Decrease of cocaine, but not heroin, self-administration and relapse by the tyrosine kinase inhibitor masitinib in male Sprague Dawley rats

Abstract

RationaleAccumulating evidence shows that cocaine, and also heroin, influence several tyrosine kinases, expressed in neurons and in non-neuronal populations such as microglia, astrocytes and mast-cells. Drug-induced activation of mast cells both triggers inflammatory processes in the brain mediated by the glial cells they activate, and facilitates histamine release which may directly influence the dopamine system. Thus, by triggering the activation and degranulation of mast cells dependent on the tyrosine kinase c-kit and Fyn, the latter being also involved in NMDA-dependent synaptic plasticity, cocaine and heroin may indirectly influence the neural mechanisms that mediate their reinforcing properties. Masitinib, a novel tyrosine kinase inhibitor with high selectivity for c-Kit, Fyn and Lyn, may alter the aberrant consequences of the activation of these tyrosine kinases by cocaine and heroin.ObjectiveWe investigated in rats the effect of a chronic oral treatment with masitinib (20 mg/kg) on the reinforcing and motivational properties of self-administered cocaine (250 μg/infusion) and heroin (40 μg/infusion).MethodsThree different cohorts of rats were trained instrumentally to respond for cocaine, heroin or food under continuous reinforcement. In each group, we assessed the influence of chronic daily treatment with masitinib on the maintenance of instrumental responding and intake and the motivation for the reinforcer. Thus, masitinib and vehicle-treated rats were challenged to adapt to high behavioural demand, to respond under a progressive ratio schedule of reinforcement and to reinstate instrumental responding after extinction and/or abstinence.ResultsMasitinib selectively decreased cocaine intake, the motivation for cocaine and the subsequent propensity to respond for cocaine under extinction, while having no effect on instrumental responding for heroin or food.ConclusionThe present findings suggest masitinib, a drug with proven efficacy in CNS disorders, could represent a novel treatment for cocaine addiction provided its influence on the reinforcing and incentive properties of the drug is confirmed.

cAMP-Fyn signaling in the dorsomedial striatum direct pathway drives excessive alcohol use

“…This possibility is in line with recent findings demonstrating that systemic administration of the Src/Fyn inhibitor, AZD0530, attenuates goal-directed alcohol self-administration in mice (Morisot et al, 2019). Xie et al previously showed that administration of the Src/Fyn inhibitor PP2 into the dorsal hippocampus attenuates context-dependent cocaine seeking (Xie et al, 2013), and more recently, Belin-Rauscent reported that oral administration of the Src PTKs inhibitor, Masitinib, attenuates selfadministration of cocaine (Belin-Rauscent et al, 2018). Thus, it would be of interest to determine whether Fyn in DMS dMSNs contributes to goal-directed seeking of other drugs of abuse.…”

The anterior insular cortex in the rat exerts an inhibitory influence over the loss of control of heroin intake and subsequent propensity to relapse

“…In marked contrast, rats with post-training AIC lesions, made once they have reached a plateau of escalated intake (Ahmed et al, 2000;McNamara et al, 2010) that usually remains stable for weeks (McNamara et al, 2010), continued to escalate their intake whereas sham-operated control rats maintained the pre-lesion plateau. The enhanced escalation following AIC lesions was accompanied by an increased propensity to relapse, as measured as a higher rate of responding for the drug under extinction following a brief period of abstinence (Belin-Rauscent et al, 2018). The effects of post-escalation AIC lesions on the further escalation of heroin intake could not be attributable to an effect on body weight, which influences the pharmacokinetic properties of the drug (Rook et al, 2006a;Rook et al, 2006b), or an increased tolerance to the reinforcing properties of heroin since AIC lesioned rats did not differ from sham controls in their increase in body weight following AIC lesions, or in their response to heroin-primed reinstatement of responding after abstinence.…”

“…Rats were kept under isoflurane anaesthesia (O 2 : 2 L/min; 5% for induction and 2-3% for maintenance and analgesia (Metacam, 1 mg/kg, sc., Boehringer Ingelheim) and implanted with a home-made indwelling catheter into their right jugular vein as previously described (Belin-Rauscent et al, 2018). Following surgery, rats received daily oral treatment with the analgesic for three days and an antibiotic (Baytril, 10mg/kg, Bayer), which they first received on the day prior to surgery, for a week.…”

“…The relapse test was designed as previously described (Belin-Rauscent et al, 2018). After 3 days of abstinence, rats were given the opportunity instrumentally to respond for heroin for 90 minutes in the context they had previously been trained to self-administer the drug, but under extinction conditions (i.e.…”

“…After 3 days of abstinence, rats were given the opportunity instrumentally to respond for heroin for 90 minutes in the context they had previously been trained to self-administer the drug, but under extinction conditions (i.e. no heroin was infused) (Belin-Rauscent et al, 2018) (Figure 3D). This was followed, as previously described (Belin et al, 2009;Rotge et al, 2017;Cocker et al, 2019), by a 30-minute non-contingent CS-induced reinstatement test, at the onset of which the heroin paired CS was presented noncontingently for 20 seconds.…”