Effets motivationnels des cannabinoïdes dans un modèle animal de la schizophrénie

Over the past few decades, the cannabis consumption and its therapeutic use have been the subject of many debates. Cannabis is the most widely used illicit drug and among patients with a diagnosis of schizophrenia, its consumption is ten times higher than in the general population. The self-medication hypothesis that has been initially proposed to account for the co-morbidity schizophrenia – cannabis is now questioned on the basis of several reports showing that long term cannabis consumption worsen schizophrenia symptoms in patients. Knowing that cannabis can provoke both rewarding and aversive effects in human and in animal, the following question can be raised: can co-morbidity schizophrenia – cannabis be explained by a salient positive or a blunted negative motivational valence of cannabis?   Even though many pre-clinical studies have been carried out in normal animals on the motivational effects of Δ9-Tetrahydrocannabinol (THC) or other synthetic cannabinoids, none has measured these effects in an animal model of schizophrenia. On the basis of this, we undertook a series of studies on the motivational valence of THC and the cannabinoid agonist WIN55,212-2 (WIN) in an animal model of schizophrenia : the neonatal ventral hippocampus lesion (NVHL).   In the first report, we present the results of four studies. The first was aimed at showing that the experimental procedures that we used reproduced some abnormal features of the animal model. Then we evaluated i) the effect of WIN (1 mg/kg) on spontaneous locomotor activity and ii) the motivational valence of THC (0.5 mg/kg) and WIN (1 mg/kg) in the young (post-natal day 28-40, PD28-40) and adult (PD56) rats with the conditioned place-preference paradigm (CPP).  As expected, amphetamine produced a higher locomotor activity in NVHL rats, an effect observed at PD56 and not at PD35 (NVHL usual test). THC tended to induce an aversion in control rats at PD56 while WIN produced a significant aversion at PD56 in NVHL rats only. We also assessed, in a second report, the valence of THC (0.5 mg/kg) and WIN (1 and 3 mg/kg), and amphetamine (0.75 mg/kg) using the brain stimulation reward paradigm. Results show that i) the enhancement effect of amphetamine on reward was shorter in adult NVHL rats; ii) THC induced a weak reward attenuation in control rats while WIN produced a marked dose-dependent attenuation in NVHL rats; this effect of WIN was blocked by AM251 (3 mg/kg), an antagonist at CB1 receptors.  For the first time, these results suggest that the endogenous cannabinoid system is altered in this animal model of schizophrenia. They indicate that an acute exposure leads to a predominance of negative valence. Even if this seems contradictory with clinical studies, these results highlight the interconnection between the drug and the socio-environment aspects. In addition, they encourage future studies to evaluate this valence on a chronic exposure paradigm with this animal model of schizophrenia.

Keyphrases: Delta-9-tetrahydrocannabinol, WIN55,212-2, AM251, Locomotion, Neonatal ventral hippocampus lesion, Delta-9-tetrahydrocannabinol, WIN55,212-2, AM251, Reward, Locomotion, Conditioned place preference, Intracerebral self-stimulation, Schizophrenia