title: Cannabidiol inhibits the reward-facilitating effect of morphine: involvement of 5-HT1A receptors in the dorsal raphe nucleus.
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 cannabidiol 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.
authors.affiliation: Laboratory of Behavioral Neuroscience, Department of Psychology, School of Social Science, University of Crete, Rethymno, Crete, Greece.
authors.forename: Vicky
authors.initials: V
authors.lastname: Katsidoni
authors.forename: Ilektra
authors.initials: I
authors.lastname: Anagnostou
authors.forename: George
authors.initials: G
authors.lastname: Panagis
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D002185:Cannabidiol / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004567:Electrodes, Implanted; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects; D008845:Microinjections; D009020:Morphine / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D011903:Raphe Nuclei / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects; D012201:Reward; D012653:Self Stimulation / Q000187:drug effects; D012684:Sensory Thresholds / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000008:administration & dosage
chemical_list: D000701:Analgesics, Opioid; D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A; D002185:Cannabidiol; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D009020:Morphine; D003042:Cocaine