Serotonergic and endocannabinoid systems are important substrates for the control of emotional behavior and growing evidence show an involvement in the pathophysiology of mood disorders. In the present study, the absence of the activity of the CB1 cannabinoid receptor impaired serotonergic negative feedback in mice. Thus, in vivo microdialysis experiments revealed increased basal 5-HT extracellular levels and attenuated fluoxetine-induced increase of 5-HT extracellular levels in the prefrontal cortex of CB1 knockout compared to wild-type mice. These observations could be related to the significant reduction in the 5-HT transporter binding site density detected in frontal cortex and hippocampus of CB1 knockout mice. The lack of CB1 receptor also altered some 5-HT receptors related to the 5-HT feedback. Extracellular recordings in the dorsal raphe nucleus revealed that the genetic and pharmacological blockade of CB1 receptor induced a 5-HT1A autoreceptor functional desensitization. In situ hybridization studies showed a reduction in the expression of the 5-HT2C receptor within several brain areas related to the control of the emotional responses, such as the dorsal raphe nucleus, the nucleus accumbens and the paraventricular nucleus of the hypothalamus, whereas an overexpression was observed in the CA3 area of the ventral hippocampus. These results reveal that the lack of CB1 receptor induces a facilitation of the activity of serotonergic neurons in the dorsal raphe nucleus by altering different components of the 5-HT feedback as well as an increase in 5-HT extracellular levels in the prefrontal cortex in mice.

We thank Dulce Real, Marta Linares and Rocío Martín for their excellent technical support, Arnau Busquets for his help on the in situ hybridization experiments and Dr Patricia Robledo for kind advices about in vivo microdialysis procedure. This study has been supported by grants from the UE /nSixth Framework Programme (NEWMOOD, LSHM-CT-2004-503474 to RM and LL), Spanish Ministry of Education & Science (SAF 2007/60249 to OV, BES-2005-8265 fellowship to EA) and Spanish Ministry of Health (ISCIII-RD/06/0001/1001/and PNSD Conv-2006 to OV)