Absence of α7-containing neuronal nicotinic acetylcholine receptors does not prevent nicotine-induced seizures

Franceschini, Davide; Paylor, Richard; Broide, Ron S.; Salas, Ramiro; Bassetto, Laura; Gotti, Cecilia; Biasi, Mariella De

doi:10.1016/s0169-328x(01)00309-6

Cited by 68 publications

(68 citation statements)

References 93 publications

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“…In particular, it was verified that SSR180711 does not induce convulsions in mice up to 100 mg/kg p.o. This is in line with the demonstration that nicotine induced convulsions with similar potency in wild-type and a7 n-AChRs knock-out (homozygous and heterozygous) mice, suggesting that the a7 subtype is not implicated in the convulsive activity of nicotine (Franceschini et al, 2002; but see Damaj et al, 1999).…”

Section: Additional Properties and Safety Profile Of Ssr180711supporting

confidence: 79%

SSR180711, a Novel Selective α7 Nicotinic Receptor Partial Agonist: (II) Efficacy in Experimental Models Predictive of Activity Against Cognitive Symptoms of Schizophrenia

Pichat

Bergis

Terranova

et al. 2006

Neuropsychopharmacol

235

155

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SSR180711 (4-bromophenyl 1,4diazabicyclo(3.2.2) nonane-4-carboxylate, monohydrochloride) is a selective a7 nicotinic receptor (n-AChR) partial agonist. Based on the purported implication of this receptor in cognitive deficits associated with schizophrenia, the present study assessed efficacy of SSR180711 (i.p. and p.o.) in different types of learning and memory involved in this pathology. SSR180711 enhanced episodic memory in the object recognition task in rats and mice (MED: 0.3 mg/kg), an effect mediated by the a7 n-AChR, as it was no longer seen in mice lacking this receptor. Efficacy was retained after repeated treatment (eight administrations over 5 days, 1 mg/kg), indicating lack of tachyphylaxia. SSR180711 also reversed (MED: 0.3 mg/kg) MK-801-induced deficits in retention of episodic memory in rats (object recognition). The drug reversed (MED: 0.3 mg/kg) selective attention impaired by neonatal phencyclidine (PCP) treatment and restored MK-801-or PCP-induced memory deficits in the Morris or linear maze (MED: 1-3 mg/kg). In neurochemical and electrophysiological correlates of antipsychotic drug action, SSR180711 increased extracellular levels of dopamine in the prefrontal cortex (MED: 1 mg/kg) and enhanced (3 mg/kg) spontaneous firing of retrosplenial cortex neurons in rats. Selectivity of SSR180711 was confirmed as these effects were abolished by methyllycaconitine (3 mg/kg, i.p. and 1 mg/kg, i.v., respectively), a selective a7 n-AChR antagonist. Additional antidepressant-like properties of SSR180711 were demonstrated in the forced-swimming test in rats (MED: 1 mg/kg), the maternal separation-induced ultrasonic vocalization paradigm in rat pups (MED: 3 mg/kg) and the chronic mild stress procedure in mice (10 mg/kg o.d. for 3 weeks). Taken together, these findings characterize SSR180711 as a promising new agent for the treatment of cognitive symptoms of schizophrenia. The antidepressant-like properties of SSR180711 are of added interest, considering the high prevalence of depressive symptoms in schizophrenic patients.

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Section: Additional Properties and Safety Profile Of Ssr180711supporting

confidence: 79%

SSR180711, a Novel Selective α7 Nicotinic Receptor Partial Agonist: (II) Efficacy in Experimental Models Predictive of Activity Against Cognitive Symptoms of Schizophrenia

Pichat

Bergis

Terranova

et al. 2006

Neuropsychopharmacol

235

155

View full text Add to dashboard Cite

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“…The role of the ␣6, ␣7, and ␤3 subunits in nicotine withdrawal is yet to be determined. These subunits are expressed in the VTA (Franceschini et al, 2002;Salas et al, 2003a;Wooltorton et al, 2003), which puts them in an ideal position to affect the rewarding effects of nicotine.…”

Section: Discussionmentioning

confidence: 99%

“…After nicotine withdrawal symptoms were recorded, mice were killed, and brains removed and rapidly frozen in Ϫ20°C isopentane. Binding was performed as described previously (Franceschini et al, 2002). Briefly, fresh frozen 20 m sections were cut, incubated in binding buffer (in mM: 50 Tris base, pH 7.4, 120 NaCl, 5 KCl, 2.5 CaCl 2 , and 1 MgCl 2 ) for 10 min and then in 500 pM […”

Section: Introductionmentioning

confidence: 99%

Decreased Signs of Nicotine Withdrawal in Mice Null for the β4 Nicotinic Acetylcholine Receptor Subunit

Salas¹,

Pieri²,

Biasi³

2004

J. Neurosci.

212

229

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Withdrawal from chronic exposure to nicotine, the main addictive component of tobacco, produces distinctive symptoms in humans. The appearance of these symptoms is a major deterrent when people try to quit smoking. To study which type of nicotine receptor is relevant for the onset of the withdrawal syndrome, we used a mouse model of nicotine withdrawal. Wild-type mice and mice null for the ␤4 (␤4Ϫ/Ϫ) or the ␤2 (␤2Ϫ/Ϫ) nicotinic acetylcholine receptor subunits were implanted with osmotic minipumps delivering 24 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 nicotine for 13 d. Subsequently, a single intraperitoneal injection of the nicotinic receptor antagonist mecamylamine induced behavioral symptoms of withdrawal measured as increased grooming, chewing, scratching, and shaking, plus the appearance of some unique behaviors such as jumping, leg tremors, and cage scratching. Mecamylamine injection triggered comparable withdrawal signs in wild-type and in ␤2Ϫ/Ϫ mice, whereas the ␤4Ϫ/Ϫ mice displayed significantly milder somatic symptoms. In addition, nicotine withdrawal produced hyperalgesia in wild-type but not ␤4 Ϫ/Ϫ mice. Finally, chronic nicotine produced an increase in epibatidine binding in several areas of the brain in both wild-type and in ␤4Ϫ/Ϫ mice, but such receptor upregulation did not correlate with the severity of withdrawal signs.Our results demonstrate a major role for ␤4-containing nicotinic acetylcholine receptors in the appearance of nicotine withdrawal symptoms. In contrast, the ␤2 subunit does not seem to greatly influence this phenomenon. We also show that the upregulation of epibatidine binding sites attributable to chronic nicotine, an effect associated with ␤2-containing receptors, is probably not related to the mechanisms underlying withdrawal.

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“…Franceschini et al (Franceschini et al, 2002) found no difference in the relative abundance of hippocampal mRNA for the α4, α5, β2 and β4 subunits in adult C57BL/6 α7 wild type, heterozygote and null mutant mice. In contrast, Yu et al (Yu et al, 2007) observed a significant increase in 3H cytisine binding on postnatal day (P) 21 as well as a significant increase in α4 subunit protein on P10, P14 and P21 in hippocampus from C57BL/ 6 α7 heterozygote as opposed to wild type mice.…”

Section: Compensatory Changesmentioning

confidence: 98%

Altered hippocampal circuit function in C3H α7 null mutant heterozygous mice

et al. 2008

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The α7 subtype of nicotinic receptor is highly expressed in the hippocampus where it is purported to modulate release of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). The α7 receptormediated release of GABA is thought to contribute to hippocampal inhibition (gating) of response to repetitive auditory stimulation. This hypothesis is supported by observations of hippocampal auditory gating deficits in mouse strains with low levels of hippocampal α7 receptors compared to strains with high levels of hippocampal α7 receptors. The difficulty with comparisons between mouse strains, however, is that different strains have different genetic backgrounds. Thus, the observed interstrain differences in hippocampal auditory gating might result from factors other than interstrain variations in the density of hippocampal α7 receptors. To address this issue, hippocampal binding of the α7 receptor-selective antagonist α-bungarotoxin as well as hippocampal auditory gating characteristics were compared in C3H wild type and C3H α7 receptor null mutant heterozygous mice. The C3H α7 heterozygous mice exhibited significant reductions in hippocampal α7 receptors levels and abnormal hippocampal auditory gating compared to the C3H wild type mice. In addition, a general increase in CA3 pyramidal neuron responsivity was observed in the heterozygous mice compared to the wild type mice. These data suggest that decreasing hippocampal α7 receptor density results in a profound alteration in hippocampal circuit function.

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Absence of α7-containing neuronal nicotinic acetylcholine receptors does not prevent nicotine-induced seizures

Cited by 68 publications

References 93 publications

SSR180711, a Novel Selective α7 Nicotinic Receptor Partial Agonist: (II) Efficacy in Experimental Models Predictive of Activity Against Cognitive Symptoms of Schizophrenia

SSR180711, a Novel Selective α7 Nicotinic Receptor Partial Agonist: (II) Efficacy in Experimental Models Predictive of Activity Against Cognitive Symptoms of Schizophrenia

Decreased Signs of Nicotine Withdrawal in Mice Null for the β4 Nicotinic Acetylcholine Receptor Subunit

Altered hippocampal circuit function in C3H α7 null mutant heterozygous mice

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