Targeting Immune Inflammation in Cocaine Use Disorder: A Human Laboratory Study with Pentoxifylline - ABSTRACT Cocaine use disorder is a persistent public health concern. Despite strides in our understanding of the neurobiological underpinnings of cocaine addiction in preclinical models, a limited amount of research has translated those findings to clinical populations. Such translation is crucial to identify neurobiological disruptions that contribute to the problems posed by cocaine use disorder and to guide treatment based on those findings. The field has long recognized the critical role of the glutamate system in cocaine use. Specifically, a wealth of data indicate that cocaine produces profound changes in the brain glutamate system, resulting in impaired glutamate homeostasis. Targeting this mechanism has some promise for treating cocaine use disorder but results have been inconsistent, suggesting other strategies are needed to address brain glutamate changes due to cocaine use. Emerging preclinical research indicates that neuroimmune signaling mediates brain glutamate changes observed following drug exposure, but very little clinical research has evaluated whether targeting neuroimmune signaling affects response to cocaine or if this strategy is a promising treatment approach. Preclinical research has shown that phosphodiesterase inhibitors ameliorate neuroimmune perturbations following stimulant use, at least in part through glutamatergic mechanisms. Further, they selectively reduce the reinforcing effects of cocaine, the development of cocaine sensitization and reinstatement to cocaine seeking. Most of the phosphodiesterase inhibitors tested preclinically are not available for use in humans, however. Pentoxifylline, a xanthine derivative and phosphodiesterase inhibitor that is used clinically to treat muscle pain in individuals with peripheral artery disease, is structurally similar to and produces anti-inflammatory effects like the phosphodiesterase inhibitors tested preclinically. Thus, the overarching goal of this study is to translate preclinical findings that used phosphodiesterase inhibitors to ameliorate neuroimmune perturbations and reduce cocaine intake to the human laboratory. We seek to demonstrate pentoxifylline reduces cocaine self-administration and abuse-related effects in individuals with cocaine use disorder. We will also evaluate safety and tolerability of pentoxifylline and cocaine combinations and determine whether pentoxifylline affects immune biomarkers. This research will directly translate findings from preclinical research and provide strong clinical evidence that pentoxifylline reduces the reinforcing and other abuse-related effects of cocaine, while also ameliorating immune perturbations associated with cocaine use. In addition, this work has key basic science implications about neuroimmune mechanisms underlying the pharmacodynamic effects of cocaine in humans.
