CREB phosphorylation regulates striatal transcriptional responses in the self-administration model of methamphetamine addiction in the rat

Abstract

Neuroplastic changes in dorsal striatum participate in the transition from casual to habitual drug use and might play a critical role in the development of methamphetamine (METH) addiction. We examined the influence of METH self-administration on gene and protein expression that may form substrates for METH-induced neuronal plasticity in the dorsal striatum. Male Sprague-Dawley rats self-administered METH (0.1 mg/kg/injection, i.v.) or received yoked saline infusions during eight 15-h sessions and were euthanized 2 h, 24 h, or 1 month after cessation of METH exposure. Changes in gene and protein expression were assessed using microarray analysis, RT-PCR and Western blots. Chromatin immunoprecipitation (ChIP) followed by PCR was used to examine epigenetic regulation of METH-induced transcription. METH self-administration caused increases in mRNA expression of the transcription factors, c-fos and fosb, the neurotrophic factor, Bdnf, and the synaptic protein, synaptophysin (Syp) in the dorsal striatum. METH also caused changes in ΔFosB, BDNF and TrkB protein levels, with increases after 2 and 24 h, but decreases after 1 month of drug abstinence. Importantly, ChIP-PCR showed that METH self-administration caused enrichment of phosphorylated CREB (pCREB), but not of histone H3 trimethylated at lysine 4 (H3K4me3), on promoters of c-fos, fosb, Bdnf and Syp at 2 h after cessation of drug intake. These findings show that METH-induced changes in gene expression are mediated, in part, by pCREB-dependent epigenetic phenomena. Thus, METH self-administration might trigger epigenetic changes that mediate alterations in expression of genes and proteins serving as substrates for addiction-related synaptic plasticity.

Dopaminergic System Dysfunction in Recreational Dexamphetamine Users

“…In a subsequent SPECT study with a more selective DAT ligand, we observed reduced striatal DAT binding in the participants who primarily used dAMPH (Schouw et al, 2013b). Our present findings are in line with the extensive preclinical literature, showing that prolonged dAMPH exposure affects the DA system: as reductions in tyrosine hydroxylase activity, long-term DA depletion, loss of the DAT and VMAT-2, reductions in post-synaptic receptors, and even dAMPH-induced apoptosis in certain cell types (Cadet et al, 2007;Krasnova et al, 2001Krasnova et al, , 2005Krasnova et al, , 2013Ricaurte et al, 2005;Soto et al, 2012) have been reported. Multiple pathways have been shown to be involved in the neurotoxicity of dAMPH.…”

Incubation of Methamphetamine and Palatable Food Craving after Punishment-Induced Abstinence

“…These studies indicate that extended cocaine exposure, which presumably leads to more profound neuroadaptations (Ahmed et al, 2005;Ben-Shahar et al, 2009), does not increase cue-induced drug seeking during late withdrawal but instead decreases cocaine seeking during early withdrawal. This idea is also supported by recent molecular studies that have documented differential transcriptional and translational adaptations at early and late withdrawal times after methamphetamine self-administration in rats (Krasnova et al, 2013).…”

Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence

“…All METH-trained rats significantly escalated their intake of the drug per session during the first 16 days and then maintained their intake for the remainder of the training session (Figure 1b). The repeated measures mixed analysis of variance for rewards earned included the between-subject factor group (control (CT), shocksensitive (SS), shock-resistant (SR)) and the within-subject factor of day (training days [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. This analysis showed a significant effect of day × group (F (38, 608) = 18.4, P o0.001).…”

“…[1][2][3] Behavioral phenomena observed during drug SA are regulated by a diversity of interconnected but distinct brain regions that include the nucleus accumbens (NAc) and dorsal striatum, among others. [4][5][6] The NAc is an important link in the circuit of addiction because it connects to brain regions that subsume positive memory 7 and decision making, 8 two cognitive processes that regulate drug-taking behaviors in rodents and humans.…”