Neurochemical mechanisms governing footshock-induced suppression of methamphetamine intake

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PROJECT SUMMARY One feature of methamphetamine use disorders (METH-UD) is that some people will continue taking METH despite negative psychosocial consequences while others will stop under the same conditions. Understanding the mechanism governing the differences between these groups will enable the development of new pharmacotherapies for METH-UD and will be important in addressing the ongoing health crisis. To model this phenomenon, scientists developed a preclinical punishment model which uses punishment conditions (e.g., increasing footshock intensity, FSI) paired with METH self-administration to differentiate shock-sensitive (SS) and shock-resistant (SR) rats. However, though widely accepted in the field, the current version of the punishment model is limited by its reliance on subjective and arbitrary endpoints to distinguish SS from SR groups and thus is limited in its robustness, reproducibility, and reliability. To address the weaknesses inherent in the current punishment protocol, we developed a novel quantitative and objective approach which we named the Quantitative Punishment Model with Clustering (QPMC). The QPMC obtains several variables from the METH taking behavior before and after the punishment regimen, followed by clustering to objectively determine distinct groups. We present preliminary data that suggests that QPMC is superior to the current punishment model with regards to identifying populations that are truly biochemically distinct. Wider adoption of QPMC will require more extensive comparisons between the two models. The objective of this proposal is to evaluate our new QPMC in comparison to the current punishment model. We propose to do this through two specific aims. In Aim 1, we will compare QPMC and the current punishment model in their ability to identify two biochemically distinct groups of rats self-administering sucrose pellets and METH (0.1 mg/kg/infusion). Given that the METH dose may alter the punishment sensitivity, Aim 2 will examine the effect of a changing METH dose on the reliability of the QPMC relative to the current punishment model. Animals from both aims will be evaluated for expression of corticotrophin releasing hormone stress systems, opioid peptide systems, and CART peptide systems in the nucleus accumbens. These molecular pathways will serve as molecular endpoints to establish biochemical distinctions between the identified groups per QPMC and the current model. Our general hypothesis is that, compared to the current punishment model, QPMC will objectively reveal distinct populations of rats self-administering METH under the punishment paradigm and will identify different endophenotypes for METH intake, leading to clearer understanding of the mechanisms that govern METH-UD.