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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 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.

SUBMITTER: Jayanthi S

PROVIDER: S-EPMC7060962 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Methamphetamine (METH) is a widely abused illicit amphetamine that causes acute biochemical and molecular changes in the brain. However, there are very few studies that have investigated the long-term effects of a single METH exposure in adult animals. The purpose of this study was thus to determine the consequences of a single injection of METH (10) mg/kg) on the biochemical and transcriptional effects of a second challenge injection of the drug (2.5 mg/kg) given one month later. Towards that end, we measured monoamine levels and gene expression by microarray and quantitative PCR analyses in the nucleus accumbens (NAc) of 4 groups of rats: saline-pretreated and saline-challenged (SS); saline-pretreated and METH-challenged (SM); METH-pretreated and saline-challenged (MS); and METH-pretreated and METH-challenged (MM). The rats were euthanized 2 hours after the acute challenge injection and NAc samples were harvested. The acute METH challenge caused increases in NAc DA and HVA levels in both the SM and MM groups. Microarray analyses revealed that an injection of METH (2.5 mg/kg) produced acute changes (1.8-fold; p < 0.01) in the expression of 418 (358 up-, 60 downregulated) genes including several immediate early genes (IEGs) such as Arc, c-fos, and fosB in the SM group. Several neuropeptides including Cart, Crf (Crh), and vasopressin were upregulated in that group. Injection of the higher dose of METH (10 mg/kg) did not influence monoamine levels but caused changes in 510 (345 up-, 165 downregulated) transcripts measured one month later (MS group). This list included Cart and Crf but not any IEGs. The MM group showed changes in 774 (572 up-, 202 downregulated) genes that also included vasopressin, Cart, and Crf whose expression was enhanced by the second METH injection. Quantitative PCR confirmed the METH-induced changes in the expression of the neuropeptides. We also confirmed the METH-induced potentiation of Crf expression in the METH-pretreated group. These observations suggest that a single injection of a moderate dose of METH can produce long-lasting changes in gene expression in the rodent NAc. The long-term increases in Crf expression also suggest that a single injection of a moderate METH dose can cause prolonged dysregulation in the endogenous stress system in the rat brain. 24 samples. SS (4), SM (6), MS (7), MM (7)

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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.

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