Novel neurotherapeutic targets for substance use disorders: Neuroplasticity, neuroinflammation, gasotransmitters and non-canonical organ systems.

Substance use disorders (SUDs) are chronic disorders marked by intense and compulsive drug-seeking behavior, coupled with a high risk of relapse. Different theories have emerged over time regarding mechanisms that induce and exacerbate SUDs. This review explores new and evolving evidence on the role of reward systems and processes and aligns those conceptual frameworks with neuroplastic and neuroinflammatory mechanisms and potential therapeutic targets. As the addiction cycle progresses, substance use shifts to long-term chronic use, marked by reduced hedonic effects and intensified compulsion. Thus, a "euphoria reward" model fails to completely capture the progression and complexity of SUDs. Substantive research suggests that the brain circuits that subserve pleasure and craving are distinct, which may explain why individuals with SUDs continue to seek out substances in the absence of pleasure. Additionally, the alleviation of negative affect, anhedonia, post-acute withdrawal symptoms, or other symptoms, may play a key part in preventing relapse. Recent studies emphasize the critical roles of neuroinflammation and oxidative stress in shaping SUDs by altering neural circuitry involved in reward, motivation, negative affect, and decision-making, thereby heightening relapse risk. Molecular adaptations, neuroplasticity and neuroinflammation appear to be important mediators of these changes. This review examines toxicity across the brain, heart and liver, focusing on mechanisms of neuroinflammation, neuroplasticity and gasotransmitter systems. It is proposed that an emphasis on developing pharmacotherapies targeting these mechanisms, while also addressing interactions between the brain and peripheral systems, both as consequences of SUDs and as drivers of the progression of SUDs, may provide new success in SUD therapeutic development.