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Behavioral evaluation of mice deficient in GABAB(1) receptor isoforms in tests of unconditioned anxiety

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Abstract

Rationale

Emerging data support a role for GABAB receptors in anxiety. GABAB receptors are comprised of a heterodimeric complex of GABAB1 and GABAB2 receptor subunits. The predominant neuronal GABAB1 receptor isoforms are GABAB(1a) and GABAB(1b). Recent findings indicate specific roles for these isoforms in conditioned fear responses, although their influence on behavior in tests of unconditioned anxiety is unknown.

Objective

The aim of this study was to examine the role of the GABAB(1) isoforms in unconditioned anxiety.

Materials and methods

Mice deficient in the GABAB(1a) or GABAB(1b) receptor isoforms were examined in a battery of anxiety tests.

Results

In most tests, genotype did not significantly affect anxious behavior, including the elevated plus maze, marble burying, and stress-induced hypothermia tests. Corticosterone and adrenocorticotropic hormone levels were similarly unaffected by genotype. Female, but not male, \( {\text{GABA}}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}_{{{\text{B}}{\left( {1{\text{a}}} \right)}}} \) and \( {\text{GABA}}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}_{{{\text{B}}{\left( {1{\text{b}}} \right)}}} \) mice showed increased anxiety relative to wild-type controls in the elevated zero maze. In the staircase test, male \( {\text{GABA}}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}_{{{\text{B}}{\left( {1{\text{b}}} \right)}}} \) mice defecated more than male \( {\text{GABA}}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}_{{{\text{B}}{\left( {1{\text{a}}} \right)}}} \) mice, although no other test parameter was influenced by genotype. In the light–dark box, female \( {\text{GABA}}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}_{{{\text{B}}{\left( {1{\text{a}}} \right)}}} \) mice spent less time in the light compartment compared to the \( {\text{GABA}}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}_{{{\text{B}}{\left( {1{\text{b}}} \right)}}} \) females, whereas male \( {\text{GABA}}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}_{{{\text{B}}{\left( {1{\text{b}}} \right)}}} \) mice made fewer light–dark transitions than \( {\text{GABA}}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}_{{{\text{B}}{\left( {1{\text{a}}} \right)}}} \) males.

Conclusions

Specific roles for either GABAB(1) isoform in unconditioned anxiety were not explicit. This differs from their contribution in conditioned anxiety and from the anxious phenotype of GABAB1 and GABAB2 subunit knockout mice. The findings suggest that the GABAB(1) isoforms have specific relevance for anxiety with a cognitive component, rather than for innate anxiety per se.

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Acknowledgements

This work was supported by the National Institutes of Mental Health/National Institute on Drug Abuse grant U01 MH69062 (LHJ, KK, JFC) and the Swiss Science Foundation (3100–067100.01, BB). The authors thank Dr. Christopher Pryce for critical reading of the manuscript. We thank Christine Hunn and Hugo Bürki for their excellent technical assistance. We would also like to thank Dr. Doncho Uzunov and Christian Kohler for endocrine measurements.

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  1. John F. Cryan

    Present address: Department of Pharmacology and Therapeutics, School of Pharmacy, University College Cork, Cork, Ireland

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  1. Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4002, Basel, Switzerland

    Laura H. Jacobson, Klemens Kaupmann & John F. Cryan

  2. Department of Clinical-Biological Sciences, Pharmazentrum, Institute of Physiology, University of Basel, 4056, Basel, Switzerland

    Bernhard Bettler

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Jacobson, L.H., Bettler, B., Kaupmann, K. et al. Behavioral evaluation of mice deficient in GABAB(1) receptor isoforms in tests of unconditioned anxiety. Psychopharmacology 190, 541–553 (2007). https://doi.org/10.1007/s00213-006-0631-9

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