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Rat strain differences in brain structure and neurochemistry in response to binge alcohol

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Abstract

Rationale

Ventricular enlargement is a robust phenotype of the chronically dependent alcoholic human brain, yet the mechanism of ventriculomegaly is unestablished. Heterogeneous stock Wistar rats administered binge EtOH (3 g/kg intragastrically every 8 h for 4 days to average blood alcohol levels (BALs) of 250 mg/dL) demonstrate profound but reversible ventricular enlargement and changes in brain metabolites (e.g., N-acetylaspartate (NAA) and choline-containing compounds (Cho)).

Objectives

Here, alcohol-preferring (P) and alcohol-nonpreferring (NP) rats systematically bred from heterogeneous stock Wistar rats for differential alcohol drinking behavior were compared with Wistar rats to determine whether genetic divergence and consequent morphological and neurochemical variation affect the brain’s response to binge EtOH treatment.

Methods

The three rat lines were dosed equivalently and approached similar BALs. Magnetic resonance imaging and spectroscopy evaluated the effects of binge EtOH on brain.

Results

As observed in Wistar rats, P and NP rats showed decreases in NAA. Neither P nor NP rats, however, responded to EtOH intoxication with ventricular expansion or increases in Cho levels as previously noted in Wistar rats. Increases in ventricular volume correlated with increases in Cho in Wistar rats.

Conclusions

The latter finding suggests that ventricular volume expansion is related to adaptive changes in brain cell membranes in response to binge EtOH. That P and NP rats responded differently to EtOH argues for intrinsic differences in their brain cell membrane composition. Further, differential metabolite responses to EtOH administration by rat strain implicate selective genetic variation as underlying heterogeneous effects of chronic alcoholism in the human condition.

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Acknowledgments

This study was supported by NIH grant numbers AA013521-INIA, AA005965, and AA017168.

Conflict of interest

All authors declare no competing financial interests.

Author information

Authors and Affiliations

  1. Psychiatry & Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Rd, Stanford, CA, 94305, USA

    Natalie M Zahr, Edith V Sullivan & Adolf Pfefferbaum

  2. Neuroscience Program, SRI International, Menlo Park, CA, 94025, USA

    Natalie M Zahr, Dirk Mayer, Torsten Rohlfing, Oliver Hsu, Shara Vinco, Juan Orduna & Adolf Pfefferbaum

  3. Radiology Department, Lucas MRS/I Center, Stanford University, Stanford, CA, 94304, USA

    Dirk Mayer

  4. Department of Comparative Medicine, Stanford University, Stanford, CA, 94305, USA

    Richard Luong

  5. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Richard L Bell

Authors
  1. Natalie M Zahr
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  2. Dirk Mayer
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  3. Torsten Rohlfing
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  4. Oliver Hsu
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  5. Shara Vinco
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  6. Juan Orduna
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  7. Richard Luong
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  8. Richard L Bell
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  9. Edith V Sullivan
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  10. Adolf Pfefferbaum
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Corresponding author

Correspondence to Natalie M Zahr.

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Fig. S1

EtOH dose given at each gavage treatment for individual EtOH animals in all three strains (includes the baseline loading dose and the extra dose on day 1). Averages for each strain indicated by larger symbols (red diamond WE, blue circle PE, green square NE). (JPEG 89 kb)

High resolution image (TIFF 2932 kb)

Fig. S2

Blood alcohol levels (BALs) measured at every time point blood was collected from individual EtOH animals in all three strains (includes the measurements taken before dosing, and the measurement taken 90 min after the second dose on each day of dosing). Averages for each strain indicated by larger symbols (red diamond WE, blue circle PE, green square NE). (JPEG 113 kb)

High resolution image (TIFF 2932 kb)

Fig. S3

EtOH dose and BALs at corresponding time points. Note: blood samples collected before dose given. Averages for each strain indicated by larger symbols (red diamond WE, blue circle PE, green square NE). (JPEG 90 kb)

High resolution image (TIFF 2932 kb)

Fig. S4

Weights of individual EtOH animals in all three strains on each day of EtOH treatment. (JPEG 66 kb)

High resolution image (TIFF 2932 kb)

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Zahr, N.M., Mayer, D., Rohlfing, T. et al. Rat strain differences in brain structure and neurochemistry in response to binge alcohol. Psychopharmacology 231, 429–445 (2014). https://doi.org/10.1007/s00213-013-3253-z

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  • DOI: https://doi.org/10.1007/s00213-013-3253-z

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