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

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 salinepretreated 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.

Potassium Channels and Their Potential Roles in Substance Use Disorders

“…Researchers in the Cadet laboratory have recently published several papers in which they attempt to mimic human MUD conditions in rodent models [ 53 , 55 , 107 , 108 , 109 ]. In those models, they have introduced an additional DSM5 criterion that is related to compulsive drug intake despite adverse consequences [ 107 ].…”

“…The potential role of potassium channels in METH taking behaviors was also investigated in a subsequent paper. In that paper, we tested the possibility that a single pre-exposure to METH could potentiate its intake during self-administration experiments [ 53 ]. Animals were therefore pre-treated with saline or METH prior to METH SA.…”

“…Because compulsive METH takers and METH-abstinent rats show differences in potassium (K + ) channel mRNA levels in their nucleus accumbens (NAc), we tested the possibility that the expression of K V potassium channels might also help to distinguish between rats that escalated METH earlier (MM group) than the other group (SM). Increased levels of mRNA and protein expression of voltage-gated K+ channels (Kv1: Kcna1, Kcna3, and Kcna6) were indeed found in the NAc of rats that escalated METH later and took less METH [ 53 ]. Rats with increased mRNA expression also showed decreased DNA methylation at the CpG-rich sites near the promoter region of these genes.…”

“…The accumulated evidence suggests that K + channels can regulate and/or facilitate the development of neuroadaptations that may be important in drug-induced progression of behaviors that are associated with the development of a SUD diagnosis [ 48 ]. Indeed, K + channel signaling appears to be impacted by exposure to various rewarding drugs that include alcohol [ 49 , 50 , 51 ], cocaine [ 52 ], methamphetamine [ 53 , 54 , 55 ], and opioids [ 56 , 57 ], morphine [ 58 , 59 ], oxycodone [ 60 ], and fentanyl [ 61 ]. Detailed effects of these drugs on potassium channels are described below.…”

Genome-Wide DNA Methylation Analysis in Male Methamphetamine Users With Different Addiction Qualities

“…Yuka et al (44) found that the rate of DNA methylation at six CpG islands of SHATI/NAT8L promoter sites is significantly higher in MA users when compared to healthy subjects. Jayanthi et al (45) reported that a single prior injection of MA enhanced MA self-administration (SA) and blocked SAinduced changes in DNA methylation and mRNA expression of potassium channels in the rat nucleus accumbens. MA produces a variety of epigenetic effects in the brain, which are seminal to establish long-lasting alterations in neuronal activity.…”