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.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$2,083,928
Indirect Cost
Name
National Institute on Drug Abuse
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Type
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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
Krasnova, Irina N; Marchant, Nathan J; Ladenheim, Bruce et al. (2014) Incubation of methamphetamine and palatable food craving after punishment-induced abstinence. Neuropsychopharmacology 39:2008-16
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
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
Krasnova, Irina N; Chiflikyan, Margarit; Justinova, Zuzana et al. (2013) CREB phosphorylation regulates striatal transcriptional responses in the self-administration model of methamphetamine addiction in the rat. Neurobiol Dis 58:132-43
Cadet, Jean Lud; Jayanthi, Subramaniam; McCoy, Michael T et al. (2013) Genome-wide profiling identifies a subset of methamphetamine (METH)-induced genes associated with METH-induced increased H4K5Ac binding in the rat striatum. BMC Genomics 14:545
Cadet, Jean Lud; Bisagno, Veronica (2013) The primacy of cognition in the manifestations of substance use disorders. Front Neurol 4:189
Griffioen, Kathleen J; Rothman, Sarah M; Ladenheim, Bruce et al. (2013) Dietary energy intake modifies brainstem autonomic dysfunction caused by mutant α-synuclein. Neurobiol Aging 34:928-35
Cadet, Jean Lud; Jayanthi, Subramaniam (2013) Epigenetics of methamphetamine-induced changes in glutamate function. Neuropsychopharmacology 38:248-9
Diaz-Ruiz, Oscar; Zhang, Yajun; Shan, Lufei et al. (2012) Attenuated response to methamphetamine sensitization and deficits in motor learning and memory after selective deletion of ýý-catenin in dopamine neurons. Learn Mem 19:341-50

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