Lack of CB1 receptor activity impairs serotonergic negative feedback.
Serotonergic and endocannabinoid systems are important substrates for the control of emotional behaviour and growing evidence show an involvement in the pathophysiology of mood disorders. In the present study, the absence of the activity of the CB(1) 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 CB(1) knockout compared with 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 CB(1) knockout mice. The lack of CB(1) receptor also altered some 5-HT receptors related to the 5-HT feedback. Extracellular recordings in the dorsal raphe nucleus (DRN) revealed that the genetic and pharmacological blockade of CB(1) receptor induced a 5-HT(1A) autoreceptor functional desensitization. In situ hybridization studies showed a reduction in the expression of the 5-HT(2C) receptor within several brain areas related to the control of the emotional responses, such as the DRN, the nucleus accumbens and the paraventricular nucleus of the hypothalamus, whereas an over-expression was observed in the CA3 area of the ventral hippocampus. These results reveal that the lack of CB(1) receptor induces a facilitation of the activity of serotonergic neurons in the DRN 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.
Aso
Ester
E
Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.
Renoir
Thibault
T
Mengod
Guadalupe
G
Ledent
Catherine
C
Hamon
Michel
M
Maldonado
Rafael
R
Lanfumey
Laurence
L
Valverde
Olga
O
D000818:Animals; D019540:Area Under Curve; D015283:Citalopram / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D025461:Feedback, Physiological / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005473:Fluoxetine / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis / Q000379:methods; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000166:cytology*; D011485:Protein Binding / Q000187:drug effects; D011903:Raphe Nuclei / Q000166:cytology; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency*; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D014316:Tritium / Q000378:metabolism
D015283:Citalopram; D005473:Fluoxetine; D043884:Receptor, Cannabinoid, CB1; D044405:Receptor, Serotonin, 5-HT2C; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014316:Tritium