CB1 knockout mice display impaired functionality of 5-HT1A and 5-HT2A/C receptors

Interaction between brain endocannabinoid (EC) and serotonin (5-HT) systems was investigated by examining 5-HT-dependent behavioral 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/C 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 both, the 5-HT1A receptor agonist (+/-)-8-OH-DPAT and the 5-HT2A/C receptor agonist (-)DOI, to stimulate [S-35]GTP gamma S binding was detected in the hippocampal CA(1) area and fronto-parietal cortex of CB1 receptor knockout mice, respectively. This study provides evidence that CB1 receptors are involved in the regulation of serotonergic responses mediated by 5-HT2A/C and 5-HT1A receptors, and suggests that a reduced coupling of 5-HT1A and 5-HT2A receptors to G proteins might be involved in these effects.