WIN 55,212-2-induced reduction of cocaine hyperlocomotion: Possible inhibition of 5-HT3 receptor function

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Abstract

We examined the effect of WIN 55,212-2 (an agonist of cannabinoid receptors) and its enantiomer WIN 55,212-3, as well as of ondansetron (an antagonist of serotonin (5-HT)3 receptors) on the cocaine-induced locomotor hyperactivity in rats. WIN 55,212-2, but not WIN 55,212-3, in doses of 3 and 6 mg/kg which did not affect the basal locomotor activity, dose-dependently reduced the hyperactivation evoked by cocaine. The inhibitory effect of WIN 55,212-2 was not affected by rimonabant (an antagonist of cannabinoid receptors). Like in the case of WIN 55,212-2, the cocaine-induced hyperlocomotion was reduced in a dose-dependent manner by ondansetron (0.03–0.3 mg/kg). The obtained results indicate that the inhibitory effect of WIN 55,212-2 on cocaine hyperactivation is stereoselective and is not mediated by cannabinoid receptors. Moreover, together with the literature data they may suggest that this effect of WIN 55,212-2 involves inhibition of the 5-HT3 receptor function.

Introduction

Cannabinoid receptor agonists resemble the serotonin (5-HT)3 receptor antagonists in terms of some of their pharmacological activities like antiemetic and nonopioid analgetic effects (Noyes et al., 1975, Dewey, 1986, Howlett et al., 1990, Karim et al., 1996, Martin et al., 1999, Simpson et al., 2000, Voog et al., 2000, Darmani, 2001). Interestingly, electrophysiological studies have demonstrated that cannabinoid CB1 receptor agonists stereoselectively inhibit 5-HT-induced, 5-HT3 receptor-mediated currents in rat nodose ganglion neurons (Fan, 1995), in excised outside-out patches of HEK 293 cells expressing recombinant human (h) 5-HT3A receptors (Barann et al., 2002) and in Xenopus oocytes expressing cloned mouse 5-HT3 receptors (Oz et al., 2002). Moreover it has also been shown that cannabinoids inhibit the phenylbiguanide-induced 5-HT3 receptor-mediated, but not the vanilloid receptor-mediated von Bezold–Jarisch reflex in rats (Godlewski et al., 2003). The inhibitory effects of the cannabinoid receptor agonists in HEK 293 cells, in Xenopus oocytes and in the von Bezold–Jarisch reflex model were not affected by the cannabinoid receptor antagonist, rimonabant (SR 141716A) (Barann et al., 2002, Oz et al., 2002, Godlewski et al., 2003). In agreement with this, radioligand binding experiments revealed that HEK 293 cells do not express CB1 (or CB2) receptors (Barann et al., 2002). On the other hand, cannabinoids in contrast to 5-HT, did not modify specific [3H]GR65630 binding to recombinant h5-HT3A receptors in HEK 293 cells, indicating that these drugs do not act at the 5-HT recognition site of the 5-HT3A receptor (Barann et al., 2002). The most plausible explanation of the cannabinoid receptor-independent cannabinoid-induced inhibition of 5-HT3 receptor function is that these drugs act at an allosteric modulatory site of this receptor (Barann et al., 2002).

In the present paper we examined whether cannabinoids resemble the effects of 5-HT3 receptor antagonists at the behavioral level. To this end we used the model of locomotor hyperactivity induced by cocaine, an effect which is blocked by 5-HT3 receptor antagonists (Reith, 1990, Svingos and Hitzemann, 1992, Kankaanpaa et al., 2002). In this study we compared the effect of WIN 55,212-2, an agonist of cannabinoid receptors (D'Ambra et al., 1992) and ondansetron, an antagonist of 5-HT3 receptors (Butler et al., 1988, Hoyer et al., 2002) on the cocaine-induced hyperlocomotion in rats. In some experiments WIN 55,212-3, an enantiomer of WIN 55,212-2 (Felder et al., 1992), and rimonabant, an antagonist of the cannabinoid receptors (Rinaldi-Carmona et al., 1994), were also used.

Section snippets

Animals

The experiment was performed on male Wistar rats (240–260 g). The rats were housed in a colony room maintained at 21 ± 1 °C and 40–50% humidity on a 12-h light–dark cycle (the lights on at 06:00 h). Rodent chow and water were available ad libitum. All the experiments were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the approval of the Bioethics Commission (compliant with the Polish Law of 21 August 1997).

Drugs

The following drugs

Basal locomotor activity

Basal locomotor activity was not affected in animals treated with WIN 55,212-2 (3–6 mg/kg; F(2, 19) = 0.334), WIN 55,212-3 (3–6 mg/kg; F(2, 21) = 0.099), rimonabant (5 mg/kg; F(1, 14) = 0.129) or ondansetron (0.03–0.3 mg/kg; F(3, 24) = 0.766; Table 1).

Cocaine-induced hyperactivation

Cocaine (10 mg/kg) significantly increased the rats' basal locomotor activity compared to saline (Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5).

A main effect of treatment was observed for rats which received injection of WIN 55,212-2 followed by cocaine (F(3, 27) = 

Discussion

The present study demonstrates that WIN 55,212-2, an agonist of the cannabinoid CB1 and CB2 receptors without affinity for numerous other neuroreceptors (D'Ambra et al., 1992, Iwamura et al., 2001), administered in doses (3 and 6 mg/kg) which did not affect the basal locomotor activity in rats, dose-dependently reduced hyperlocomotion evoked by cocaine (10 mg/kg) in the animals. Moreover, the agonist administered in a dose of 6 mg/kg inhibited hyperlocomotion induced by cocaine given in doses

Acknowledgements

We thank Sanofi for the gift of rimonabant. This study was supported by the Institute of Pharmacology and the Deutsche Forschungsgemeinschaft.

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