Relationship between nicotine-induced seizures and hippocampal nicotinic receptors

doi:10.1016/0024-3205(85)90628-9

Life Sciences

Volume 37, Issue 1, 8 July 1985, Pages 75-83

https://doi.org/10.1016/0024-3205(85)90628-9 Get rights and content

Abstract

A controversy has existed for several years concerning the physiological relevance of the nicotinic receptor measured by α-bungarotoxin binding. Using mice derived from a classical F2 and backcross genetic design, a relationship between nicotine-induced seizures and α-bungarotoxin nicotinic receptor concentration was found. Mice sensitive to the convulsant effects of nicotine had greater α-bungarotoxin binding in the hippocampus than seizure insensitive mice. The binding sites from seizure sensitive and resisntant mice were equally affected by treatment with dithiothreitol, trypsin or heat. Thus it appears that the difference between seizure sensitive and insensitive animals may be due to a difference in hippocampal nicotinic receptor concentration as measured with α-bungarotoxin binding.

References (32)

B.J. Morley et al.
Life Sci.
(1979)
T.C. Chou et al.
Eur. J. Pharmacol.
(1969)
C.P. Ko et al.
Brain Res.
(1976)
A.W. Duggan et al.
Brain Res.
(1976)
P.M. Salvaterra et al.
J. Biol. Chem.
(1976)
C. McQuarrie et al.
J. Biol. Chem.
(1976)
L.G. Abood et al.
Life Sci.
(1980)
O.H. Lowry et al.
J. Biol. Chem.
(1951)
P.C. Jobe et al.
Biochem. Pharmacol.
(1981)
R.S. Aronstam et al.
Brain Res.
(1979)

J.O. McNamara

Brain Res.

(1978)

M.C. Byrne et al.

Exp. Neurol.

(1980)

R.M. Dasheiff et al.

Brain Res.

(1980)

S.T. Carbonetto et al.

R. Miledi et al.

J. Schmidt

Mol. Pharmacol.

(1977)

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Recent human genetic studies have identified genetic variants in multiple nicotinic acetylcholine receptor (nAChR) subunit genes that are associated with risk for nicotine dependence and other smoking-related measures. Genetic variability also exists in the nAChR subunit genes in mice. Most studies on mouse nAChR subunit gene variability to date have focused on Chrna4, the gene that encodes the α4 nAChR subunit and Chrna7, the gene that encodes the α7 nAChR subunit. However, genetic variability exists for all nAChR genes in mice. In this review, we will describe what is known about nAChR subunit gene polymorphisms in mice and how it relates to variability in nAChR expression and function in brain. The relationship between nAChR genetic variability in mice and the effects of nicotine on several behavioral and physiological measures also will be discussed. In addition, an overview of the contribution of other genetic variation to nicotine sensitivity in mice will be provided. Finally, the potential for natural genetic variability to confound and/or modify the results of studies that utilize genetically engineered mice will be considered. As an example of the ability of a natural genetic variant to modify the effect of an engineered mutation, data will be presented that demonstrate that the effect of Chrna5 deletion on oral nicotine intake is dependent upon naturally occurring variant alleles of Chrna4.
This article is part of the Special Issue entitled ‘The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition’.
Nicotinic Cholinergic Mechanisms in Alzheimer's Disease
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For instance, studies using hippocampal slices show that nAChR α7 KO mice exhibit lower seizure susceptibility after exposure to Aβ than found for WT controls (Minkeviciene et al., 2009). Pharmacological experiments demonstrate a positive correlation between the number of α-bungarotoxin (Bgt) binding sites in the hippocampus and sensitivity to nicotine-induced seizures (Miner & Collins, 1989; Miner, Marks, & Collins, 1984, 1985). Pharmacological study indicates that α7-nAChRs are important in mediating nicotine-induced seizures (Damaj, Glassco, Dukat, & Martin, 1999).
Alzheimer's disease (AD) is a neurodegenerative condition characterized by increased accumulation of Aβ and degeneration of cholinergic signaling between basal forebrain and hippocampus. Nicotinic acetylcholine receptors (nAChRs) are important mediators of cholinergic signaling in modulation of learning and memory function. Accumulating lines of evidence indicate that a nAChR subtype, α7 receptor (α7-nAChR), plays an important role in modulations of excitatory neurotransmitter release, improvement of learning and memory ability, and enhancement of cognitive function. Importantly, the expression and function of α7-nAChRs is altered in the brain of AD animal models and AD patients, suggesting that this nAChR subtype participates in AD pathogenesis and may serve as a novel therapeutic target for AD treatment. However, the mechanisms underlying the role of α7-nAChRs in AD pathogenesis are very complex, and either neuroprotective effects or neurotoxic effects may occur through the α7-nAChRs. These effects depend on the levels of α7-nAChR expression and function, disease stages, or the use of α7-nAChR agonists, antagonists, or allosteric modulators. In this chapter, we summarize recent progresses in the roles of α7-nAChRs played in AD pathogenesis and therapy.
Genetic matters: Thirty years of progress using mouse models in nicotinic research
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This result suggested that mice expressing higher levels of α7-nAChR were more prone to nicotine-induced seizures. This potential relationship between seizure sensitivity and α-bungarotoxin binding was consistent with the results of previous studies in which the inheritance of these measures was examined with a classical genetic cross between C3H and DBA/2 mice that are relatively sensitive or resistant to nicotine-induced seizures, respectively [46,47]. These studies revealed that resistance to seizures was dominant as was expression of lower levels of α-bungarotoxin binding sites.
This research update summarizes thirty years of studies on genetic influences on responses to the acute or chronic administration of nicotine. Early studies established that various inbred mice are differentially sensitive to the effects of the drug. Classical genetic analyses confirmed that nicotine effects on locomotion, body temperature and seizures are heritable. A significant inverse correlation between the locomotor and hypothermic effects and the density of nicotine binding sites suggested that differential expression α4β2-neuronal nicotinic acetylcholine receptor (nAChR) mediated some of this genetic variability. Subsequent studies with α4 and β2 nAChR null (decreased sensitivity) and gain of function mutants (increased sensitivity) supports the role of the α4β2*nAChR subtype. However, null mutant mice still respond to nicotine, indicating that other nAChR subtypes also mediate these responses. Mice differing in initial sensitivity to nicotine also differ in tolerance development following chronic treatment: those mice that are initially more sensitive to nicotine develop tolerance at lower treatment doses than less sensitive mice, indicating that tolerance is an adaptive response to the effects of nicotine. In contrast, the sensitivity of mice to pre-pulse inhibition of acoustic startle response is correlated with the expression of α7-nAChR. While genetic variability in nAChR expression and function is an important factor contributing to differences in response to nicotine, the observations that altered activity of opioid, glutamate, and cannabinoid receptors among others also change nicotine sensitivity reinforces the proposal that the genetics of nicotine response is more complex than differences in nAChRs.
Chrna7 genotype is linked with alpha7 nicotinic receptor expression but not alpha7 RNA levels
2009, Brain Research
Studies using the radio-labeled nicotinic receptor antagonist [¹²⁵I]-α-bungarotoxin, which binds to α7 subunit containing nicotinic receptors, have demonstrated that mouse strains vary considerably in the number of α7-containing nicotinic receptors in brain. In addition, brain region specific differences in α-bungarotoxin binding between the mouse strains C3H/Ibg and DBA/2 have been linked to polymorphisms in Chrna7, the gene that encodes the α7 subunit. In the studies described here, we evaluated whether the relationship between Chrna7 genotype and individual differences in α-bungarotoxin binding levels in adult brain might be due to an effect of Chrna7 genotype on α7 RNA levels. Quantitative autoradiography of coronal brain slices from F2 mice derived from the parental strains C3H/Ibg and DBA/2 demonstrate that Chrna7 genotype is not linked to α7 RNA levels. In contrast, quantitative autoradiography confirmed the linkage of Chrna7 genotype with α-bungarotoxin binding levels in hippocampus, striatum, and more precisely defined areas within these brain regions where Chrna7 genotype is associated with the level of α-bungarotoxin binding. The fact that Chrna7 genotype is linked to individual differences in α-bungarotoxin binding, but not α7 RNA levels, suggests that the observed linkage between Chrna7 genotype and α-bungarotoxin levels may be due to genetic influences on the post-transcriptional regulation of α7 nicotinic receptor expression.
Contribution of Animal Models and Preclinical Human Studies to Medication Development for Nicotine Dependence
2008, Animal and Translational Models for CNS Drug Discovery
Nicotine is one of the major components in tobacco responsible for addiction. It alone can lead to preferential self-administration of a tobacco product over a control vehicle. Humans show a greater preference for nicotine over a control substance in studies examining intravenous, nasal, and medicinal gum administration. Smokers tend to compensate for this alteration by smoking more if the levels of nicotine are reduced or blocked by a nicotinic receptor antagonist or by smoking less if exogenous or higher levels of nicotine are administered. Considering though the critical role of nicotine in tobacco addiction and the financial issues involved in drug discovery, it appears sufficient for drug discovery efforts to focus on animal models of nicotine dependence with little consideration for the contributing properties of other tobacco ingredients to nicotine dependence. Animal models of nicotine dependence with good construct validity mimic in experimental animals the cardinal features of tobacco addiction. However, considering the difficulties inherent in reproducing both the physical act of tobacco smoking and the social factors that are involved in the acquisition, maintenance, and relapse to smoking, certain compromises must be made in the development and validation of suitable animal models. Human studies with laboratory preclinical models that use objective measures would add more confidence to data obtained from animal disease models. Thus, resources need to be invested in this endeavor.
Ethanol blocks nicotine-induced seizures in mice: comparison with midazolam and baclofen
2006, Alcohol
Low doses of ethanol may antagonize the pharmacological effects of nicotine. Recently, it has been shown that the effects of ethanol on nicotine discrimination are not correlated with blood ethanol levels. The aim of the present study was to evaluate whether ethanol (0.5–2 g/kg, i.p.) could block nicotine-induced seizures in C57BL/6J mice and to correlate ethanol's actions with blood ethanol concentrations. For comparison, the effects of a γ-aminobutyric acid A (GABA_A)/benzodiazepine receptor positive modulator, midazolam (0.25–40 mg/kg, i.p.), and a γ-aminobutyric acid B receptor agonist, baclofen (2.5–20 mg/kg, i.p.), were assessed in the same procedure. Nicotine (3–9 mg/kg, s.c.) induced clonic–tonic seizures in a dose-dependent manner. Ethanol, administered 5 or 50 min before nicotine, dose dependently antagonized seizures elicited by 6 mg/kg nicotine. The anticonvulsant effects of ethanol correlated with blood ethanol levels and were comparable to those exerted by midazolam. Baclofen antagonized only the tonic component of nicotine-induced convulsions. The anticonvulsant doses of ethanol (0.5–2 g/kg), midazolam (0.5–1 mg/kg), and baclofen (5–10 mg/kg) did not affect spontaneous locomotor activity in a control experiment. The present results indicate that (i) ethanol may block nicotine-induced seizures in mice at doses that do not alter locomotor activity and (ii) the antiseizure effects of ethanol depend on blood ethanol levels and are comparable to those exerted by the GABA_A positive modulator midazolam.

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Relationship between nicotine-induced seizures and hippocampal nicotinic receptors

Abstract

Life Sci.

Eur. J. Pharmacol.

Brain Res.

Brain Res.

J. Biol. Chem.

J. Biol. Chem.

Life Sci.

J. Biol. Chem.

Biochem. Pharmacol.

Brain Res.

Brain Res.

Exp. Neurol.

Brain Res.

Mol. Pharmacol.