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Fronto-temporal-mesolimbic gene expression and heritable differences in amphetamine-disrupted sensorimotor gating in rats

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Abstract

Rationale

Differences in sensitivity to the prepulse inhibition (PPI)-disruptive effects of D2-family agonists in Sprague–Dawley (SD) vs. Long Evans (LE) rats are heritable, reflect differential activation of DA signaling in the nucleus accumbens (NAC), and are associated with differences in expression of specific NAC genes. These differences may inform us about the biology of PPI deficits in disorders such as schizophrenia.

Objectives

After confirming these strain-based PPI differences, we measured expression of four genes in NAC and other regions that regulate PPI: medial prefrontal cortex and ventral hippocampus (VH).

Methods

Startle and PPI were assessed in SD and LE rats administered d-amphetamine (0 vs. 4.5 mg/kg, sc). Two weeks later, brain tissue was processed for comt, nrg1, grid2, and csnk1e expression; blood comt expression was also tested.

Results

Data confirmed expected PPI phenotypes. Gene expression levels differed across strains, sexes, and brain regions, with LE > SD expression in most genes and regions, and female > male expression for all NAC genes. Within any brain region, expression of the four genes was highly inter-correlated; across regions, correlations were less robust, reflecting distinct strain- or sex-based subgroups. PPI amphetamine sensitivity at 120 ms correlated significantly with NAC nrg1 expression, while amphetamine sensitivity for 30 ms PPI and startle magnitude correlated significantly with VH nrg1 and blood comt expression.

Conclusions

Rat strains differing in a schizophrenia-linked phenotype also differ in expression levels of genes associated both with that phenotype, and with schizophrenia, within brain regions associated with that phenotype and schizophrenia.

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Acknowledgments

Expert technical assistance was provided by Ms. Samantha Hines and Mr. Steven Pham. Assistance in manuscript preparation was provided by Ms. Maria Bongiovanni. Gene expression measures were performed with the support of the Genomics Core at the UC San Diego Center for AIDS Research (AI36214), the VA San Diego Healthcare System, and the Veterans Medical Research Foundation. Supported by NIH grants: MH068366, MH059803, MH065571, and MH042228

Conflicts of interest

Drs. Swerdlow’s and Light’s work has been funded by the NIH/NIMH. Dr. Swerdlow has been a paid consultant for participation in a Scientific Advisory Board for Neurocrine, Inc., for work unrelated to this project. Dr. Light has received compensation as a paid consultant for participation in a Scientific Advisory Board for Astellas for work unrelated to this project. Drs. Shilling, Trim, and Saint Marie and Ms. Breier declare no potential conflict of interest.

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Authors and Affiliations

  1. Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, 92093-0804, USA

    Neal R. Swerdlow, Paul D. Shilling, Michelle Breier, Ryan S. Trim, Gregory A. Light & Richard Saint Marie

  2. VA San Diego Healthcare System, San Diego, CA, USA

    Gregory A. Light

  3. VISN 22, Mental Illness Research, Education and Clinical Center (MIRECC), San Diego, CA, USA

    Gregory A. Light

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  1. Neal R. Swerdlow
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  2. Paul D. Shilling
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  3. Michelle Breier
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  4. Ryan S. Trim
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  5. Gregory A. Light
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  6. Richard Saint Marie
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Correspondence to Neal R. Swerdlow.

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Swerdlow, N.R., Shilling, P.D., Breier, M. et al. Fronto-temporal-mesolimbic gene expression and heritable differences in amphetamine-disrupted sensorimotor gating in rats. Psychopharmacology 224, 349–362 (2012). https://doi.org/10.1007/s00213-012-2758-1

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  • DOI: https://doi.org/10.1007/s00213-012-2758-1

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