Cannabidiol inhibits the reward-facilitating effect of morphine: involvement of 5-HT 1A receptors in the dorsal raphe nucleus Vicky Katsidoni, Ilektra Anagnostou & George Panagis Laboratory of Behavioral Neuroscience, Department of Psychology, School of Social Science, University of Crete, Rethymno, Crete, Greece ABSTRACT Cannabidiol is a non-psychotomimetic constituent of Cannabis sativa, which induces central effects in rodents. It has been shown that cannabidiol attenuates cue-induced reinstatement of heroin seeking. However, to the best of our knowledge, its effects on brain stimulation reward and the reward-facilitating effects of drugs of abuse have not yet been examined. Therefore, we investigated the effects of cannabidiol on brain reward function and on the reward- facilitating effect of morphine and cocaine using the intracranial self-stimulation (ICSS) paradigm. Rats were prepared with a stimulating electrode into the medial forebrain bundle (MFB), and a guide cannula into the dorsal raphe (microinjection experiments), and were trained to respond for electrical brain stimulation. A low dose of cannabidiol did not affect the reinforcing efficacy of brain stimulation, whereas higher doses significantly elevated the threshold frequency required for MFB ICSS. Both cocaine and morphine lowered ICSS thresholds. Cannabidiol inhibited the reward-facilitating effect of morphine, but not cocaine. This effect was reversed by pre-treatment with an intra-dorsal raphe injection of the selective 5-HT1A receptor antagonist WAY-100635. The present findings indicate that can- nabidiol does not exhibit reinforcing properties in the ICSS paradigm at any of the doses tested, while it decreases the reward-facilitating effects of morphine. These effects were mediated by activation of 5-HT1A receptors in the dorsal raphe. Our results suggest that cannabidiol interferes with brain reward mechanisms responsible for the expression of the acute reinforcing properties of opioids, thus indicating that cannabidiol may be clinically useful in attenuating the rewarding effects of opioids. Keywords Cannabinoid, cocaine, intracranial self-stimulation, morphine, opioids, serotonin. Correspondence to: George Panagis, University of Crete, School of Social Sciences, Department of Psychology, Laboratory of Behavioral Neuroscience, 74100 Rethymno, Crete, Greece. E-mail: panagis@psy.soc.uoc.gr INTRODUCTION The plant Cannabis sativa contains more than 400 differ- ent compounds, i.e. cannabinoids, 80 of which have not been identified in any other plant (Pertwee 2008; Izzo et al. 2009). Extracts of the plant elicit a complex subjec- tive experience in humans that includes psychotomimetic symptoms (Johns 2001). Most studies regarding canna- bis actions have focused on D 9 -tetrahydrocannabinol (D 9 -THC), which is the main psychoactive compound of the plant and binds to specific G-protein-coupled recep- tors. Administration of D 9 -THC to experimental animals exhibits typical pharmacological effects, including hypolocomotion, catalepsy, antinociception and hypo- thermia (Compton et al. 1992). These effects are mediated by cannabinoid-1 (CB1) receptors. Cannabidiol (CBD) is another natural component of Cannabis sativa that unlike D 9 -THC is devoid of psy- chotomimetic activity (Mechoulam, Parker & Gallily 2002; Mechoulam et al. 2007). However, several studies revealed that CBD induces central effects, such as antipsychotic, antidepressant, anxiolytic, hypnotic, anticraving and anticonvulsive (effects) (Carlini et al. 1973; Monti 1977; Guimaraes et al. 1990; Moreira, Aguiar & Guimaraes 2006; Ren et al. 2009; Casarotto et al. 2010; Long et al. 2010; Zanelati et al. 2010; Schubart et al. 2011). Moreover, CBD can antagonize or inhibit some behavioral effects of D 9 -THC both in animals (Zuardi & Karniol 1983; Formukong, Evans & Evans 1988; Vann et al. 2008; Malone, Jongejan & Taylor 2009) and in humans (Karniol et al. 1974; Zuardi et al. 1982; Morgan et al. 2010a,b). The mechanism that PRECLINICAL STUDY Addiction Biology doi:10.1111/j.1369-1600.2012.00483.x © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction Addiction Biology, 18, 286–296