1. ¹Max Planck Institute of Psychiatry, Munich, Germany
2. ²Department of Physiological Chemistry, Johannes Gutenberg University, Mainz, Germany
3. ³U 862 Centre de Recherche INSERM François Magendie, Université Bordeaux 2, Bordeaux, France
4. ⁴F. Hoffmann-La Roche AG, Pharma Division, Preclinical Research, Basel, Switzerland
5. ⁵Department of Neurosurgery, University Hospital Basel, Basel, Switzerland

Correspondence: MA Steiner, Research Group Neuronal Plasticity, Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany. E-mails: steiner@mpipsykl.mpg.de; steinmi@uni-mainz.de

Received 2 October 2006; Revised 11 May 2007; Accepted 4 June 2007; Published online 7 August 2007.

Abstract

Dysregulation of the endocannabinoid system is known to interfere with emotional processing of stressful events. Here, we studied the role of cannabinoid receptor type 1 (CB1) signaling in stress-coping behaviors using the forced swim test (FST) with repeated exposures. We compared effects of genetic inactivation with pharmacological blockade of CB1 receptors both in male and female mice. In addition, we investigated potential interactions of the endocannabinoid system with monoaminergic and neurotrophin systems of the brain. Naive CB1 receptor-deficient mice (CB1^{- /-} ) showed increased passive stress-coping behaviors as compared to wild-type littermates (CB1^+/+) in the FST, independent of sex. These findings were partially reproduced in C57BL/6N animals and fully reproduced in female CB1^+/+ mice by pharmacological blockade of CB1 receptors with the CB1 receptor antagonist SR141716. The specificity of SR141716 was confirmed in female CB1^{- /-} mice, where it failed to affect behavioral performance. Sensitivity to the antidepressants desipramine and paroxetine was preserved, but slightly altered in female CB1^{- /-} mice. There were no genotype differences between CB1^+/+ and CB1^{- /-} mice in monoamine oxidase A and B activities under basal conditions, nor in monoamine content of hippocampal tissue after FST exposure. mRNA expression of vesicular glutamate transporter type 1 was unaffected in CB1^{- /-} mice, but mRNA expression of brain-derived neurotrophic factor (BDNF) was reduced in the hippocampus. Our results suggest that impaired CB1 receptor function promotes passive stress-coping behavior, which, at least in part, might relate to alterations in BDNF function.