Ibrutinib as a Potential Therapeutic for Cocaine Use Disorder (CUD)

Technical Summary:

Ibrutinib has been shown to prevent various neurobehavioral and neurotoxic effects of cocaine use. It is a covalent inhibitor of Bruton’s tyrosine kinase and influences intracellular cascades involved in the pro-inflammatory response, Ca+ signaling, and protein kinase activity. These processes are also involved in cocaine use and cocaine-induced seizures. This principle was tested utilizing the Drosophila melanogaster model to evaluate its effects on cocaine-induced phenotypes. The Drosophila dopamine transporter contains a binding site that can accommodate cocaine and exposure to cocaine gives rise to motor responses that resemble behaviors observed in rodents. In addition, flies express an ortholog of Brutons’ tyrosine kinase, BTK29A, in the central brain. Startle behavior and the prevalence of seizure activity was measured in male and female flies following acute consumption of solid food, solid food supplemented with cocaine, or solid food supplemented with cocaine and Ibrutinib. It was observed that both male and female flies that consumed Ibrutinib with cocaine spent more time moving than flies that only consumed cocaine. Male flies that consumed Ibrutinib and cocaine showed a significant decrease in the prevalence of seizures. Fewer cocaine-induced seizures were also observed in Ibrutinib-treated females, but this observation did not reach statistical significance since the incidence of cocaine-induced seizures was lower in females than in males.