The action of chlorpromazine at an isolated cholinergic synapse

doi:10.1016/0006-8993(79)90018-0

Brain Research

Volume 164, Issues 1–2, 23 March 1979, Pages 227-236

https://doi.org/10.1016/0006-8993(79)90018-0 Get rights and content

Abstract

The effects of chlorpromazine (CPZ) on cholinergic transmission were studied at the isolated neuromuscular synapse of the frog. It was found that 5 × 10⁻⁶M CPZ produces the following effects: (1) a reduction in end-plate potential amplitude, mainly through inhibition of transmitter release at presynaptic nerve terminals; (2) a reduction in amplitude of focally recorded end-plate current without detectable change in nerve terminal potential: (3) a decrease in amplitude of miniature end-plate potentials; and (4) an increase in the frequency of spontaneous liberation of transmitter both in normal and calcium-free Ringer's solution. It is concluded that CPZ inhibits cholinergic transmission by a complex action on presynaptic and postsynaptic elements. The relation of these findings to central cholinergic activities of CPZ is discussed.

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Citation Excerpt :
Chlorpromazine was the first to be reported to produce increased muscle weakness in a schizophrenic patient with MG by McQuillen in 1963 [9]. The drug was found to have combined presynaptic and postsynaptic neuromuscular blocking effect in some studies; inhibiting release of acetylcholine and demonstrating competitive inhibition of AchR similar to d-tubocurarine blockage; sometimes called membrane-stabilizing effect [10,11]. Risperidone is a second-generation antipsychotic (SGAs) that works through antagonism of D2 and 5-HT2A receptors and used to control delusions, hallucinations, agitation and aggression in different psychotic disorders.
Myasthenia gravis is an autoimmune disease characterized by muscle weakness due to autoantibodies affecting the neuromuscular junction. Co-occurrence of myasthenia gravis and schizophrenia is very rare and raises a challenge in management of both diseases. Antipsychotic drugs exhibit anticholinergic side effects and have the potentials of worsening myasthenia. Long-acting risperidone is an injectable atypical antipsychotic drug that has not been previously reported to worsen myasthenia gravis in literature. We report the first case report of worsening of myasthenia after receiving long-acting risperidone injection for schizophrenia in a 29-year-old female with both diseases. She started to have worsening 2 weeks following the first injection and her symptoms persisted despite receiving plasma exchange. This could be explained by the pharmacokinetics of the drug. We recommend that long-acting risperidone should be used with caution in patients with myasthenia gravis, and clinicians must be aware of the potential risks of this therapy.
Inhibition of skeletal muscle nicotinic receptors by the atypical antipsychotic clozapine
2002, Neuropharmacology
We have previously observed that certain atypical antipsychotic drugs reduce the amplitude and duration of miniature end-plate currents (EPCs) at the frog neuromuscular junction (Effects of atypical antipsychotics on vertebrate neuromuscular transmission, Nguyen, Q.-T., Yang, J., Miledi, R. Neuropharmacology 42, 2002, 670–676), therefore suggesting that these drugs act on nicotinic acetylcholine receptors. In this study we examined the effects of the atypical antipsychotic clozapine on nicotinic receptors of frog neuromuscular end-plates or in Xenopus oocytes expressing the α₁β₁γδ mouse skeletal muscle nicotinic receptor. At neuromuscular junctions, postsynaptic currents were reduced by micromolar concentrations of clozapine. This compound also acted presynaptically by increasing the quantal content of EPCs of muscles without noticeably affecting paired-pulse facilitation. In oocytes, clozapine inhibited α₁β₁γδ receptors with an IC₅₀ of 10 μM and a Hill coefficient of 1. Blockage of α₁β₁γδ receptors by clozapine bears several hallmarks of open-channel blockers, including faster response decays, strong voltage dependence of the block, large rebound currents upon wash, and reduction of peak responses even at saturating concentrations of acetylcholine. However, clozapine increased the EC₅₀ for acetylcholine and its blocking effect was enhanced by preincubation. These results suggest that clozapine antagonizes muscle nicotinic receptors by blocking open channels, and possibly also by another mechanism which still remains to be investigated.
Effects of atypical antipsychotics on vertebrate neuromuscular transmission
2002, Neuropharmacology
A study was made of the effects of the atypical antipsychotics clozapine, olanzapine, sulpiride and risperidone on nicotinic synaptic transmission at the frog neuromuscular junction. At concentrations higher than 10 μM, these atypical antipsychotics partially reduced the amplitude of miniature end-plate currents (mEPCs) in a dose-dependent and reversible manner. Atypical antipsychotics were, however, less effective than typical neuroleptics of the phenothiazine family at inhibiting mEPCs. In addition to decreasing mEPC amplitude, the atypical antipsychotics reduced the half-decay time of mEPCs. In the case of clozapine, the reduction in mEPC amplitude and duration was not markedly voltage-dependent. Beside their post-synaptic effects, all atypical neuroleptics, except sulpiride, increased the frequency of mEPCs in a concentration-dependent manner, with the strongest effect seen with clozapine. Altogether, these results raise the possibility that atypical neuroleptics could derive some of their therapeutic effects not only from their well-known inhibitory action on dopaminergic receptors, but also from their pre- and post-synaptic modulation of nicotinic neurotransmission.
Modulation of spontaneous quantal release of neurotransmitters in the hippocampus
2001, Progress in Neurobiology
Presynaptic action potentials trigger the exocytosis of neurotransmitters. However, even in the absence of depolarisation-dependent Ca²⁺ entry nearby release sites, spontaneous vesicular release still occurs. Even though this happens at low rate, such spontaneous release may play a trophic role in maintaining the shape of dendritic structures. Like evoked responses, action potential-independent release is subject to modulation. This review describes some of the regulatory factors that rapidly and presynaptically regulate the ongoing Ca²⁺-independent release of neurotransmitters in the hippocampus. For instance, the electrical activity of the nerve ending, neurotransmitters, hypertonic solutions, neurotoxins, polycations, neurotrophic factors, immunoglobulins, cyclothiazide and psychotropic drugs can all modify the rate of spontaneous release. This can be achieved through various mechanisms that can be Ca²⁺-dependent or Ca²⁺-independent, protein kinase-dependent or independent. Since action potential-independent release contributes to the maintenance of dendritic structures, neuromodulators are likely to influence the density and/or length of dendritic spines, which in turn may modulate information processing in the central nervous system (CNS).
Acute application of the tricyclic antidepressant desipramine presynaptically stimulates the exocytosis of glutamate in the hippocampus
1999, Neuroscience
Tricyclic antidepressants (e.g., imipramine, desipramine) are currently used in the treatment of mood disorders such as depression. At the cellular level they inhibit the re-uptake of the exocytosed monoamines serotonin and noradrenaline. However, they also stimulate phospholipase C activity and the production of the second messenger inositol 1,4,5-trisphosphate. Since phospholipase C activation can also lead to the production of the protein kinase C activator diacylglycerol, we have undertaken experiments to see whether acutely applied desipramine could change the synaptic strength of neurons in a protein kinase C-dependent manner. Experiments performed with cultured hippocampal neurons dissociated from neonatal rats revealed that desipramine rapidly enhanced the spontaneous vesicular release of glutamate. This was observed by measuring the frequency of tetrodotoxin-resistant spontaneous excitatory postsynaptic currents. Analysis of amplitude distribution histograms indicated a presynaptic site of action. The protein kinase inhibitor staurosporine and down-regulation of protein kinase C activity greatly reduced the desipramine-dependent enhancement of the frequency of tetrodotoxin-resistant spontaneous excitatory postsynaptic currents. This presynaptic modulation requires SNARE proteins because cleavage of SNAP-25 with the botulinum neurotoxin A strongly reduced the desipramine-induced glutamate release. Thus, acute applications of desipramine stimulated the ongoing neurotransmitter release pathway, probably by activating protein kinase C.
Our data indicate that tricyclic antidepressant drugs not only act on serotoninergic and/or noradrenergic cells but can also modify the activity of glutamatergic neurons.
Effects of atropine, pirenzepine, imipramine and phenothiazines on the mammalian neuromuscular junction
1992, General Pharmacology
- 1.
  1. Trifluoperazine (EC₅₀ = 11.5 nM), chlorpromazine (13.8 μM), imipramine (15 μM), atropine (75.8 μM), and pirenzepine (316.2 μM), all produced neuromuscular facilitation and antagonized the blockade produced by oxotremorine (20 and 30 μM) in the rat isolated diaphragm.
- 2.
  2. These antagonists did not change the responses of curarized diaphragms to direct stimulation, or the twitch tension produced by retrograde injection of acetylcholine.
- 3.
  3. Trifluoperazine (2.5 ng, intra-arterially) reduced the tetanic fade produced by further intra-arterial injection of d-tubocurarine (10 μg/kg) in the in situ cat tibial muscle.
- 4.
  4. These results indicate that these antagonists may interact with muscarinic autoreceptors to increase acetylcholine output in the neuromuscular junction.

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^*: Present address: Department of Neurology, Hadassah University Hospital, P.O.B. 499, Jerusalem, Israel.

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The action of chlorpromazine at an isolated cholinergic synapse

Abstract

J. Physiol. (Lond.)

Science

J. Neurochem.

Dual action of praseodymium (Pr3+) on transmitter release at the frog neuromuscular synapse

Nature (Lond.)

On the role of mitochondria in transmitter release from motor nerve terminals

J. Physiol. (Lond.)

The effect of chlorpromazine on the frog neuromuscular junction

Isr. J. med. Sci.

The inhibition of sarcoplasmic calcium pump by prenylamine, reserpine, chlorpromazine and imipramine

Arch. Pharmak. exp. Path.

Interactions between sodium and calcium ions in the process of transmitter release at the neuromuscular junction

J. Physiol. (Lond.)

Quantal components of the endplate potential

J. Physiol. (Lond.)

Co-operative actions of calcium ions in transmitter release at the neuromuscular junction

J. Physiol. (Lond.)

Presynaptic action of hemicholinium at the neuromuscular junction

J. Physiol. (Lond.)

The Pharmacological Basis of Therapeutics

The Pharmacological Basis of Therapeutics

The mechanism of excitability blockade by chlorpromazine

J. Pharmacol. exp. Ther.

Chlorpromazine blood levels in psychotic patients

Arch. gen. Psychiat.

Dual action of praseodymium (Pr³⁺) on transmitter release at the frog neuromuscular synapse