An EEG analysis of convulsive activity produced by cholinergic agents

doi:10.1016/0364-7722(81)90089-8

Progress in Neuro-Psychopharmacology

Volume 5, Issue 4, 1981, Pages 383-388

Progress in Neuro-Ps...

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Abstract

1.
1. EEG activity was assessed in rats following the intraventricular injection of cholinergic agonists (carbamylcholine and nicotine tartrate), nicotinic antagonists (d-tubocurarine and α-bungarotoxin), ganglionic blockers (mecamylamine and hexamethonium), decamethonium, antibodies prepared against purified electric fish acetylcholine receptor, and human sera from myasthenic and epileptic patients.
2.
2. Seizures were produced only by agonists and nicotinic antagonists.
3.
3. Carbamylcholine produced clonic/tonic convulsions. Nicotine resulted in a depressed EEG with sporadic seizures.
4.
4. Both antagonists produced clonic/tonic seizures and spike activity. Carbamylcholine-induced seizures were blocked by scopolamine.
5.
5. No agent was found to block antagonist-induced seizures.

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Cited by (27)

Nicotinic acetylcholine receptors and epilepsy
2023, Pharmacological Research
Despite recent advances in understanding the causes of epilepsy, especially the genetic, comprehending the biological mechanisms that lead to the epileptic phenotype remains difficult. A paradigmatic case is constituted by the epilepsies caused by altered neuronal nicotinic acetylcholine receptors (nAChRs), which exert complex physiological functions in mature as well as developing brain. The ascending cholinergic projections exert potent control of forebrain excitability, and wide evidence implicates nAChR dysregulation as both cause and effect of epileptiform activity. First, tonic-clonic seizures are triggered by administration of high doses of nicotinic agonists, whereas non-convulsive doses have kindling effects. Second, sleep-related epilepsy can be caused by mutations on genes encoding nAChR subunits widely expressed in the forebrain (CHRNA4, CHRNB2, CHRNA2). Third, in animal models of acquired epilepsy, complex time-dependent alterations in cholinergic innervation are observed following repeated seizures. Heteromeric nAChRs are central players in epileptogenesis. Evidence is wide for autosomal dominant sleep-related hypermotor epilepsy (ADSHE). Studies of ADSHE-linked nAChR subunits in expression systems suggest that the epileptogenic process is promoted by overactive receptors. Investigation in animal models of ADSHE indicates that expression of mutant nAChRs can lead to lifelong hyperexcitability by altering i) the function of GABAergic populations in the mature neocortex and thalamus, ii) synaptic architecture during synaptogenesis. Understanding the balance of the epileptogenic effects in adult and developing networks is essential to plan rational therapy at different ages. Combining this knowledge with a deeper understanding of the functional and pharmacological properties of individual mutations will advance precision and personalized medicine in nAChR-dependent epilepsy.
Neuroservice proconvulsive (NS-PC) set: A new platform of electrophysiology-based assays to determine the proconvulsive potential of lead compounds
2019, Journal of Pharmacological and Toxicological Methods
Citation Excerpt :
For instance 4-AP caused seizures in humans after poisoning (Spyker, Lynch, Shabanowitz, & Sinn, 1980) or during therapeutical trials of this drug (Thesleff, 1980) as in brain slices (Avoli et al., 1996; Rutecki, Lebeda, & Johnston, 1987). So did bicuculline (de Feo, Mecarelli, & Ricci, 1985), kainate (Fisher & Alger, 1984) and carbachol (Cohen, Morley, & Snead, 1981; Cruickshank, Brudzynski, & McLachlan, 1994). The list of other compounds that both triggered seizures or convulsions in vivo and EDs in vitro in brain slices remains long (PTZ, pilocarpine, penicillin, SNC-80, aminophylline, picrotoxin, NMDA, soman - non exhaustive list).
Failures in drug development often result from the emergence of unexpected adverse drug reactions. It is clear that adverse drug reactions, including seizure liability, should be assessed earlier. The goal of the present work was to develop a new platform of in vitro assays, NS-PC set (for Neuroservice proconvulsive set), to determine the proconvulsive potential of compounds earlier in preclinical development.
Assays were based on electrophysiological recordings in acute hippocampal slices performed with multielectrode arrays. 4 reference proconvulsive/seizurogenic compounds (4-aminopyridine, bicuculline, kainate and carbachol) and 4 anti-epileptic drugs (AEDs; phenobarbital, carbamazepine, clonazepam and valproic acid) were evaluated on electrophysiological endpoints involved in seizure risk (neuronal excitability, balance of excitatory/inhibitory synaptic transmission, occurrence of neuronal synchronization mechanisms materialized by epileptiform discharges).
The reference compounds increased the number and area under the curve of population spikes, triggered epileptiform discharges and enhanced the firing rate of CA1 neurons. The effects of the 4 antiepileptic drugs were assessed on these 3 parameters. They were able to partially of completely reverse the effects of proconvulsive compounds.
The use of reference proconvulsive compounds and AEDs validated the electrophysiological parameters to detect proconvulsive risk. Systematic evaluation of compounds with the 3 complementary endpoints increase the probability to detect seizure liability in vitro. Depending on the compound mechanism of action, only one or two of the identified parameters might be modified.
Intracerebroventricular administration of cigarette smoke condensate induced generalized seizures reduced by muscarinic receptor antagonist in rats
2018, Epilepsy and Behavior
Citation Excerpt :
In our study, the first to evaluate the effect of intracerebral injection of CSC in inducing seizure behaviors in rats, the central administration of CSC induces an epileptic behavior manifested by tonic–clonic seizures similar to those provoked by KA. These results are in accordance with several electrophysiological studies that indicated that the intracerebroventricular administration of nicotine produces tonic–clonic seizures that originate in the hippocampal structure [16,35,38]. After its intracerebral injection, KA may reach vulnerable brain areas and exert strong excitatory actions on certain neuronal pathways, which in turn may cause seizures and some excitotoxic brain damage in target neurons.
Tobacco smoking is considered the greatest risk factor for early death caused by noncommunicable diseases. Currently, there are more than one billion tobacco smokers in the world predisposed to many diseases including heart attack, stroke, cancer, and premature birth or birth defects related to the consumption of cigarettes. However, studies on the association between tobacco smoking and seizures or epilepsy are insufficient and not well documented. In the present study, the authors examined the convulsive effects of the intracerebroventricular administration of cigarette smoke condensate (CSC, 2 μl/Rat) in rats and compared it with the intensity of seizures in the kainic acid (KA)-induced seizure model of epilepsy. The role of the cholinergic system was also investigated by testing the effect of the muscarinic acetylcholine receptors (mAChRs) antagonist atropine (2 ml/kg) on CSC-induced seizures.
The results indicate that a central injection of CSC produces an epileptic behavior similar to that induced by KA, the similarities include the following parameters: time latency of seizures, latency and duration of tonic–clonic seizures, duration of seizures, survival, and tonic–clonic rate. However, a pretreatment with atropine reduced seizures and all their parameters.
Nicotine decreases the activity of glutamate transporter type 3
2014, Toxicology Letters
Citation Excerpt :
Temporal lobe seizures are related to hippocampal sclerosis, a characteristic feature of hippocampal pathology (Bouilleret et al., 1999; Wieser, 2004). In addition, dysfunction of EAAT3 has been reported to be related to temporal lobe epilepsy (Crino et al., 2002; Mathern et al., 1999), and in vivo electrophysiological studies have revealed that nicotine-induced seizures originate in the hippocampus (Cohen et al., 1981; Floris et al., 1964). Therefore, nicotine may elicit seizures through attenuation of EAAT3 activity.
Nicotine, the main ingredient of tobacco, elicits seizures in animal models and cigarette smoking is regarded as a behavioral risk factor associated with epilepsy or seizures. In the hippocampus, the origin of nicotine-induced seizures, most glutamate uptake could be performed primarily by excitatory amino acid transporter type 3 (EAAT3). An association between temporal lobe epilepsy and EAAT3 downregulation has been reported. Therefore, we hypothesized that nicotine may elicit seizures through the attenuation of EAAT3 activity. We investigated chronic nicotine exposure (72 h) cause reduction of the activity of EAAT3 in a Xenopus oocyte expression system using a two-electrode voltage clamp. The roles of protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) were also determined. Nicotine (0.001–1 μM) resulted in a time- and dose-dependent decrease in EAAT3 activity with maximal inhibition at nicotine concentrations of 0.03 μM or higher and at an exposure time of 72 h. V_max on the glutamate response was significantly reduced in the nicotine group (0.03 μM for 72 h), but the K_m value of EAAT3 for glutamate was not altered. When nicotine-exposed oocytes (0.03 μM for 72 h) were pretreated with phorbol-12-myristate-13-acetate (PMA, a PKC activator), the nicotine-induced reduction in EAAT3 activity was abolished. PKC inhibitors (staurosporine, chelerythrine, and calphostin C) significantly reduced basal EAAT3 activity, but there were no significant differences among the PKC inhibitors, nicotine, and PKC inhibitors + nicotine groups. Similar response patterns were observed among PI3K inhibitors (wortmannin and LY294002), nicotine, and PI3K inhibitors + nicotine. In conclusion, this study suggests that nicotine decreases EAAT3 activity, and that this inhibition seems to be dependent on PKC and PI3K. Our results may provide an additional mechanism for nicotine-induced seizure.
The effect of dorsal hippocampal administration of nicotinic and muscarinic cholinergic ligands on pentylenetetrazol-induced generalized seizures in rats
2012, Epilepsy and Behavior
Citation Excerpt :
For example, neurochemical evidence indicates that activation of presynaptic nAChRs enhances the release of neurotransmitters, such as acetylcholine (ACh), GABA, and glutamate [23–25]. In laboratory animals, administration of low doses of nicotine impacts nociception [26,27], locomotor activity [28], thermoregulation [29], learning, memory, and attention, whereas high doses of nicotine induce seizures [30–33]. In addition, genetic studies have indicated that mutated nAChRs may be important in certain forms of idiopathic epilepsy [34,35].
In the present study, the effects of intrahippocampal injections of cholinergic ligands on pentylenetetrazol (PTZ)-induced seizures were investigated in rats. The rats were assigned to 1 of the following 9 groups: saline, nicotine (0.5 or 1 μg), atropine (0.25 or 1 μg), oxotremorine-M (0.1 or 1 μg), or mecamylamine (2 or 8 μg). Cholinergic ligands were administered via intrahippocampal infusion 30 min before seizure induction (intraperitoneal injection of 80 mg/kg PTZ). Results show that antagonists caused nonsignificant increases in the latency of tonic‐clonic seizures, significant decreases in the duration of tonic‐clonic seizures, significant decreases in the latency of death, and increases in mortality rate. Agonists led to increases in the duration of tonic‐clonic seizures, decreases in the latency of death, and decreases in mortality rate. These results provide compelling evidence that cholinergic ligands show modulatory effects on a PTZ model of acute seizure in the rat hippocampus.
The intrahippocampal administration of the neurosteroid allopregnanolone blocks the audiogenic seizures induced by nicotine
2005, Brain Research
Citation Excerpt :
It has been suggested [19] that nicotine has bimodal effects on anxiety: the injection of low doses of nicotine in the dorsal raphe has anxiolytic effects [6,7], whereas higher doses have anxiogenic effects when injected into the dorsal hippocampus or the lateral septum [19,25]. On the other hand, high doses of nicotine induce clonic–tonic seizures after systemic and i.c.v. injections [10,45,46,60] that originate in the hippocampus [8]. Pharmacological and biochemical data have suggested that α7-containing nnAChRs contribute to these seizures [10].
Allopregnanolone (AlloP), GABA_A positive modulator, has efficacy as anticonvulsant. In contrast, nicotine and pregnenolone sulfate (PregS) act as potent convulsants. The present study aims to evaluate whether a promnesic dose of PregS and/or an anxiolytic dose of AlloP administered in the hippocampus can affect the audiogenic seizures induced by nicotine administration. Rats were assigned at random to six groups that received two consecutive intrahippocampal (dorsal CA1) injections once a week during three consecutive weeks. First injection: nicotine (4.6 μg, 20 mM) or saline, second injection: PregS (5 ng, 24 μM), AlloP (0.2 μg, 1.26 μM) or saline. After the last injections, locomotor activity and audiogenic seizures were tested. AlloP decreased the horizontal and vertical activity, suggesting sedative effects. Nicotine induced behavioral convulsions and AlloP acted as an anticonvulsant. AlloP reversed the seizures induced by nicotine and decreased the audiogenic convulsions in comparison with the controls. PregS also reversed the nicotine-induced audiogenic seizures in the nicotine group but not in the control group. These results suggest that anticonvulsive effects of AlloP and PregS are mediated by different action mechanisms such as GABA_A positive modulation, or negative modulatory action on neural nicotinic acetylcholine receptors. Even though several brain structures could be involved, these results highlight the important role played by hippocampal cholinergic and GABAergic activities, as well as neurosteroids, especially AlloP, in preventing convulsive behavior.

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¹: Present address: Department of Psychology, Bloomsburg State College, Bloomsburg, PA 17815

²: Present address: The Boys Town Institute, 555 North 30th St. Omaha, NE 68131

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Full-length original paperAn EEG analysis of convulsive activity produced by cholinergic agents

Abstract

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Neuropharmacology

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Full-length original paper
An EEG analysis of convulsive activity produced by cholinergic agents