Pretreatment with methamphetamine (METH) can attenuate toxicity due to acute METH challenges. The majority of previous reports have focused mainly on the effects of the drug on the striatal dopaminergic system. In the present study, we used a regimen that involves gradual increases in METH administration to rats in order to mimic progressively larger doses of the drug used by some human METH addicts. We found that this METH preconditioning was associated with complete protection against dopamine depletion caused by a METH challenge (5 mg/kg x 6 injections given 1 h apart) in the striatum and cortex. In contrast, there was no preconditioning-mediated protection against METH-induced serotonin depletion in the striatum and hippocampus, with some protection being observed in the cortex. There was also no protection against METH-induced norepinephrine (NE) depletion in the hippocampus. These results indicate that, in contrast to the present dogmas, there might be differences in the mechanisms involved in METH toxicity on monoaminergic systems in the rodent brain. Thus, chronic injections of METH might activate programs that protect against dopamine toxicity without influencing drug-induced pathological changes in serotoninergic systems. Further studies will need to evaluate the cellular and molecular bases for these differential responses. In addition, we have begun to investigate the epigenetic changes that are associated with the chronic use of drugs such as methamphetamine. We have found evidence that histone de-acetylation plays an important role in regulating glutamate receptors in the dorsal striatum. We are also investigating the effects of methamphetamine on HDAC enzmes and on trophic factors.

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Budget End
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8
Fiscal Year
2016
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Name
National Institute on Drug Abuse
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González, Betina; Torres, Oscar V; Jayanthi, Subramaniam et al. (2018) The effects of single-dose injections of modafinil and methamphetamine on epigenetic and functional markers in the mouse medial prefrontal cortex: potential role of dopamine receptors. Prog Neuropsychopharmacol Biol Psychiatry 88:222-234
Torres, Oscar V; Jayanthi, Subramaniam; McCoy, Michael T et al. (2018) Selective Activation of Striatal NGF-TrkA/p75NTR/MAPK Intracellular Signaling in Rats That Show Suppression of Methamphetamine Intake 30 Days following Drug Abstinence. Int J Neuropsychopharmacol 21:281-290
Jayanthi, Subramaniam; Gonzalez, Betina; McCoy, Michael T et al. (2018) Methamphetamine Induces TET1- and TET3-Dependent DNA Hydroxymethylation of Crh and Avp Genes in the Rat Nucleus Accumbens. Mol Neurobiol 55:5154-5166
González, Betina; Jayanthi, Subramaniam; Gomez, Natalia et al. (2018) Repeated methamphetamine and modafinil induce differential cognitive effects and specific histone acetylation and DNA methylation profiles in the mouse medial prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry 82:1-11
Krasnova, Irina N; Gerra, Maria Carla; Walther, Donna et al. (2017) Compulsive methamphetamine taking in the presence of punishment is associated with increased oxytocin expression in the nucleus accumbens of rats. Sci Rep 7:8331
Torres, Oscar V; Jayanthi, Subramanian; Ladenheim, Bruce et al. (2017) Compulsive methamphetamine taking under punishment is associated with greater cue-induced drug seeking in rats. Behav Brain Res 326:265-271
Cadet, J L; Brannock, C; Krasnova, I N et al. (2017) Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence. Mol Psychiatry 22:1196-1204
Cadet, Jean Lud; Brannock, Christie; Jayanthi, Subramaniam et al. (2015) Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat. Mol Neurobiol 51:696-717
Cadet, Jean Lud; Brannock, Christie; Ladenheim, Bruce et al. (2014) Enhanced upregulation of CRH mRNA expression in the nucleus accumbens of male rats after a second injection of methamphetamine given thirty days later. PLoS One 9:e84665
Bisagno, Verónica; Cadet, Jean Lud (2014) Stress, sex, and addiction: potential roles of corticotropin-releasing factor, oxytocin, and arginine-vasopressin. Behav Pharmacol 25:445-57

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