Effect of Combined Methamphetamine and Oxycodone Use on the Synaptic Proteome in an In Vitro Model of Polysubstance Use

Abstract

Polysubstance use (PSU) generally involves the simultaneous use of an opioid along with a stimulant. In recent years, this problem has escalated into a nationwide epidemic. Understanding the mechanisms and effects underlying the interaction between these drugs is essential for the development of treatments for those suffering from addiction. Currently, the effect of PSU on synapses—critical points of contact between neurons—remains poorly understood. Using an in vitro model of primary neurons, we examined the combined effects of the psychostimulant methamphetamine (METH) and the prescription opioid oxycodone (oxy) on the synaptic proteome using quantitative mass-spectrometry-based proteomics. A further ClueGO analysis and Ingenuity Pathway Analysis (IPA) indicated the dysregulation of several molecular functions, biological processes, and pathways associated with neural plasticity and structural development. We identified one key synaptic protein, Striatin-1, which plays a vital role in many of these processes and functions, to be downregulated following METH+oxy treatment. This downregulation of Striatin-1 was further validated by Western blot. Overall, the present study indicates several damaging effects of the combined use of METH and oxy on neural function and warrants further detailed investigation into mechanisms contributing to synaptic dysfunction.

In vitro drug-drug interactions in rat liver between oxycodone and commonly co-consumed drugs

“…Thus, limited drug-drug interactions might be expected between methamphetamine and oxycodone. Thus primarily pharmacodynamic, rather than pharmacokinetic, effects might be responsible for the drug-drug interactions of opioids and methamphetamine co-use, such as the observation that oxycodone and methamphetamine together cause damage of neural function (Meyer et al, 2022).…”

Identification of YWHAH as a Novel Brain-Derived Extracellular Vesicle Marker Post Long-Term Midazolam Exposure during Early Development

“…Protein quantification was performed using Pierce BCA protein assay (Thermo Scientific, Rockford, IL, USA) and followed the procedure described in our earlier studies [ 3 , 17 ]. 50 µg of protein per sample from 6 animals was subjected to mass spectrometry (MS) analysis.…”

“…The analysis was based on the label-free quantitative mass spectrometry protocol. The details of the MS protocol and reagents used are described in our recently published studies [ 3 , 17 ].…”

“…The in-house mascot 2.6.2. (Matrix Science, Boston, MA, USA) search engine was used further to identify the proteins from tandem mass spectrometry data, as described in our published studies [ 3 , 17 ]. The search targeted total tryptic peptides and allowed for two missed cleavage sites.…”