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Nicotine effects in adolescence and adulthood on cognition and α4β2-nicotinic receptors in the neonatal ventral hippocampal lesion rat model of schizophrenia

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Abstract

Rational

Nicotine use in schizophrenia has traditionally been explained as “self-medication” of cognitive and/or nicotinic acetylcholinergic receptor (nAChR) abnormalities.

Objectives

We test this hypothesis in a neurodevelopmental rat model of schizophrenia that shows increased addiction behaviors including enhanced nicotine reinforcement and drug-seeking.

Methods

Nicotine transdermal patch (5 mg/kg/day vs. placebo × 10 days in adolescence or adulthood) effects on subsequent radial-arm maze learning (15 sessions) and frontal-cortical-striatal nAChR densities (α4β2; [3H]-epibatidine binding) were examined in neonatal ventral hippocampal lesion (NVHL) and SHAM-operated rats.

Results

NVHL cognitive deficits were not differentially affected by nicotine history compared to SHAMs. Nicotine history produced minimal cognitive effects while increasing food–reward consumption on the maze, compounding with NVHL-induced overconsumption. Acute nicotine (0.5 mg/kg) delivered before the final maze sessions produced modest improvements in maze performance in rats with nicotine patch histories only, but not differentially so in NVHLs. Consistent with in vivo neuroimaging of β2 nAChR binding in schizophrenia smokers vs. non-smokers and healthy controls, adult NVHLs showed 12% reductions in nAChR binding in MPFC (p < 0.05) but not ventral striatum (<5% changes, p > .40), whereas nicotine history elevated nAChRs across both regions (>30%, p < 0.001) without interacting with NVHLs. Adolescent vs. adult nicotine exposure did not alter nAChRs differentially.

Conclusions

Although replicating nicotine-induced upregulation of nAChRs in human smokers and demonstrating NVHL validity in terms of schizophrenia-associated nAChR density patterns, these findings do not support hypotheses explaining increased nicotine use in schizophrenia as reflecting illness-specific effects of nicotine to therapeutically alter cognition or nAChR densities.

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Acknowledgments

The authors sincerely thank Irina Esterlis et al. for their permission to represent their comparable human data in graphical form for this manuscript (Esterlis et al. 2014). Of note, the Yale (human) and IU (animal modeling) investigative teams were not aware of each other’s parallel study designs or results until after publication of Esterlis et al. and manuscript preparation of this report.

Funding

This study was supported by NSF GK-12 Doctoral Training Program Grant (SAB) and NIAAA (R01 AA020396) (EAE).

Conflict of interest

The authors have no conflicts of interest to report.

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Authors and Affiliations

  1. Laboratory for Translational Neuroscience of Dual Diagnosis & Development, Suite 314D, 320 West 16th Street, Indianapolis, IN, 46202, USA

    Sarah A. Berg, Alena M. Sentir & R. Andrew Chambers

  2. IU Neuroscience Center, Suite 314D, 320 West 16th Street, Indianapolis, IN, 46202, USA

    Sarah A. Berg, Alena M. Sentir, Richard L. Bell, Eric A. Engleman & R. Andrew Chambers

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  1. Sarah A. Berg
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  2. Alena M. Sentir
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  3. Richard L. Bell
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  4. Eric A. Engleman
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  5. R. Andrew Chambers
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Correspondence to R. Andrew Chambers.

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Berg, S.A., Sentir, A.M., Bell, R.L. et al. Nicotine effects in adolescence and adulthood on cognition and α4β2-nicotinic receptors in the neonatal ventral hippocampal lesion rat model of schizophrenia. Psychopharmacology 232, 1681–1692 (2015). https://doi.org/10.1007/s00213-014-3800-2

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  • DOI: https://doi.org/10.1007/s00213-014-3800-2

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