Interaction between brain endocannabinoid (EC) and serotonin (5-HT) systems was investigated by examining 5-HT-dependent behavioural and biochemical responses in CB1 receptor knockout mice. CB1 knockout animals exhibited a significant reduction in the induction of head twitches and paw tremor by the 5-HT2A receptor selective agonist ()DOI, as well as a reduced hypothermic response following administration of the 5-HT1A receptor agonist (±)-8-OH-DPAT. Additionally, exposure to the tail suspension test induced enhanced despair responses in CB1 knockout mice. However, the tricyclic antidepressant imipramine and the 5-HT selective reuptake inhibitor fluoxetine induced similar decreases in the time of immobility in the tail suspension test in CB1 receptor knockout and wild-type mice. No differences were found between both genotypes with regard to 5-HT2A receptor and 5-HT1A receptors levels, measured by autoradiography in different brain areas. However, a significant decrease in the ability of the 5-HT1A receptor agonist (±)-8-OH-DPAT to stimulate 35SGTPS binding was detected in the hippocampal CA1 area of CB1 receptor knockout mice. This study provides evidence that CB1 receptors are involved in the regulation of serotonergic responses mediated by 5-HT2A and 5-HT1A receptors, and suggests that a reduced coupling of 5-HT1A receptors to Gi/o proteins in the hippocampus might be involved in these effects.

S. Mato and E. Aso were recipients of predoctoral fellowships from the Marqués de Valdecilla Foundation and the Spanish MCYT (BES-2005-8265), respectively. E. Castro is a fellow researcher under an University of Cantabria- Faes Farma contract. The technical assistance of Ms. Lourdes Lanza and Ms. Josefa Castillo is kindly acknowledged. This study was partially supported by Ministerio de Ciencia y Tecnología (CICYT SAF04-00941 to AP; SAF2004/0568 to OV; BFU2004/00920BFI to RM,and GEN2003-20651-C06-06 to RM), the European Communities (NEWMOOD LSHM-CT-2003 5003474 to RM) and Generalitat de Catalunya (2005SGR00131 to RM)