Actions of Nicotine Upon the Limbic System

Stumpf, Ch.; Gogolák, G.

doi:10.1111/j.1749-6632.1967.tb13720.x

Cited by 37 publications

(6 citation statements)

References 26 publications

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“…The reduced sensitivity in WSP mice to nicotine-induced convulsions is consistent with previous findings in 19 inbred strains in which the seizure-prone DBA/2Ibg strain was most resistant to intravenous nicotine-induced seizures (Miner and Collins, 1989). Additional studies (Miner et al, 1984(Miner et al, , 1985(Miner et al, , 1986 demonstrated that sensitivity to nicotine-induced convulsions correlated with levels of the nicotinic ACh receptor (nAChR) subtype that binds ␣-bungarotoxin with high affinity in the hippocampus, the brain region where nicotine-induced convulsions are believed to be initiated (Brown, 1967;Dunlop et al, 1960;Floris et al, 1964;Stumpf and Gogolak, 1967). Because 10 genes encode mammalian nAChR subunits (Lindstrom, 1997), one possibility is that differences in one or more of the genes contribute to differential nicotine sensitivity.…”

Section: Convulsant Sensitivity Studiessupporting

confidence: 86%

The Relationship Between Hippocampal Acetylcholine Release and Cholinergic Convulsant Sensitivity in Withdrawal Seizure–Prone and Withdrawal Seizure–Resistant Selected Mouse Lines

Mark

Finn²

2002

Alcoholism Clin & Exp Res

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These results suggest that differences in cholinergic activity and postsynaptic sensitivity to cholinergic convulsants may be associated with ethanol withdrawal severity and implicate cholinergic mechanisms in alcohol withdrawal. Specifically, WSP mice may have lower sensitivity to cholinergic convulsants compared with WSR because of postsynaptic receptor desensitization brought on by higher activity of cholinergic neurons.

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Section: Convulsant Sensitivity Studiessupporting

confidence: 86%

The Relationship Between Hippocampal Acetylcholine Release and Cholinergic Convulsant Sensitivity in Withdrawal Seizure–Prone and Withdrawal Seizure–Resistant Selected Mouse Lines

Mark

Finn²

2002

Alcoholism Clin & Exp Res

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“…Hippocampal circuits are thought to participate in the convulsant effects of nicotine (Stumpf and Gogolak, 1967;Freund and Wehner, 1987), and ␣7* nAChRs are highly expressed throughout the hippocampus Radcliffe and Dani, 1998;Ji and Dani, 2000). To examine the potential cellular mechanisms underlying the increased sensitivity of ϩ/T mice to nicotine, we characterized and compared ␣7-type currents in hippocampal slices from ϩ/T and ϩ/ϩ mice.…”

Section: Resultsmentioning

confidence: 99%

“…Experiments conducted on several inbred mouse strains have indicated a positive correlation between sensitivity to nicotine-induced seizures and the number of ␣-bungarotoxin (␣-BTX) binding sites in the hippocampus (Miner et al, 1984(Miner et al, , 1985Miner and Collins, 1989), the brain area in which nicotine-induced seizure activity may originate (Stumpf and Gogolak, 1967;Freund and Wehner, 1987). Because ␣7-containing nicotinic acetylcholine receptors (␣7* nAChRs) represent the major binding site for ␣-BTX in the mammalian brain (Chen and Orr-Urtreger et al, 1997), it was suggested that ␣7* nAChRs might contribute to the convulsant effects of nicotine.…”

mentioning

confidence: 99%

Increased Sensitivity to Nicotine-Induced Seizures in Mice Expressing the L250T α7 Nicotinic Acetylcholine Receptor Mutation

Broide

Salas

et al. 2002

Mol Pharmacol

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High doses of nicotine, the addictive component of tobacco, induce clonic-tonic seizures in animals. Pharmacological and biochemical data have suggested that ␣7-containing neuronal nicotinic receptors (nAChRs) contribute to these seizures. To study potential ␣7 contributions, we examined ␣7 subunits with a Leu250-to-Thr substitution in the channel domain, which creates a gain-of-function mutation. Previous studies have shown that mice homozygous for the ␣7 L250T mutation (T/T) die shortly after birth, but animals heterozygous for the mutation (ϩ/T) are viable and grow to adulthood. Hippocampal neurons from the ϩ/T mice exhibited altered ␣7-type currents with increased amplitudes and slower desensitization kinetics, confirming a partial gain of function for the ␣7 nAChR. We found that ϩ/T mice were more sensitive to the convulsant effects of nicotine compared with their wild-type (ϩ/ϩ) littermates. Furthermore, although their behavior was normal in basal conditions, ϩ/T mice showed a unique nicotine-induced phenotype, consisting of head-bobbing and paw-tapping movements. Increased sensitivity to nicotine-induced seizures occurred despite a 60% decline in brain ␣7 nAChR protein levels. There were no changes in the levels of ␣4, ␣5, ␣6, ␣7, ␤2, and ␤4 mRNA, or in [125 I]epibatidine and [ 3 H]nicotine binding between ϩ/T and ϩ/ϩ mice. Recent data from our laboratory show that ␣7-null mice maintain normal sensitivity to nicotine-induced seizures. Hence, these present findings suggest that alterations in the properties rather than absence of ␣7 nAChRs might affect the mechanisms underlying the convulsive properties of nicotine.

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“…Whereas WT mice display spike-wave EEG during seizures (10 mg/kg nicotine), L9ЈA (2 mg/kg) show no recognizable ictal activity with electrodes positioned at various cortical locations. Previous studies with anesthetized rabbits suggest that nicotine-induced seizures leading to spike-wave discharges originate in the hippocampus (Floris et al, 1964;Stumpf and Gogolak, 1967). We cannot rule out WT seizures with secondary bilateral synchrony in which there is rapid generalization from one or multiple foci, one of which could be the hippocampus.…”

Section: Nicotine-induced Seizures: Type Sensitivity and Pharmacologymentioning

confidence: 99%

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4^*Nicotinic Receptors

Fonck¹,

Cohen²,

Nashmi³

et al. 2005

J. Neurosci.

120

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A leucine to alanine substitution (L9ЈA) was introduced in the M2 region of the mouse ␣4 neuronal nicotinic acetylcholine receptor (nAChR) subunit. Expressed in Xenopus oocytes, ␣4(L9ЈA)␤2 nAChRs were Ն30-fold more sensitive than wild type (WT) to both ACh and nicotine. We generated knock-in mice with the L9ЈA mutation and studied their cellular responses, seizure phenotype, and sleepwake cycle. Seizure studies on ␣4-mutated animals are relevant to epilepsy research because all known mutations linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) occur in the M2 region of ␣4 or ␤2 subunits. Thalamic cultures and synaptosomes from L9ЈA mice were hypersensitive to nicotine-induced ion flux. L9ЈA mice were ϳ15-fold more sensitive to seizures elicited by nicotine injection than their WT littermates. Seizures in L9ЈA mice differed qualitatively from those in WT: L9ЈA seizures started earlier, were prevented by nicotine pretreatment, lacked EEG spike-wave discharges, and consisted of fast repetitive movements. Nicotine-induced seizures in L9ЈA mice were partial, whereas WT seizures were generalized. When L9ЈA homozygous mice received a 10 mg/kg nicotine injection, there was temporal and phenomenological separation of mutant and WT-like seizures: an initial seizure ϳ20 s after injection was clonic and showed no EEG changes. A second seizure began 3-4 min after injection, was tonic-clonic, and had EEG spike-wave activity. No spontaneous seizures were detected in L9ЈA mice during chronic video/EEG recordings, but their sleep-wake cycle was altered. Our findings show that hypersensitive ␣4* nicotinic receptors in mice mediate changes in the sleep-wake cycle and nicotineinduced seizures resembling ADNFLE.

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Actions of Nicotine Upon the Limbic System

Cited by 37 publications

References 26 publications

The Relationship Between Hippocampal Acetylcholine Release and Cholinergic Convulsant Sensitivity in Withdrawal Seizure–Prone and Withdrawal Seizure–Resistant Selected Mouse Lines

The Relationship Between Hippocampal Acetylcholine Release and Cholinergic Convulsant Sensitivity in Withdrawal Seizure–Prone and Withdrawal Seizure–Resistant Selected Mouse Lines

Increased Sensitivity to Nicotine-Induced Seizures in Mice Expressing the L250T α7 Nicotinic Acetylcholine Receptor Mutation

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4^*Nicotinic Receptors

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Actions of Nicotine Upon the Limbic System

Cited by 37 publications

References 26 publications

The Relationship Between Hippocampal Acetylcholine Release and Cholinergic Convulsant Sensitivity in Withdrawal Seizure–Prone and Withdrawal Seizure–Resistant Selected Mouse Lines

The Relationship Between Hippocampal Acetylcholine Release and Cholinergic Convulsant Sensitivity in Withdrawal Seizure–Prone and Withdrawal Seizure–Resistant Selected Mouse Lines

Increased Sensitivity to Nicotine-Induced Seizures in Mice Expressing the L250T α7 Nicotinic Acetylcholine Receptor Mutation

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4*Nicotinic Receptors

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Product

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Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4^*Nicotinic Receptors