Modification of 5-HT2 receptor mediated behaviour in the rat by oleamide and the role of cannabinoid receptors

Oleamide (cis-9,10-octadecenoamide) is an endogenous brain lipid which has been suggested to induce sleep in experimental animals. The mechanism of ac tion is unclear but shares many of the characteristics of endogenous cannab inoids such as anandamide and has been shown to enhance in vitro responses to 5-HT and GABA. In the present study we investigated the effects of oleam ide on two motor behaviours, back muscle contractions (BMC) and wet-dog sha kes (WDS) induced in rats by treatment with the 5-HT2 receptor agonist DOI ((+ / -)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride). We t hen examined the potential involvement of CB1 cannabinoid receptors in the responses to oleamide and the mechanism of interaction between CB1 and 5-HT 2 receptors. Oleamide and the cannabinoid receptor agonist HU210 (6aR)-tran s-3-(1,1-dimethylheptyl)6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-di benzo[b,d]pyran-9-methanol) produced a hypolocomotion which was prevented b y the CB, antagonist SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1 1H- pyrazole-3-carboxamide hydrochloride). Despite having no effect alone, olea mide and HU210 potentiated BMC induced by treatment with DOI. SR141716A alo ne did not affect the response to DOI but it blocked the potentiations caus ed by oleamide or HU210. WDS were unaffected by oleamide and slightly reduc ed by HU210. In vitro, oleamide and HU210 enhanced the high affinity bindin g of 5-HT to 5-HT2 receptors on rat cerebral cortex membranes labelled with H-3-ketanserin. Neither agent, however, altered 5-HT-stimulated phosphoino sitide hydrolysis in rat cerebral cortex slices. Oleamide occupied CB1 cann abinoid receptors on rat brain membranes labelled with H-3-CP55940 with an IC50 of 10 mu M. The data presented are consistent with oleamide acting via a cannabinoid recognition site to enhance 5-HT2 receptor function in vivo. The mechanism of the modulation is still unclear but it does not appear to involve a potentiation of 5-HT2 receptor-stimulated phosphoinositide hydro lysis. (C) 1999 Elsevier Science Ltd. All rights reserved.