Nicotinic receptors and schizophrenia

Ripoll, Nadège; Bronnec, Marie; Bourin, Michel

doi:10.1185/030079904125004060

Cited by 93 publications

(78 citation statements)

References 160 publications

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“…These findings, taken together with the idea that schizophrenia patients have a strongly increased likelihood of smoking (for reviews, see Dalack et al, 1998;Ripoll et al, 2004), have led to the 'self-medication hypothesis' that proposes that schizophrenia patients may attempt to transiently remedy otherwise deficient attentional processes; this effect, however, could vary depending on genetic background (Kumari and Postma, 2005). Prepulse inhibition studies also contribute to the view that neurocognitive dysfunction in schizophrenia could be based on a dysfunctional nAChR system: George et al (2006) demonstrated that tobacco smoking selectively enhances PPI deficits in schizophrenia and more recently it was also shown that nasally administered nicotine increases PPI in schizophrenia patients and healthy controls (Hong et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Sensorimotor Gating is Associated with CHRNA3 Polymorphisms in Schizophrenia and Healthy Volunteers

Petrovsky

Quednow

Ettinger

et al. 2010

Neuropsychopharmacol

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Attentional gating deficits, commonly measured by prepulse inhibition (PPI) of the acoustic startle response (ASR), have been established as an endophenotype of schizophrenia. Prepulse inhibition is heritable and has been associated with polymorphisms in serotonin and dopamine system genes. Prepulse inhibition can be enhanced by nicotine, and therefore it has been proposed that schizophrenia patients smoke to ameliorate their early attentional deficits. The PPI-enhancing effects of nicotine in rodents are strain dependent, suggesting a genetic contribution to PPI within the nicotinic acetylcholine receptor (nAChR) system. Recent human genetic studies also imply that tobacco dependence is affected by polymorphisms in the a3/a5 subunits of the nAChR (CHRNA3/CHRNA5) gene cluster. We, therefore, investigated the impact of two common CHRNA3 polymorphisms (rs1051730/rs1317286) on PPI, startle reactivity, and habituation of the ASR in two independent samples of 107 healthy British volunteers and 73 schizophrenia patients hailing from Germany. In both samples, PPI was influenced by both CHRNA3 polymorphisms (combined p-value ¼ 0.0027), which were strongly linked. Moreover, CHRNA3 genotype was associated with chronicity, treatment, and negative symptoms in the schizophrenia sample. These results suggest that sensorimotor gating is influenced by variations of the CHRNA3 gene, which might also have an impact on the course and severity of schizophrenia.

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Section: Introductionmentioning

confidence: 99%

Sensorimotor Gating is Associated with CHRNA3 Polymorphisms in Schizophrenia and Healthy Volunteers

Petrovsky

Quednow

Ettinger

et al. 2010

Neuropsychopharmacol

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“…The usefulness of nicotinic treatments for a variety of neuropsychiatric indications including schizophrenia has been suggested [78][79][80][81][82]. Attentional improvement by nicotinic agents may be a key therapeutic effect for these psychiatric disorders [83,84].…”

Section: The Potential Of Nicotinic Treatment For the Cognitive Impaimentioning

confidence: 99%

Nicotinic interactions with antipsychotic drugs, models of schizophrenia and impacts on cognitive function

Levin

Rezvani

2007

Biochemical Pharmacology

109

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People with schizophrenia often have substantial cognitive impairments, which may be related to nicotinic receptor deficits, (α7 and α4β2), documented in the brains of people with schizophrenia. The large majority of people with schizophrenia smoke cigarettes. Thus, nicotinic interactions with antipsychotic drugs are widespread. Complementary co-therapies of novel nicotinic ligands are being developed to add to antipsychotic therapy to treat the cognitive impairment of schizophrenia. Thus, it is critical to understand the interaction between nicotinic treatments and antipsychotic drugs. Nicotinic interactions with antipsychotic drugs, are complex since both nicotine and antipsychotics have complex actions. Nicotine stimulates and desensitizes nicotinic receptors of various subtypes and potentiates the release of different neurotransmitters. Antipsychotics also act on a verity of receptor systems. For example, clozapine acts as an antagonist at a variety of neurotransmitter receptors such as those for dopamine, serotonin, norepinepherine and histamine. In a series of studies, we have found that in normally functioning rats, moderate doses of clozapine impair working memory and that clozapine blocks nicotine-induced memory and attentional improvement. Clozapine and nicotine can attenuate each other's beneficial effects in reversing the memory impairment caused by the psychototmimetic drug dizocilpine. A key to the clozapine-induced attenuation of nicotineinduced cognitive improvement appears to be its 5HT 2 antagonist properties. The selective 5HT 2 antagonist ketanserin has a similar action of blocking nicotine-induced memory and attentional improvements. It is important to consider the interactions between nicotinic and antipsychotic drugs to develop the most efficacious treatment for cognitive improvement in people with schizophrenia.

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“…Neuronal nAChRs have been implicated in a variety of disease states, including Alzheimer's disease [8], schizophrenia [9], a genetically transmissible form of epilepsy [10], inflammation and pain [11], and the autoimmune disease myasthenia gravis [12]. As such, there is great interest in characterizing ligands that can discriminate between different subunit arrangements of this receptor.…”

Section: Introductionmentioning

confidence: 99%

Hydrophobic residues at position 10 of α-conotoxin PnIA influence subtype selectivity between α7 and α3β2 neuronal nicotinic acetylcholine receptors

Hopping

Wang

Hogg³

et al. 2014

Biochemical Pharmacology

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Neuronal nicotinic acetylcholine receptors (nAChRs) are a diverse class of ligand-gated ion channels involved in neurological conditions such as neuropathic pain and Alzheimer's disease.-Conotoxin [A10L]PnIA is a potent and selective antagonist of the mammalian 7 nAChR with a key binding interaction at position 10. We now describe a molecular analysis of the receptorligand interactions that determine the role of position 10 in determining potency and selectivity for the 7 and 3 2 nAChR subtypes. Using electrophysiological and radioligand binding methods on a suite of [A10L]PnIA analogs we observed that hydrophobic residues in position 10 maintained potency at both subtypes whereas charged or polar residues abolished 7 binding.Molecular docking revealed dominant hydrophobic interactions with several 7 and 3 2 receptor residues via a hydrophobic funnel. Incorporation of norleucine (Nle) caused the largest (8-fold) increase in affinity for the 7 subtype (Ki = 44 nM) though selectivity reverted to 3 2 (IC 50 = 0.7 nM). It appears that that placement of a single methyl group determines selectivity between 7 and 3 2 nAChRs via different molecular determinants.

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Nicotinic receptors and schizophrenia

Cited by 93 publications

References 160 publications

Sensorimotor Gating is Associated with CHRNA3 Polymorphisms in Schizophrenia and Healthy Volunteers

Sensorimotor Gating is Associated with CHRNA3 Polymorphisms in Schizophrenia and Healthy Volunteers

Nicotinic interactions with antipsychotic drugs, models of schizophrenia and impacts on cognitive function

Hydrophobic residues at position 10 of α-conotoxin PnIA influence subtype selectivity between α7 and α3β2 neuronal nicotinic acetylcholine receptors

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