CROSSTALK BETWEEN CANNABINOID 1 AND GLUCOCORTICOID RECEPTORS. IMPLICATIONS FOR LEARNING AND MEMORY.

GRANJA GALEANO, GINA; DOMINGUEZ-RUBIO, ANA PAULA; ZAPPIA, CARLOS DANIEL; ZORRILLA ZUBILETE, MARIA; FITZSIMONS CARLOS; FRANCHI, ANA; MONCZOR FEDERICO

Bariloche

Simposio; SISTAM - The Third South American Symposium in Signal Transduction and Molecular Medicine; 2015

ASBMB/IUBMB

p { margin-bottom: 0.25cm; direction: ltr; color: rgb(0, 0, 0); line-height: 120%; }p.western { font-family: "Liberation Serif","Times New Roman",serif; font-size: 12pt; }p.cjk { font-family: "Droid Sans Fallback"; font-size: 12pt; }p.ctl { font-family: "FreeSans"; font-size: 12pt; }a:link { } Cannabinoid receptors (CB) are GPCRs generally coupled to Gi protein and the glucocorticoid receptor (GR) is an intracellular receptor that mediates its main functions acting as a transcription factor. CB receptor type 1 and GR are coexpressed in several areas of the central nervous system, including hippocampus, which is known to be involved in learning and memory processes. Consistently, it has been suggested that the cannabinoid system participates in glucocorticoid-mediated processes regulating its activity. We have previously described that CB1 signaling regulates GR activity in neuroblastoma N2A cells in-vitro. To confirm this modulation of GR activity by CB1, we studied the expression of Glucocorticoid Induced Leucine Zipper (GILZ), a classic GR-inducible gene, in-vivo in the hippocampus of Wild Type and KO CB1-/- CD1 mice. Dexamethasone induced a two-fold increase in GILZ expression, while co-treatment with the CB1 antagonist AM251 induced an extra 60% increment over Dex effect (p<0.05) in WT animals. In contrast, Dex induced an three-fold increment in GILZ expression, while cotreatment with AM251 had no detectable effect in KO mice, indicating that CB1 expression and signaling inhibits GR transcriptional activity in the hippocampus. Since GR modulates post-traumatic learning and memory processes we decided to study animal behavior. When exposed to the test arena for the first time, KO mice did not present any detectable locomotive alterations in the behavioral tasks tested, however did not diminished their activity after 24h, indicating a deficit in the habituation memory. On the other hand, when the associative memory was evaluated with a passive-avoidance test, CB1-/- KO mice showed a higher latency to enter the dark compartment (p<0.05). Our results suggest that CB1 expression and signaling modulates glucocorticoid transcriptional activity in the hippocampus, influencing glucocorticoid-regulated post-traumatic learning and memory processes.