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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.
Br J Pharmacol. 2009 Nov; 158(6):1579-87.BJ

Abstract

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 microM) and AM251 (1 microM) decreased the firing rate of about 50% of all the recorded DRN 5-HT cells. The GABA(A)receptor antagonist picrotoxin (20 microM) (Sigma) prevented and also reversed the inhibitory effect of rimonabant (1 microM) and AM251 (1 microM), 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 microM) (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 microM) also inhibited the firing activity of a number of 5-HT neurons, but this inhibition was not blocked by rimonabant (1 microM) or AM251 (1 microM), and the stable analogue R-(+) N-(2-hydroxy-1methylethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (methanandamide, Tocris Cookson) (10 microM) did not mimic this effect. The selective CB(1) receptor agonist arachidonoyl-2-chloroethylamide (ACEA) (1 microM) 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.

Authors+Show Affiliations

Department of Pharmacology, University of the Basque Country, Leioa, Bizkaia, Spain.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19845674

Citation

Mendiguren, Aitziber, and Joseba Pineda. "Effect of the CB(1) Receptor Antagonists Rimonabant and AM251 On the Firing Rate of Dorsal Raphe Nucleus Neurons in Rat Brain Slices." British Journal of Pharmacology, vol. 158, no. 6, 2009, pp. 1579-87.
Mendiguren A, Pineda J. Effect of the CB(1) receptor antagonists rimonabant and AM251 on the firing rate of dorsal raphe nucleus neurons in rat brain slices. Br J Pharmacol. 2009;158(6):1579-87.
Mendiguren, A., & Pineda, J. (2009). Effect of the CB(1) receptor antagonists rimonabant and AM251 on the firing rate of dorsal raphe nucleus neurons in rat brain slices. British Journal of Pharmacology, 158(6), 1579-87. https://doi.org/10.1111/j.1476-5381.2009.00434.x
Mendiguren A, Pineda J. Effect of the CB(1) Receptor Antagonists Rimonabant and AM251 On the Firing Rate of Dorsal Raphe Nucleus Neurons in Rat Brain Slices. Br J Pharmacol. 2009;158(6):1579-87. PubMed PMID: 19845674.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of the CB(1) receptor antagonists rimonabant and AM251 on the firing rate of dorsal raphe nucleus neurons in rat brain slices. AU - Mendiguren,Aitziber, AU - Pineda,Joseba, Y1 - 2009/10/20/ PY - 2009/10/23/entrez PY - 2009/10/23/pubmed PY - 2010/2/26/medline SP - 1579 EP - 87 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 158 IS - 6 N2 - 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 microM) and AM251 (1 microM) decreased the firing rate of about 50% of all the recorded DRN 5-HT cells. The GABA(A)receptor antagonist picrotoxin (20 microM) (Sigma) prevented and also reversed the inhibitory effect of rimonabant (1 microM) and AM251 (1 microM), 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 microM) (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 microM) also inhibited the firing activity of a number of 5-HT neurons, but this inhibition was not blocked by rimonabant (1 microM) or AM251 (1 microM), and the stable analogue R-(+) N-(2-hydroxy-1methylethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (methanandamide, Tocris Cookson) (10 microM) did not mimic this effect. The selective CB(1) receptor agonist arachidonoyl-2-chloroethylamide (ACEA) (1 microM) 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. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/19845674/Effect_of_the_CB_1__receptor_antagonists_rimonabant_and_AM251_on_the_firing_rate_of_dorsal_raphe_nucleus_neurons_in_rat_brain_slices_ L2 - https://doi.org/10.1111/j.1476-5381.2009.00434.x DB - PRIME DP - Unbound Medicine ER -