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At least 19 recordsLinked to original sources

PubMed1994

The pharmacology of the nicotinic antagonist, chlorisondamine, investigated in rat brain and autonomic ganglion.

1. A single administration of the ganglion blocker, chlorisondamine (10 mg kg-1, s.c.) is known to produce a quasi-irreversible blockade of the central actions of nicotine in the rat. The mechanism of this persistent action is not known. It is also unclear whether chlorisondamine can block neuronal responses to excitatory amino acids and whether chronic blockade of nicotinic responses also occurs in the periphery. 2. Acute administration of chlorisondamine (10 mg kg-1, s.c.) to rats resulted in a blockade of central nicotinic effects (ataxia and prostration) when tested 1 to 14 days later, but caused no detectable cell death in tissue sections sampled throughout the rostrocaudal extent of the brain which were stained in order to reveal neuronal degeneration. 3. Long-term blockade of central nicotinic effects by chlorisondamine was not associated with significant alterations in the density (Bmax) of high-affinity [3H]-nicotine binding to forebrain cryostat-cut sections. 4. In cultured dissociated mesencephalic cells of the foetal rat, chlorisondamine and mecamylamine inhibited [3H]-dopamine release evoked by N-methyl-D-aspartate (NMDA, 10(-4) M), but only at high concentrations (IC50 approx. 600 and 70 microM, respectively). A high concentration of chlorisondamine (10(-3) M) had no effect on responses to quisqualate (10(-5) M) and only slightly reduced responses to kainate (10(-4) M). Mecamylamine (10(-3) M) was ineffective against both agonists. 5. In adult rat hippocampal slices, chlorisondamine depressed NMDA receptor-mediated synaptically-evoked field potentials, but again only at high concentrations (10(-4)-10(-3) M). Synaptic responses that were mediated by non-NMDA excitatory amino acid receptors were less affected. 6. In rat isolated superior cervical ganglion, electrically-evoked synaptic transmission was reduced 1 h after acute in vivo administration of chlorisondamine (0.1 mg kg-1, s.c.). However, in vivo administration of a higher dose (10 mg kg-1, s.c.) did not significantly affect ganglionic transmission when tested two weeks later, despite the continued presence of central nicotinic blockade.7. These results indicate that the persistent CNS nicotinic blockade by chlorisondamine is not accompanied by changes in nicotinic [3H]-nicotine binding site density or by neuronal degeneration in the brain; that at doses sufficient to produce nicotinic receptor blockade, chlorisondamine acts in a pharmacologically selective manner; and that chronic central blockade is not accompanied by long-term peripheral ganglionic blockade.

Amino Acids↗

PubMed1994

Blockade of nicotinic receptor-mediated release of dopamine from striatal synaptosomes by chlorisondamine administered in vivo.

1. The chronic nicotinic blockade produced following in vivo administration of chlorisondamine was investigated in vitro. Nicotine-induced [3H]-dopamine release from striatal synaptosomes was used as a measure of central nicotinic receptor function. 2. In synaptosomal preparations from rats pretreated with a single administration of chlorisondamine (10 mg kg-1, s.c.), 1, 7, 21, 42, 63 or 84 days before they were killed, responses to (-)-nicotine (10(-6) M) were blocked. 3. In vivo administration of chlorisondamine (10 mg kg-1, s.c.), 7 days before rats were killed, produced a nicotinic blockade in vitro that was insurmountable even with a high concentration of (-)-nicotine (10(-4) M). 4. Both in vitro and in vivo administration of chlorisondamine blocked nicotinic responses to acetylcholine (10(-4) M). In contrast, neither in vitro nor in vivo administration of chlorisondamine reduced [3H]-dopamine release induced by high K+ (20 x 10(-3) M) or (+)-amphetamine (10(-6) M). 5. Nicotinic blockade resulting from in vitro administration of chlorisondamine (10(-5) M) recovered partially after 60 min wash-out, and completely by 90 min. In contrast, no recovery was seen in synaptosomes prepared from rats pretreated with chlorisondamine (10 mg kg-1, s.c.) in vivo. 6. Thus, in vivo treatment with chlorisondamine results in a quasi-irreversible, insurmountable block of CNS nicotinic receptors. The persistence of this block ex vivo indicates that physical trapping by the blood brain barrier is not solely responsible for the persistent blockade seen in vivo. The resistance of this blockade to prolonged in vitro wash-out suggests that the underlying mechanism differs from that associated with in vitro administration.

Acetylcholine↗

PubMed1983

Blockade of cholinergic channels by chlorisondamine on a crustacean muscle.

Details of the blocking action of chlorisondamine, a ganglionic nicotinic blocker, on the excitatory cholinergic currents of the spiny lobster gastric mill 1 (g.m.1) muscle are described. The steady-state block of cholinergic ionophoretic currents produced by chlorisondamine is strongly voltage-dependent. During a hyperpolarizing voltage step, a sequence of ionophoretic agonist pulses in the presence of chlorisondamine shows a large interpulse interaction manifested as a gradual diminution in response amplitude. The extent of diminution is dependent on the number of the pulse in a series and not on the duration of the interval between pulses. The slowly developing blockade is entirely dependent on agonist application. If agonist application is suspended for various time intervals following the development of a given blocked level in chlorisondamine, no recovery from the block is observed whether the rest interval is at the step potential or at more depolarized potentials. Recovery from a given blocked level can be observed if, during a depolarizing voltage step (to -60 mV) away from the potential at which the block was established (-140 mV), agonist is applied before return to the initial potential (-140 mV). Chlorisondamine produces a dose-dependent reduction in excitatory junctional current (e.j.c.) decay rate that is linear with chlorisondamine concentration and markedly dependent on voltage (approximately equal to 35 mV/e-fold change). Reduction in the amplitude of e.j.c.s occurred at concentrations of chlorisondamine that produced no detectable effect on e.j.c. decay. Alterations in e.j.c. amplitude showed time- and use-dependent aspects similar to those observed for ionophoretic currents. These results are discussed primarily in terms of a sequential model in which, following the binding of chlorisondamine to the opened ion channel, the channel can undergo a transition to a stable-blocked state that requires reactivation by agonist to become unblocked. This stable-blocked state is considered a closed-blocked channel.

Acetylcholine↗

PubMed1983

Excitatory junctional responses and glutamate responses at the crayfish neuromuscular junction in the presence of chlorisondamine.

At the crayfish neuromuscular junction chlorisondamine reduced the amplitude of both the excitatory junctional potential and the glutamate current in a dose-dependent manner in concentrations above 3 microM, and it is suggested that the drug is a powerful non-competitive antagonist for glutamate. Chlorisondamine did not act presynaptically on the crayfish neuromuscular junction. A double exponential decay of excitatory synaptic currents was observed in the presence of chlorisondamine, suggesting that this drug is an open channel blocker for the excitatory neurotransmitter. The glutamate current tail was prolonged in the presence of chlorisondamine. This prolongation increased with increasing iontophoretic current of glutamate. The rate of recovery from the refractory form of the glutamate receptor to the free reactive one was hardly affected by chlorisondamine. The inhibitory action of chlorisondamine on glutamate responses was voltage-dependent and hyperpolarization reduced the drug action. Chlorisondamine depressed the glutamate current even in Na-free, Ca-rich solution.

Animals↗

PubMed1994

Regulation of nicotinic receptors in rat brain following quasi-irreversible nicotinic blockade by chlorisondamine and chronic treatment with nicotine.

1. Chronic administration of nicotinic agonists in vivo increases the density of brain nicotinic binding sites. It has been proposed that this up-regulation results from agonist-induced functional blockade of nicotinic receptors. This hypothesis was tested by examining post mortem [3H]-nicotine and [125I]-alpha-bungarotoxin ([125I]-alpha BTX) binding following treatment in vivo with the quasi-irreversible and insurmountable CNS nicotinic blocker chlorisondamine, given either alone or in combination with chronic nicotine administration. 2. In rats that had not received chlorisondamine pretreatment, chronic nicotine administration (0.6 mg kg-1 s.c., twice daily for 12 days) increased [3H]-nicotine binding density (Bmax) in forebrain tissue sections by 19%, with no change in the apparent dissociation constant (KD). Chlorisondamine (10 mg kg-1, s.c.), given once prior to the chronic treatment phase, neither increased [3H]-nicotine binding by itself, nor altered the extent of nicotine-induced up-regulation. Nevertheless, chlorisondamine pretreatment resulted in a persistent blockade of CNS nicotinic receptors, as demonstrated by complete block of acute locomotor responses to nicotine. 3. In a second experiment, [3H]-nicotine and [125I]-alpha BTX binding was measured in tissue homogenates prepared from several brain regions. In the absence of chlorisondamine pretreatment, chronic nicotine administration (1 mg kg-1 s.c., twice daily for 12 days) increased the Bmax of [3H]-nicotine binding in the cerebral cortex (by 34%), striatum (by 28%), midbrain (by 16%) and hippocampus (by 36%); KD was unchanged. As before, this up-regulation was neither mimicked nor blocked by chlorisondamine pretreatment (10 mg kg-1, s.c., given twice), despite persistent blockade of acute locomotor responses to nicotine. Chronic nicotine treatment also increased the Bmax (but not KD) of [125I]-alpha BTX binding in cerebral cortex (by 35%), hippocampus (by 46%) and midbrain (by 35%). Chlorisondamine altered neither Bmax nor KD when given alone, but significantly attenuated the nicotine-induced up-regulation of toxin binding sites in midbrain, with a similar trend in the other two regions.4. The finding that chronic receptor blockade neither mimicked nor blocked the agonist-induced up-regulation of [3H]-nicotine binding sites suggests that up-regulation of these receptors is not determined by their functional status. In contrast, it appears that chronic nicotine-induced up-regulation of[125I]-alpha BTX binding sites may result from receptor activation.

Animals↗

PubMed1993

Effects of central nicotinic cholinergic receptor blockade produced by chlorisondamine on learning and memory performance in rats.

The effects of chronic nicotinic receptor blockade on the performance of learning and memory tasks were determined using chlorisondamine, a compound which produces central nicotinic cholinergic receptor blockade that lasts for several weeks after a single icv administration. Chlorisondamine treatment did not affect the acquisition of spatial information in the Morris water maze or in the radial arm maze, tasks in which performance is reportedly disrupted by acute administration of the nicotinic antagonist, mecamylamine. Chlorisondamine also did not affect performance in the inhibitory avoidance task and did not alter the memory enhancement found in this task after post-training administration of nicotine. Mecamylamine, however, completely blocked the memory-enhancing effects of nicotine. In contrast to the differential ability to chlorisondamine and mecamylamine to block nicotine's memory-enhancing effects, these antagonists produced comparable blockade of nicotine's effects on open field behavior. It is unlikely that the different effects of systemically administered mecamylamine and centrally administered chlorisondamine on nicotine-induced memory enhancement are due to mecamylamine's peripheral effects, since hexamethonium, a peripherally active nicotinic antagonist, did not block nicotine-induced memory enhancement. The different pattern of effects of mecamylamine and chlorisondamine may be related to compensatory mechanisms being selectively induced by chronic blockade produced by chlorisondamine and not by acute blockade produced by mecamylamine. Alternatively, different effects of these two nicotinic cholinergic antagonists on the performance of learning and memory tasks might be related to selective actions of these compounds at nicotinic receptor subtypes or at nonnicotinic receptors.

Animals↗

PubMedDate not supplied

Effects of chlorisondamine and restraint on cortical [3H]ketanserin binding, 5-HT2A receptor-mediated head shakes, and behaviours in models of anxiety.

A recent study has indicated that ganglionic transmission mediates acute restraint-elicited increases in brain tryptophan (5-HT precursor) levels, 5-HT synthesis and (possibly) release. Because restraint-induced release of 5-HT has been shown to be associated with a paradoxical increase in cortical 5-HT2A receptor binding, we have examined the influence of 5-HT synthesis/release upon cortical 5-HT2A receptor binding and 5-HT2A receptor-mediated head shakes in 3-hr restrained rats pretreated with the ganglionic blocker chlorisondamine. In keeping with past reports regarding the effects of restraint and ganglionic blockade upon anxiety, we have also measured the behavioural effects of restraint and/or chlorisondamine in two animal models of anxiety, the elevated plus-maze and the social interaction test. Chlorisondamine pretreatment (2.5 mg/kg, 20 min beforehand) prevented restraint-elicited defaecation and body weight decreases. Although stress amplified the head shake response to the injection of the 5-HT2A/5-HT2C receptor agonist 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI, 1 or 2 mg/kg 2 hr after the end of restraint), cortical [3H]ketanserin binding remained unaltered. Chlorisondamine treatment was inactive, except for the amplification of the head shake response to DOI (2 mg/kg) in restrained rats. When exposed to the social interaction test, neither restraint nor chlorisondamine affected social interaction, locomotion, or rearings. In the elevated plus-maze, the percent number of open arms entered and the total number of arms entered were decreased by acute restraint, whilst chlorisondamine pretreatment was inactive.

Animals↗

PubMed1984

Chronic central nicotinic blockade after a single administration of the bisquaternary ganglion-blocking drug chlorisondamine.

Drug-naive rats were tested for horizontal and vertical activity in photocell cages, for up to 80 min starting immediately after a subcutaneous injection of (-)-nicotine bitartrate or 0.9% w/v NaCl solution (saline). Nicotine (0.1 to 0.4 mg kg-1 base) depressed vertical activity and induced ataxia in the first 20 min, but increased both horizontal and vertical activity later in the session; these actions were dose-dependent. A single intraventricular (i.v.t.) injection of chlorisondamine Cl (2 microgram base), a quaternary ganglion-blocking drug, given one to two weeks before testing, blocked the ataxic and stimulant actions of nicotine. The antagonistic actions of chlorisondamine (0.2, 1.0, 5.0 micrograms i.v.t., single administration) were shown to be dose-dependent. The stimulant actions of nicotine were blocked in a dose-dependent way for the duration of the experiment (5 weeks); nicotine's depressant actions were completely blocked at two weeks but not at five weeks. A ganglion-blocking dose of chlorisondamine (0.1 mg kg-1), given subcutaneously (s.c.), failed to reduce the behavioural actions of nicotine, whereas a much higher systemic dose (10 mg kg-1 s.c.) was effective for at least five weeks. Chlorisondamine failed to alter the behavioural effects of (+)-amphetamine or apomorphine, while blocking those of nicotine. It is concluded that chlorisondamine antagonizes some of nicotine's central actions in a potent, long-lasting and pharmacologically selective way.

Animals↗

PubMed1994

Blockade of nicotinic receptor-mediated release of dopamine from striatal synaptosomes by chlorisondamine and other nicotinic antagonists administered in vitro.

1. Central nicotinic receptor function examined in vitro, by measuring nicotine-induced [3H]-dopamine release from rat striatal synaptosomes. 2. The agonists (-)-nicotine, acetylcholine, 1,1-dimethyl-4-phenylpiperazinium (DMPP) and cytisine (10(-7)-10(-4) M) all increased [3H]-dopamine release in a concentration-dependent manner. Cytisine did not produce a full agonist response, compared to the other agonists. 3. The actions of nicotine, acetylcholine and cytisine were largely dependent on external Ca2+. In contrast, DMPP (10(-5) and 10(-4) M) evoked a marked release of [3H]-dopamine even in the absence of Ca2+. Nevertheless, in the presence of external Ca2+, responses to DMPP were completely blocked by the nicotinic antagonists chlorisondamine and mecamylamine (5 x 10(-5) M); in the absence of external Ca2+, blockade was only partial. 4. Chlorisondamine, mecamylamine and dihydro-beta-erythroidine (10(-8)-10(-4) M) produced a concentration-dependent block of responses to nicotine (10(-6) M). Approximate IC50 values were 1.6, 0.3 and 0.2 x 10(-6), respectively. Chlorisondamine and mecamylamine blocked responses to nicotine (10(-7)-10(-4) M) insurmountably, whereas dihydro-beta-erythroidine behaved in a surmountable fashion. 5. The occurrence of use-dependent block was tested by briefly pre-exposing the synaptosomes to nicotine during superfusion with antagonist, and determining the response to a subsequent nicotine application. Consistent with a possible channel blocking action, brief pre-exposure to agonist increased the antagonist potency of chlorisondamine (approximately 25 fold). No significant use-dependent block was detected with dihydro-beta-erythroidine.

Animals↗

PubMed1986

Chlorisondamine blocks acquisition of the conditioned taste aversion produced by (-)-nicotine.

Intraventricular microinjection (5 micrograms) of the bisquaternary ganglion-blocking drug chlorisondamine prevented acquisition of nicotine-induced conditioned taste aversion (CTA) in rats. This appeared to be a specific effect because chlorisondamine did not attenuate the conditioned taste aversion caused by apomorphine. These results support findings from other behavioural procedures indicating that centrally administered chlorisondamine causes a long-term blockade of central nicotinic mechanisms.

Animals↗

PubMed1993

Chlorisondamine, a non-competitive ganglionic blocker, antagonizes the cardiovascular effects of cocaine in conscious squirrel monkeys.

Cocaine (0.3 mg/kg i.v.) produced prolonged pressor and tachycardiac responses in conscious squirrel monkeys. Peak pressor and tachycardiac responses following cocaine were 32.7 +/- 3.3 mm Hg and 78.8 +/- 7.4 beats/min, respectively. Pretreatment with 1 mg/kg chlorisondamine, a noncompetitive ganglionic blocker, attenuated the pressor (18.3 +/- 3.8 mm Hg) and tachycardiac (63.7 +/- 10 beats/min) effects of cocaine, while 5 mg/kg chlorisondamine completely prevented these effects of cocaine. This finding supports the conclusion that the cardiovascular effects of cocaine are centrally mediated.

Animals↗

PubMed1980

Antagonism by chlorisondamine and propranolol, but not by atenolol, of the circadian phase-dependent phentolamine-induced changes in the cardiac noradrenaline turnover in the rat.

The effects of phentolamine alone or in combination with propranolol, atenolol and chlorisondamine were studied on the concentration and turnover of noradrenaline in the heart of light-dark (L:D = 12:12 h) synchronized rats. In order to detect possible circadian phase-dependent variations in the drug effects, the same experiments were performed in the light-period and dark-period, respectively. The parameters of the turnover were calculated from the exponential decline of i.v. injected 3H-(-)-noradrenaline. Phentolamine significantly decreased the noradrenaline concentration during L, but not during D. Reduction in 3H-noradrenaline accumulation by phentolamine was 42.3% during L and 22.2% during D. Phentolamine increased the turnover rate of cardiac noradrenaline more than 3-fold in either photoperiod. Chlorisondamine reversed all the effects of phentolamine studied. Propranolol, but not atenolol, antagonized the effects of phentolamine in a dose-dependent and stereospecific way, being more effective when applied during D. Thus, the chronopharmacological studies in unrestrained rats show a circadian phase-dependency of the effects of adrenoceptor blocking drugs. It is concluded that a central site of action is responsible for the antagonism by propranolol of the phentolamine-induced increase in the turnover of the cardiac noradrenaline in vivo.

Animals↗

PubMed1995

Intraneuronal accumulation and persistence of radiolabel in rat brain following in vivo administration of [3H]-chlorisondamine.

1. Chlorisondamine (CHL), a bisquaternary amine, produces a remarkably long-lasting blockade of central responses to nicotine. The mechanism underlying this blockade is not known. The main aim of this study was to test for possible accumulation of [3H]-CHL in rat brain during the period of chronic blockade. 2. Rats received CHL, either systemically (10 mg kg-1) or centrally (10 micrograms i.c.v.). Seven days later, striatal synaptosomes prepared from these animals were tested for nicotine-induced [3H]-dopamine release. This experiment showed that i.c.v. administration of CHL was as effective as systemic administration in producing ex vivo blockade of central nicotinic receptors. 3. Rats received bilateral i.c.v. infusions of [3H]-CHL (10 micrograms) and radioactivity was subsequently quantified in dissected cerebral cortex, striatum, hippocampus, midbrain and cerebellum. Radiolabel was detected at all three survival times (1, 7, and 21 days). Regional heterogeneity was apparent at 7 and 21 days survival. Radiolabel was almost exclusively confined to the insoluble subcellular fraction in all areas sampled. 4. The anatomical distribution of radiolabel was also visualized in brain sections. Rats received bilateral i.c.v. infusions of [3H]-CHL (10 micrograms) and were killed at 1, 7, 21 or 84 days. Immediately before they were killed, all rats were tested behaviourally, and central nicotinic blockade was demonstrated at 1, 7 and 21 days; partial recovery was observed at 84 days. Particularly at longer survival times, tritium was found to be heavily concentrated in the substantia nigra pars compacta, ventral tegmental area, dorsal raphé nucleus, and the granular layer of the cerebellum. 5. The possibility of retrograde axonal transport of radiolabel was then examined. Rats received a unilateral intrastriatal infusion of [3H]-CHL (0.34 or 0.034 micrograms) one week before they were killed. Autoradiographic labelling was largely confined to the site of infusion and to the ipsilateral substantia nigra pars compacta and dorsal raphé nucleus. 6. Thus, after i.c.v. administration, CHL (and/or centrally-formed derivatives) is initially widely distributed within the brain and is then selectively retained within a few brain areas. A persistent accumulation occurs within putative dopaminergic and 5-hydroxytryptaminergic neurones, at least partly through uptake by terminals and/or axons followed by retrograde transport. This persistent and anatomically-selective intraneuronal accumulation possibly underlies the long-term central nicotinic blockade associated with chlorisondamine.

Animals↗

PubMed1998

Blockade of the reward-potentiating effects of nicotine on lateral hypothalamic brain stimulation by chlorisondamine.

Chlorisondamine, a quarternary nicotinic antagonist, was given in a dose that crosses the blood-brain barrier, is taken up and concentrated intracellularly by dopaminergic neurons, and induces long-term blockade of the locomotor stimulant and rewarding effects of nicotine. This treatment had no effect on the rewarding effects of lateral hypothalamic brain stimulation, failing to shift the function that relates reward strength to rate of responding (rate-frequency function). That the treatment regimen was sufficient to block nicotinic receptors in the reward system was confirmed by the fact that it completely blocked the ability of normally effective nicotine to potentiate the rewarding effects of stimulation (shift this function to the left). These data add evidence that the direct, endogenous cholinergic contribution to brain stimulation reward is muscarinic and fit with other evidence that the potentiation of brain stimulation reward by exogenous nicotine involves actions on nicotinic receptors native to dopaminergic neurons.

Animals↗

PubMed1969