Neurochemical and Inflammatory Dysregulation During Synthetic Cathinone Self-Administration

Research Triangle Institute, Durham NC

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Abstract

Project Summary Products referred to as ?bath salts? continue to be used as stimulants, and are available for purchase over the internet. The vast majority of these products contain synthetic cathinones, such as alpha- pyrrolidinopentiophenone (?-PVP) and mephedrone. Anecdotal reports of human use suggest that synthetic cathinones often provoke abnormal behavior including violence, psychotic behavior, paranoia, delusions, and self-injurious behavior. Preclinical and clinical literature shows that synthetic cathinones produce typical stimulant-like effects. Understanding the abuse liability of different synthetic cathinones is imperative for developing treatment for users because treatment solutions will likely differ between mechanisms of action, and treatment design will be guided by the differences. The goal of this proposal is to behaviorally differentiate different stages of synthetic cathinone addiction using the escalation of self-administration rodent model of addiction, then measure the underlying neurotransmitter metabolome (>20 compounds) and cytokine profile (42 compounds) in multiple brain regions to assess how neuronal and non-neuronal signaling changes between stimulant mechanism, and duration of self-administration. In Aim 1, male and female rats will be trained to self-administer synthetic cathinones ?-PVP or mephedrone, or saline using autoshaping. Rats in each drug group will then be divided into three groups that represent different points in the addiction cycle. One group will stop self-administering after autoshaping, the second will self-administer during 1 hr sessions for 21 days, and the third group will self-administer during 6 hr sessions for 21 days. Aim 2 will examine effects of noncontingent synthetic cathinone administration with rats yoked to those from Aim 1. In Aim 3, samples of seven addiction-related brain regions and plasma will be obtained from rats in Aims 1-2. Selected brain tissue will be profiled using a liquid chromatography electrochemical array (LCECA) platform used to assess neurotransmitters and their metabolites. High-throughput cytokine-based arrays (Ray Biotech) will be used to measure cytokines to examine neuroinflammation. Our hypothesis is that stimulant-induced neuroplasticity differs between stimulants by mechanism (uptake inhibitor vs releaser), time (disease progression), and sex, and that these differences are due to underlying neuronal and non-neuronal neurochemical changes and regulation that can be measured using targeted metabolomics techniques. More specifically, we expect that rats showing escalating drug intake will display the most neurochemical changes, particularly in areas of the brain critical to addiction such as striatum and prefrontal cortex, and we predict sex differences in stimulant- induced neuroplasticity. This would lead to an improved understanding of the changes that occur during the development of addiction, and provide biomarkers indicating the state of disease progression. Knowledge about these addiction-related changes will aid in the development of treatment for synthetic cathinone abusers.