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 CB(1) receptor knockout mice. CB(1) knockout animals exhibited a significant reduction in the induction of head twitches and paw tremor by the 5-HT(2A/C) receptor selective agonist (+/-) DOI, as well as a reduced hypothermic response following administration of the 5-HT(1A) receptor agonist (+/-)-8-OH-DPAT. Additionally, exposure to the tail suspension test induced enhanced despair responses in CB(1) 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 CB(1) receptor knockout and wild-type mice. No differences were found between both genotypes with regard to 5-HT(2A) receptor and 5-HT(1A) receptors levels, measured by autoradiography in different brain areas. However, a significant decrease in the ability of both, the 5-HT(1A) receptor agonist (+/-)-8-OH-DPAT and the 5-HT(2A/C) receptor agonist (-)DOI, to stimulate [(35)S]GTPgammaS binding was detected in the hippocampal CA(1) area and fronto-parietal cortex of CB(1) receptor knockout mice, respectively. This study provides evidence that CB(1) receptors are involved in the regulation of serotonergic responses mediated by 5-HT(2A/C) and 5-HT(1A) receptors, and suggests that a reduced coupling of 5-HT(1A) and 5-HT(2A) receptors to G proteins might be involved in these effects.
Mato
Susana
S
Department of Physiology and Pharmacology, University of Cantabria, Cantabria, Spain.
Aso
Ester
E
Castro
Elena
E
Martín
Miquel
M
Valverde
Olga
O
Maldonado
Rafael
R
Pazos
Angel
A
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography / Q000379:methods; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency*; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D000662:Amphetamines; D043884:Receptor, Cannabinoid, CB1; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine