In vivo characterization of the anti-addictive properties of COR659 in rodents

Background. Several studies demonstrated that the GABAB receptor plays a key role in mediating the reinforcing properties of alcohol and drugs of abuse at the brain reward circuitry level. These data suggested that activation of the inhibitory GABAergic neurotransmitter system by an orthosteric agonist or a positive allosteric modulator (PAM) of the GABAB receptor could represent a potential pharmacological strategy to treat chronic diseases such as alcohol and substance use disorders. Recently, we demonstrated that COR659, a novel PAM of the GABAB receptor, possesses anti-alcohol properties, as it effectively reduced the reinforcing and motivational properties of alcohol in selectively bred Sardinian alcohol-preferring (sP) rats. Moreover, we found that COR659 reduced chocolate self-administration in Wistar rats, likely acting as an antagonist/inverse agonist at the cannabinoid CB1 receptor. COR659 is a unique molecule that exerts its pharmacological effects via a composite mechanism of action, made by positive allosteric modulation of the GABAB receptor and antagonism/inverse agonism of the cannabinoid CB1 receptor”. Aim of the study. The aim of the present study was to provide a further characterization of the anti-addictive properties of COR659 in rodents. Specifically, we investigated whether COR659 (i) retained its ability to reduce alcohol self-administration after chronic treatment, (ii) reduced cue-induced reinstatement of alcohol seeking, (iii) interfered with binge-like drinking, and (iv) prevented locomotor stimulation induced by different drugs of abuse, in rodents. Results. (i) Repeated (10 consecutive days) treatment with COR659 effectively suppressed lever-responding for alcohol in sP rats with a limited development of tolerance to its effects on alcohol self-administration. (ii) Acute treatment with COR659 suppressed the reinstatement of alcohol-seeking behavior in sP rats induced by the presentation of a stimulus complex previously associated to alcohol availability. (iii) In the binge-like drinking experiments, COR659 reduced alcohol intake in sP rats and C57BL/6J mice. Lastly, (iv) treatment with COR659 efficiently prevented locomotor stimulation induced by administration of cocaine, amphetamine, nicotine, and morphine in CD1 mice. Notably, all these effects of COR659 occurred at doses largely lower than those inducing hypolocomotion and sedation. Conclusions. Altogether, the present data extend the anti-addictive properties of COR659 to several rodent behaviors related to alcohol and drugs of abuse and support the hypothesis that positive allosteric modulation of the GABAB receptor may be a potential pharmacotherapy in treating alcohol and substance use disorders.