Contents lists available at ScienceDirect Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet Research article The effects of acute and repeated methylenedioxypyrovalerone (MDPV) administration on striatal transcriptome networks in male long evans rats Christopher J. Martyniuk a, ⁎ , Marjory Pompilus b , Jordan Schmidt a , Allison Duncan a , Marcelo Febo b, ⁎⁎ a Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611 USA b Department of Psychiatry, Evelyn F. and William L. McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA ARTICLE INFO Keywords: Drug abuse Anxiety Transcriptome Immune system ABSTRACT The psychoactive drug methylenedioxypyrovalerone (MDPV) elicits feelings of euphoria and hyperexcitability, but can also result in paranoia, agitation, and depression by unknown mechanisms. We identified molecular networks in the rat striatum that were affected by single or repeated exposure to MDPV. Male Long Evans rats were injected with either saline or MDPV (1 mg/kg) (single or repeated MDPV) over 5 days. To distinguish the effects of repeated MDPV from a single exposure, an additional group received saline over 4 days and then MDPV on the 5th day. Twenty-four hours after the final injection, the left dorsal striatum was processed for tran- scriptomics. The transcriptome response was subtle after 24 h, and a single gene passed an FDR correction (LOC103691845) following repeated MDPV treatment. Gene set and subnetwork enrichment analyses were conducted to improve data interpretation from a network perspective. Consistent with the mode of action of MDPV, networks related to the nigrostriatal dopaminergic system were altered in the rat striatum. Transcriptional networks related to cognition, short and long-term memory, and synaptic transmission were over-represented in the striatum of rats repeatedly injected with MDPV. This study identifies potential tran- scriptional networks altered by single or repeated MDPV exposure, which can be interrogated further to elu- cidate molecular mechanisms underlying cathinone abuse. 1. Introduction Cathinone (β-keto-amphetamine) derivatives have emerged as a novel class of street drugs with high abuse liability [24]. As of 2014 there were ∼77 different synthetic ‘bath salts’ used worldwide, with 31 of these entering the legal market in that year alone [14]. Among the major constituents of bath salts, methylenedioxypyrovalerone (MDPV) is one of the most harmful due to its lasting effects on social interac- tions, mood, and cognitive function. MDPV has a high potency to in- hibit dopamine (DA) and norepinephrine (NE) transporters (DAT and NET) and can produce typical psychostimulant-like effects that can be stronger than methamphetamine [1], and is up to 100 times more po- tent as a DAT reuptake inhibitor [13,22]. MDPV increases locomotor activation [10], elevates extracellular levels of dopamine in the striatum [5], and produces high rates of intravenous self-administration (IVSA) [1]. These studies support the idea that the rewarding effects of MDPV underlie its high potential for abuse. Recently we observed altered DAT protein levels in striatum and increased neuroimaging measures of connectivity after a 24 h single MDPV exposure in rats [17]. Identification of candidate molecular pathways dysregulated by MDPV exposure and acute injection, parti- cularly during this time window when MDPV levels are diminished, is a key step in defining novel mechanisms mediating its adverse effects. MDPV can accumulate in the dorsal striatum, and its concentration within this basal ganglia structure correlates with its locomotor sti- mulant effects [36]. MDPV concentration peak in rat striatal tissue at 20–40 min after subcutaneous administration of a 1 mg/kg dose and levels start to decline by 60 min [36]. Moreover, striatal levels of MDPV (∼200 ng/g tissue) are still detected between 90–180 min and based upon our previous study, there remain persistent changes lasting up to 24 h [9,17]. Importantly, the temporal dynamics of MDPV concentra- tions in rat striatum closely paralleled the locomotor activity changes in response to MDPV. Here, we aimed to measure gene expression 24 h after MDPV administration to identify molecular pathways that may https://doi.org/10.1016/j.neulet.2019.134499 Received 26 March 2019; Received in revised form 12 September 2019; Accepted 13 September 2019 ⁎ Corresponding author. ⁎⁎ Corresponding author at: Department of Psychiatry, UF College of Medicine, PO Box 100256, Gainesville, FL, 32610, USA. E-mail addresses: cmartyn@ufl.edu (C.J. Martyniuk), febo@ufl.edu (M. Febo). Neuroscience Letters 712 (2019) 134499 Available online 16 September 2019 0304-3940/ © 2019 Elsevier B.V. All rights reserved. T