Ibudilast attenuates expression of behavioral sensitization to cocaine in male and female rats

Abstract

There are no FDA-approved pharmacotherapies for cocaine use disorder, indicating a need to identify novel reagents with therapeutic potential. Ibudilast is an anti-inflammatory glial attenuator and non-selective phosphodiesterase inhibitor currently undergoing clinical evaluations for methamphetamine, opiate, and alcohol abuse disorders. We previously showed that twice daily (b.i.d.) ibudilast reduces the development of methamphetamine sensitization in male mice. However, nothing is known about the ability of ibudilast to modulate the expression of sensitization that occurs after drug re-exposure during abstinence, effects on cocaine-mediated behaviors, or potentially sexually dimorphic effects. Male and female rats were administered cocaine for 7 days and expression of sensitization was assessed by cocaine challenge after 21 days abstinence. On test days, 15 mg/kg i. p. cocaine was evaluated, whereas 30 mg/kg was administered on intervening days. Lower test doses avoid competition of non-motor behaviors with locomotion. In all measures where sensitization was expressed, ibudilast (7.5 and 10 mg/kg, i. p., b. i.d. for 3 days and once on test day) reversed this behavior to levels seen after acute exposure, but not below. There were some intriguing sexually dimorphic effects that were not a function of estrous cycle. Specifically, distance travelled in the center of the test arena and rearing only sensitized in male rats, and ibudilast reversed these behaviors to levels seen after acute cocaine exposure. In females, center distance travelled was reduced below acute cocaine levels by 7.5 mg/kg ibudilast. Increased distance travelled in the center versus periphery is thought to model anxiolytic-like behavior due to increased predation risk. Taken together, these data suggest that the clinical evaluation of ibudilast could be extended to cocaine use disorder.