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Enhanced methamphetamine self-administration in a neurodevelopmental rat model of schizophrenia

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Abstract

Rationale

Substance abuse is more prevalent among patients with schizophrenia than in the general population. The considerable overlap in neurobiological disruptions thought to underlie each condition suggests that addictive behavior may represent a primary symptom of schizophrenia.

Objective

This study investigated drug-seeking in a neurodevelopmental animal model of schizophrenia, the neonatal ventral hippocampal lesion (NVHL) model.

Materials and methods

At postnatal day 7, rats received an excitotoxic ventral hippocampus lesion or a sham procedure and were trained as adults to self-administer methamphetamine (0.1 mg/kg/infusion) or respond for natural reinforcement (water or food).

Results

NVHL rats were faster than shams to acquire the operant response for either drug self-administration or water reinforcement, suggesting that simple instrumental learning may be enhanced in these animals. NVHL and sham rats displayed no differences in fixed-ratio (FR) responding for either methamphetamine or food, and both groups of animals were equally sensitive to methamphetamine dose changes (0.05, 0.1, or 0.2 mg/kg/infusion). However, under a progressive-ratio (PR) schedule, NVHL animals reached significantly higher break points (NVHL 18 infusions; sham 12 infusions) for methamphetamine but not food reinforcement, suggesting enhanced motivation to acquire drug and/or elevated incentive value of the drug that did not generalize to another form of reinforcement.

Conclusions

These data indicate that developmental disruption of the hippocampus elevates rats’ vulnerability to drug-seeking behavior under PR conditions. Furthermore, drug self-administration in the NVHL animal emulates addictive behavior in schizophrenia, making this model useful for investigating the mechanisms of dual diagnosis, including the neurobiological and behavioral similarities between addiction and schizophrenia.

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Acknowledgements

This work was supported by NIH award DA14020 to P.O’D. and an SMCM Faculty Development Grant to A.M.B. We thank Nicole Barnhardt, Katrina Emmerich, Atara Marzouk, Megan MacFarland, Casimira Ruiz, and Ronald Saul for their assistance with histological processing, and Suzanne Asmann and Laurie Warner for their assistance with behavioral testing.

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Author notes

  1. Patricio O’Donnell

    Present address: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, 20 Penn Street, Room S251, Baltimore, MD, 21201, USA

Authors and Affiliations

  1. Department of Psychology and Neuroscience Program, St. Mary’s College of Maryland, 18952, E. Fisher Road, St. Mary’s City, MD, 20686, USA

    Anne Marie Brady

  2. Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY, USA

    Anne Marie Brady, Sarah E. McCallum, Stanley D. Glick & Patricio O’Donnell

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  1. Anne Marie Brady
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  2. Sarah E. McCallum
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Correspondence to Anne Marie Brady.

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Brady, A.M., McCallum, S.E., Glick, S.D. et al. Enhanced methamphetamine self-administration in a neurodevelopmental rat model of schizophrenia. Psychopharmacology 200, 205–215 (2008). https://doi.org/10.1007/s00213-008-1195-7

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  • DOI: https://doi.org/10.1007/s00213-008-1195-7

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