A Single Prior Injection of Methamphetamine Enhances Methamphetamine Self-Administration (SA) and Blocks SA-Induced Changes in DNA Methylation and mRNA Expression of Potassium Channels in the Rat Nucleus Accumbens

Subramaniam Jayanthi,Bruce Ladenheim,Jean Lud Cadet,Oscar V Torres

doi:10.1007/s12035-019-01830-3

Subramaniam Jayanthi, Bruce Ladenheim + Show 2 more

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https://doi.org/10.1007/s12035-019-01830-3

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Abstract

The transition from occasional to escalated psychostimulant use is accelerated by prior drug exposure. These behavioral observations may be related to long-lasting transcriptional and/or epigenetic changes induced by the drug pre-exposure. Herein, we investigated if a single methamphetamine (METH) injection would enhance METH self-administration (SA) and impact any METH SA-induced epigenetic or transcriptional alterations. We thus injected a single METH dose (10 mg/kg) or saline to rats before training them to self-administer METH or saline. There were three experimental groups in SA experiments: (1) a single saline injection followed by saline SA (SS); (2) a single saline injection followed by METH SA (SM); and (3) a single METH injection followed by METH SA (MM). METH-pretreated rats escalated METH SA earlier and took more METH than saline-pretreated animals. Both groups showed similar incubation of cue-induced METH craving. Because compulsive METH takers and METH-abstinent rats show differences in potassium (K+) channel mRNA levels in their nucleus accumbens (NAc), we wondered if K+ channel expression might also help to distinguish between SM and MM groups. We found increases in mRNA and protein expression of shaker-related voltage-gated K+ channels (Kv1: Kcna1, Kcna3, and Kcna6) and calcium-activated K+ channels (Kcnn1) in the SM compared to MM rats. SM rats also showed decreased DNA methylation at the CpG-rich sites near the promoter region of Kcna1, Kcna3 and Kcnn1 genes in comparison to MM rats. Together, these results provide additional evidence for potentially using K+ channels as therapeutic targets against METH use disorder.

Highlights

METH use disorder (MUD) is a very serious, potentially lethal, biopsychosocial disease
Recent observations have suggested that potassium (K+) channels might be involved in modulating the compulsive intake of several drugs of abuse including alcohol [9, 10], cocaine [11], methamphetamine [5], nicotine [12], and opioids [13]
Of more direct relevance to the present study, METH SA caused decreased GIRK currents in midbrain DA neurons of mice [39] while we recently found that suppression of METH SA behaviors in the presence of footshock punishment was associated with increased expression of K+ channels in the rat nucleus accumbens (NAc) [5]

Summary

Introduction

METH use disorder (MUD) is a very serious, potentially lethal, biopsychosocial disease. According to the U.S National Survey on Drug Use and Health [2], 375,000 Americans (aged 18–25) and 1.2 million (aged 26 or older) are active METH users. Studies on potential molecular substrates of substance use disorders (SUDs) have identified some interesting targets for pharmacological interventions [5,6,7]. These include biochemical signaling pathways including the glutamatergic system [7], specific gene networks [8], as well as epigenetic regulatory mechanisms [6, 7]. Recent observations have suggested that potassium (K+) channels might be involved in modulating the compulsive intake of several drugs of abuse including alcohol [9, 10], cocaine [11], methamphetamine [5], nicotine [12], and opioids [13]

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