Monoamine reuptake inhibition and nicotine receptor antagonism reduce amplitude and gating of auditory evoked potentials

doi:10.1016/j.neuroscience.2005.03.027

Neuroscience

Volume 133, Issue 3, 2005, Pages 729-738

https://doi.org/10.1016/j.neuroscience.2005.03.027 Get rights and content

Abstract

Background

Sensory encoding deficits have been extensively studied as endophenotypic markers of schizophrenia using auditory evoked potentials. In order to increase understanding of the neurochemical basis of such deficits, we utilized an animal model to test whether monoamine reuptake inhibition and nicotine receptor antagonism reduce the amplitude and gating of the P20 and N40 auditory components.

Methods

C57BL/6J mice received 12 days of chronic vehicle, bupropion, haloperidol or bupropion plus haloperidol. Auditory evoked potentials were then recorded in alert mice to measure the amplitude and gating of evoked components during a paired click paradigm similar to tasks used to measure the P50 and N100 auditory potentials in schizophrenia. Evoked potentials were recorded prior to and following acute nicotine.

Results

Bupropion reduced the amplitude and gating of the N40 evoked potential in mice, similar to the P50 and N100 endophenotypes associated with sensory encoding deficits in schizophrenia. This deficit was fully reversed only by the combination of haloperidol and nicotine, suggesting that dopamine reuptake inhibition and nicotine antagonism both contribute to the observed phenotype. Furthermore, nicotine increased P20 amplitude across all groups supporting a role for nicotine agonists in pre-attentive sensory encoding deficits.

Conclusions

We propose that the combination of monoamine inhibition and nicotine receptor antagonism may serve as a useful model for preclinical screening of pharmaceutical compounds aimed at treating sensory encoding deficits in schizophrenia.

Section snippets

Animals

Male C57BL/6J mice were obtained from Jackson Laboratories (Bar Harbor, ME, USA) for auditory testing (n=36). All protocols were conducted in accordance with University Laboratory Animal Resources guidelines and were approved by the Institutional Animal Care and Use Committee. Mice were housed in groups of four, had free access to food and water in a light and temperature-controlled Association for the Assessment and Accreditation of Laboratory Animal Care (AALAC)-accredited animal facility and

P20

The P20 displayed gating with a significant reduction in the amplitude of response following the second stimulus relative to the first across all drug conditions (F(1, 32)=17.71, P<0.001) (Fig. 3A). There was no significant effect of chronic drug treatment on the amplitude of the P20 (F(3, 32)=2.338, P=0.092) (Fig. 3B). However, there was a significant increase in P20 amplitude following nicotine across all groups (F(1, 32)=8.606, P=0.006) (Fig. 3C). There were no interactions between either

Discussion

We have proposed that the antidepressant bupropion has construct validity as a pharmacological model of schizophrenia based on its activity as a serotonin, norepinephrine, and dopamine reuptake inhibitor as well as a nicotine receptor antagonist. This premise is supported by several case reports of bupropion-induced psychosis and a review of clinical trails by the manufacturer in which 5% of participants experience hallucinations or delusions (Johnston et al 1986, Howard and Warnock 1999,

Acknowledgments

We thank Dr. Karen Stevens, Dr. Robert Freedman, and Dr. Julie Blendy for helpful comments and guidance during this study. A pilot grant to S.J.S. from P50 CA84718 (C.L.), P50 MH 6404501 (R.E.G., S.J.K., S.J.S.) and The Stanley Medical Research Institute (S.J.S.) supported this research.

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Clinical neuroscienceMonoamine reuptake inhibition and nicotine receptor antagonism reduce amplitude and gating of auditory evoked potentials

Abstract

Background

Methods

Results

Conclusions

Section snippets

Animals

P20

Discussion

Acknowledgments

Brain Res

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Brain Res Brain Res Rev

Psychiatry Res

Psychiatry Res

Psychiatry Res

Psychiatry Res

Neurosci Biobehav Rev

Neuropharmacology

Brain Res Cogn Brain Res

Brain Res

Neurosci Lett

Neuroscience

Life Sci

Biol Psychiatry

Schizophr Res

Schizophr Res

Pharmacol Biochem Behav

Neuroimage

Biol Psychiatry

Psychiatry Res

Neuroscience

Cell

Pharmacol Biochem Behav

Life Sci

Electroencephalogr Clin Neurophysiol

Neurosci Lett

Neuropsychopharmacology

Biol Psychiatry

Brain Res

Brain Res Bull

Normalization of auditory physiology by cigarette smoking in schizophrenic patients

Am J Psychiatry

Schizophrenia, sensory gating, and nicotinic receptors

Schizophr Bull

Bupropiona review of its mechanism of antidepressant activity

J Clin Psychiatry

Effects of cigarette smoking on cognitive processing

Int J Neurosci

Characterization of the bupropion cue in the ratlack of evidence for a dopaminergic mechanism

Psychopharmacology (Berl)

Clinical neuroscience
Monoamine reuptake inhibition and nicotine receptor antagonism reduce amplitude and gating of auditory evoked potentials