Cognitive Deficits in Schizophrenia: Focus on Neuronal Nicotinic Acetylcholine Receptors and Smoking

Abstract

Patients with schizophrenia present with deficits in specific areas of cognition. These are quantifiable by neuropsychological testing and can be clinically observable as negative signs. Concomitantly, they self-administer nicotine in the form of cigarette smoking. Nicotine dependence is more prevalent in this patient population when compared to other psychiatric conditions or to non-mentally ill people. The target for nicotine is the neuronal nicotinic acetylcholine receptor (nAChR). There is ample evidence that these receptors are involved in normal cognitive operations within the brain. This review describes neuronal nAChR structure and function, focusing on both cholinergic agonist-induced nAChR desensitization and nAChR up-regulation. The several mechanisms proposed for the nAChR up-regulation are examined in detail. Desensitization and up-regulation of nAChRs may be relevant to the physiopathology of schizophrenia. The participation of several subtypes of neuronal nAChRs in the cognitive processing of non-mentally ill persons and schizophrenic patients is reviewed. The role of smoking is then examined as a possible cognitive remediator in this psychiatric condition. Finally, pharmacological strategies focused on neuronal nAChRs are discussed as possible therapeutic avenues that may ameliorate the cognitive deficits of schizophrenia.

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Abbreviations

ACh:

Acetylcholine

AES:

Apathy Evaluation Scale

αBgt:

α-Bungarotoxin

BPRS:

Brief Psychiatric Rating Scale

DHβE:

Dihydro-β-erythroidine

DMPP:

1,1-dimethyl-4-phenylpiperazinium

FDA:

Food and Drug Administration

GABA:

Gamma aminobutyric acid

5-HT:

5-Hydroxytryptamine

MATRICS:

Measurement and Treatment Research to Improve Cognition in Schizophrenia

NIMH:

National Institute of Mental Health

MCC:

Methylcarbamylcholine

nAChR:

Nicotinic acetylcholine receptor

NMDA:

N-methyl-d-aspartic acid

OL:

Open Label

PANSS:

Positive and Negative Symptom Scale for Schizophrenia

PKA:

Protein kinase A

PKC:

Protein kinase C

RBANS:

Repeatable Battery for the Assessment of Neuropsychological status

RCFT:

Rey Complex Figure Test

RCT:

Randomized Controlled Trial

SANS:

Scale for the Assessment of Negative Symptms in Schizoprenia

SCIP:

Scale for the Assessment of Cognitive Impairment in Psychosis

SGA:

Second generation antipsychotics

SN:

Substantia nigra

TMA:

Tetramethylammonium

VTA:

Ventral tegmental area

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Acknowledgments

The authors are grateful to Drs. Gretchen Lopez-Hernandez, and Javier Sanchez for insights and perspectives. Work in the author’s laboratory (JLD) is supported by the National Institutes of Health grants 2RO1GM56371–10, GM08102–27 and SNRP U54NS0430311. This work was supported in part by grants from the National Institutes of Health NIGMS 2RO1GM56371-10, GM08102-27, NINDS SNRP U54NS0430311 and UPR Insitutional Funds for Research.

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Ochoa, E.L.M., Lasalde-Dominicci, J. Cognitive Deficits in Schizophrenia: Focus on Neuronal Nicotinic Acetylcholine Receptors and Smoking. Cell Mol Neurobiol 27, 609–639 (2007). https://doi.org/10.1007/s10571-007-9149-x

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Keywords

  • Schizophrenia
  • Nicotinic receptors