Smoking and schizophrenia: abnormal nicotinic receptor expression

Leonard, Sherry; Breese, Charles R.; Adams, Catherine E.; Benhammou, Khalid; Gault, Judith; Stevens, Karen E.; Lee, Michael; Adler, Lawrence E.; Olincy, Ann; Ross, Randal G.; Freedman, Robert

doi:10.1016/s0014-2999(00)00035-2

Cited by 154 publications

(103 citation statements)

References 57 publications

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“…Over the past 10 years, there has been a remarkable expansion in research on the therapeutic potential of nAChR ligands, particularly because correlations have been traced between nicotinic cholinergic dysfunctions in the brain and the severity of certain symptoms of neurologic disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Down Syndrome (DS), schizophrenia, and some forms of epilepsy (Steinlein et al, 1995;Kuryatov et al, 1997;Hellstrom-Lindahl et al, 1999;Nordberg, 1999;Sihver et al, 1999;Perry et al, 1990Perry et al, , 2000Leonard et al, 2000;Court et al, 2001). A number of unconventional ligands that modulate nAChR activity have been discovered and, as a consequence of a continuum of basic and clinical research, the cholinesterase inhibitor galantamine, which also acts as a nicotinic allosteric potentiating ligand (APL), was recently approved by the Food and Drug Administration (FDA) for treatment of patients with AD in the United States.…”

Section: Introductionmentioning

confidence: 99%

Unconventional ligands and modulators of nicotinic receptors

et al. 2002

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ABSTRACT:Evidence gathered from epidemiologic and behavioral studies have indicated that neuronal nicotinic receptors (nAChRs) are intimately involved in the pathogenesis of a number of neurologic disorders, including Alzheimer's disease, Parkinson's disease, and schizophrenia. In the mammalian brain, neuronal nAChRs, in addition to mediating fast synaptic transmission, modulate fast synaptic transmission mediated by the major excitatory and inhibitory neurotransmitters glutamate and GABA, respectively. Of major interest, however, is the fact that the activity of the different subtypes of neuronal nAChR is also subject to modulation by substances of endogenous origin such as choline, the tryptophan metabolite kynurenic acid, neurosteroids, and ␤-amyloid peptides and by exogenous substances, including the so-called nicotinic allosteric potentiating ligands, of which galantamine is the prototype, and psychotomimetic drugs such as phencyclidine and ketamine. The present article reviews and discusses the effects of unconventional ligands on nAChR activity and briefly describes the potential benefits of using some of these compounds in the treatment of neuropathologic conditions in which nAChR function/expression is known to be altered.

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Section: Introductionmentioning

confidence: 99%

Unconventional ligands and modulators of nicotinic receptors

et al. 2002

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“…Further, the changes in cerebral KYNA levels observed after prolonged nicotine administration may account for the ability of nicotine to influence neuronal viability in vivo (Akaike et al, 1994;Marin et al, 1994;O'Neill et al, 1998). The present findings are also relevant for the pathophysiology of schizophrenia since both glutamate receptor and a7 nAChR dysfunction have been implicated in the disease process (Carlsson and Carlsson, 1990;Freedman et al, 1995;Tamminga, 1998;Leonard et al, 2000;Schilstr + om et al, 2000;Coyle and Tsai, 2004). Thus, the elevated levels of KYNA measured in the brain and cerebrospinal fluid (Erhardt et al, 2001a;Schwarcz et al, 2001) may contribute to the presumed hypoglutamatergic and hypocholinergic tone in schizophrenic individuals.…”

Section: Discussionmentioning

confidence: 66%

“…Several lines of evidence suggest a role of nicotinic acetylcholine receptors (nAChRs) in the pathophysiology of schizophrenia (Adler et al, 1998;Guan et al, 1999;Breese et al, 2000;Leonard et al, 2000). This connection was initially proposed because of the high incidence of heavy smoking in schizophrenic individuals (Hughes et al, 1986;Lohr and Flynn, 1992).…”

Section: Introductionmentioning

confidence: 99%

“…Compared to control subjects with similar smoking habits, a7 nAChR density is reduced in the cerebral cortex and hippocampus of individuals with schizophrenia (Freedman et al, 1995;Adler et al, 1998;Leonard et al, 2000;Guan et al, 1999). Therefore, since cerebral a7 nAChRs are normally upregulated in heavy smokers (Benwell et al, 1988;Breese et al, 2000) and after chronic nicotine administration in animals (Olale et al, 1997;Sparks and Pauly, 1999), a7 nAChRs in patients appear to have an abnormally blunted reaction to excessive smoking.…”

Section: Introductionmentioning

confidence: 99%

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Prolonged Nicotine Administration Results in Biphasic, Brain-Specific Changes in Kynurenate Levels in the Rat

Rassoulpour

Albuquerque

et al. 2004

Neuropsychopharmacol

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The content of the endogenous NMDA and a7 nicotinic acetylcholine receptor antagonist kynurenate (KYNA) is increased in the cerebral cortex and cerebrospinal fluid of patients with schizophrenia. In view of the very high incidence of smoking in schizophrenic individuals, a study was designed to examine the effect of acute and prolonged nicotine administration on brain KYNA levels in experimental animals. Adult male rats received subcutaneous nicotine injections twice daily for up to 10 days, and animals were routinely killed 1 h after the last injection. Neither acute treatment nor a 2-day regimen with 1 mg/kg nicotine ( ¼ 0.35 mg/kg pure base) caused changes in cerebral KYNA levels. Four-or 6 day-treatment with this dose resulted in 20-40% decreases in cerebral KYNA content. Animals treated with 1 or 10 mg/kg nicotine for 10 days showed dose-dependent, significant increases in KYNA in hippocampus, striatum, and cortex, but not in the serum. Discontinuation of nicotine treatment for 7 days restored brain KYNA to control levels. Separate animals, implanted with osmotic minipumps delivering 2 mg/kg of nicotine/day for 10 days also showed significant elevations in brain KYNA. Hippocampal microdialysis, performed in animals receiving nicotine (1 mg/kg) for 10 days, revealed a significant increase in basal extracellular KYNA levels compared to controls, whereas acute treatment with this dose produced no such change. Measurements of KYNA's bioprecursor kynurenine in brain or blood did not reveal any nicotine-induced changes. These results indicate that nicotine has a brain-specific, biphasic effect on the transamination of kynurenine to KYNA. Such nicotine-induced fluctuations in brain KYNA may cause functional changes in processes that regulate glutamatergic and cholinergic neurotransmission in the normal and diseased brain.

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“…Patients with schizophrenia have a deficiency of α7 nicotinic receptors in the hippocampus and frontal cortex [29,30]. In particular, α7 receptors in the hippocampus appear to be important for the cognitive impairment [31][32][33]. This cognitive impairment may be due to decreased desensitization of hippocampal α7 receptors in schizophrenics [34].…”

Section: Nicotinic Systems and The Cognitive Impairment Of Schizophreniamentioning

confidence: 99%

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

Levin

Rezvani

2007

Biochemical Pharmacology

108

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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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Smoking and schizophrenia: abnormal nicotinic receptor expression

Cited by 154 publications

References 57 publications

Unconventional ligands and modulators of nicotinic receptors

Unconventional ligands and modulators of nicotinic receptors

Prolonged Nicotine Administration Results in Biphasic, Brain-Specific Changes in Kynurenate Levels in the Rat

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

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