated. The effects of gallamine are compared with the condition of reticular reflex myoclonus.

The painlike effect of gallamine and naloxone differs from sickness induced by lithium chloride.

In rats, the conditioned place and taste aversions produced by 31.8 mg/kg lithium chloride were compared with those produced by 10 mg/kg gallamine in Experiment 1 and 20 mg/kg or 2.5 mg/kg naloxone in Experiments 2 and 3, respectively. Lithium produced stronger taste aversions than gallamine or the two doses of naloxone, but gallamine and naloxone each produced stronger place aversions than lithium. These findings support the distinction between two kinds of drug-induced aversive effects, having different associative properties. One effect, called sickness, is more associable with taste than with place cues; the second effect is, like pain, more associable with place than with taste.

Cardiac vagolytic action of some neuromuscular blockers.

Cardiac vagolytic effect of four commonly used neuromuscular blockers, (viz. D-tubocurarine, decamethonium, pancuronium and gallamine) was compared in midcollicular decerebrate rats. The intravenous doses of neuromuscular blockers used (d-tubocurarine: 0.1 mg/kg; decamethonium: 2 mg/kg; pancuronium: 0.1 mg/kg; gallamine: 20 mg/kg) were sufficient to produce the paralysis of respiratory muscles. Bradycardia was induced by electrical stimulation of the vagus or by injecting dimethyl-phenyl-piperazinium (DMPP; a ganglionic stimulant). It was observed that d-tubocurarine and decamethonium were devoid of cardiac vagolytic action. On the other hand, pancuronium and gallamine inhibited significantly the bradycardia induced by electrical stimulation of the vagus or injection of DMPP; gallamine was found to have greater vagolytic action. The pressor responses to DMPP were not attenuated by pancuronium and gallamine indicating that in the dose administered, these agents did not block the ganglia. Bradycardia induced by the administration of acetylcholine in the left atrium was also attenuated by pancuronium and gallamine suggesting that the drugs produce cardiac vagolytic action by acting on the post-synaptic cholinergic receptors of the heart.

[Neuroactive compounds and vertebral teratogenesis in the bird embryo (author's transl)]. / Neuroactifs et tératogenèse vertébrale chez l'embryon d'oiseau.

Anticholinesterasic and depolarizing (analogues of acetylcholine) agents administered to quail embryos after 3 days of incubation give rise to vertebral fusions in addition to neck deformities. Antagonists of acetylcholine (gallamine and hexamethonium) produce only vertebral joint fusions. The incidence of all these compounds in the vertebral defects by the way of there neuroactive properties is proposed.