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Effect of the CB 1 receptor antagonists rimonabant and AM251 on the firing rate of dorsal raphe nucleus neurons in rat brain slices
Author(s) -
Mendiguren Aitziber,
Pineda Joseba
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00434.x
Subject(s) - am251 , rimonabant , cannabinoid receptor , chemistry , cannabinoid , dorsal raphe nucleus , agonist , pharmacology , endocannabinoid system , medicine , endocrinology , receptor , serotonin , biology , serotonergic , biochemistry
Background and purpose: Previous studies have suggested a regulation of 5‐hydroxytryptamine (5‐HT) neurons by the endocannabinoid system. The aim of our work was to examine the effect of two CB 1 receptor antagonists, SR141716A (rimonabant, Sanofi‐Synthélabo Recherche, Montpellier, France) and N‐(piperidin‐1‐yl)‐5‐(4‐iodophenyl)‐1‐(2,4‐dichlorophenyl)‐4‐methyl‐1H‐pyrazole‐3‐carboxamide (AM251, Tocris Cookson, Bristol, UK), on the firing rate of dorsal raphe nucleus (DRN) neurons. Experimental approach: Single‐unit extracellular recordings were performed to study the effect of CB 1 receptor antagonists in slices of the DRN from rat brain. Key results: Rimonabant (1 µM) and AM251 (1 µM) decreased the firing rate of about 50% of all the recorded DRN 5‐HT cells. The GABA A receptor antagonist picrotoxin (20 µM) (Sigma) prevented and also reversed the inhibitory effect of rimonabant (1 µM) and AM251 (1 µM), suggesting that CB 1 receptors regulate 5‐HT neurons through the GABAergic system. However, the CB 1 /CB 2 receptor agonist R‐(+)‐[2,3‐dihydro‐5‐methyl‐3‐[(morpholinyl)‐methyl]pyrrolol[1,2,3‐de]‐1,4‐benzoxazinyl]‐(1‐naphthalenyl) methanone mesylate salt (10 µM) (WIN55212‐2, Sigma, St. Louis, MO, USA) failed to change the firing activity of non‐5‐HT (presumably GABAergic) neurons in the DRN. The endocannabinoid N‐(2‐hydroxyethyl)‐5Z,8Z,11Z,14Z‐eicosatetraenamide (anandamide, Tocris Cookson) (10 µM) also inhibited the firing activity of a number of 5‐HT neurons, but this inhibition was not blocked by rimonabant (1 µM) or AM251 (1 µM), and the stable analogue R‐(+) N‐(2‐hydroxy‐1methylethyl)‐5Z,8Z,11Z,14Z‐eicosatetraenamide (methanandamide, Tocris Cookson) (10 µM) did not mimic this effect. The selective CB 1 receptor agonist arachidonoyl‐2‐chloroethylamide (ACEA) (1 µM) only slightly increased the firing rate of DRN 5‐HT cells. Conclusions and implications: These results suggest a tonic/constitutive regulation of DRN 5‐HT neurons by the endocannabinoid system, which may occur through a CB 1 receptor‐mediated inhibition of the GABAergic system. The inhibitory effect of anandamide may be mediated through a CB 1 receptor‐independent mechanism.