Research Article: Methamphetamine Self-Administration Is Associated with Persistent Biochemical Alterations in Striatal and Cortical Dopaminergic Terminals in the Rat

Date Published: January 20, 2010

Publisher: Public Library of Science

Author(s): Irina N. Krasnova, Zuzana Justinova, Bruce Ladenheim, Subramaniam Jayanthi, Michael T. McCoy, Chanel Barnes, John E. Warner, Steven R. Goldberg, Jean Lud Cadet, Olivier Jacques Manzoni.

Abstract: Methamphetamine (meth) is an illicit psychostimulant that is abused throughout the world. Repeated passive injections of the drug given in a single day or over a few days cause significant and long-term depletion of dopamine and serotonin in the mammalian brain. Because meth self-administration may better mimic some aspects of human drug-taking behaviors, we examined to what extent this pattern of drug treatment might also result in damage to monoaminergic systems in the brain. Rats were allowed to intravenously self-administer meth (yoked control rats received vehicle) 15 hours per day for 8 days before being euthanized at either 24 hours or at 7 and 14 days after cessation of drug taking. Meth self-administration by the rats was associated with a progressive escalation of daily drug intake to 14 mg/kg per day. Animals that self-administered meth exhibited dose-dependent decreases in striatal dopamine levels during the period of observation. In addition, there were significant reductions in the levels of striatal dopamine transporter and tyrosine hydroxylase proteins. There were also significant decreases in the levels of dopamine, dopamine transporter, and tyrosine hydroxylase in the cortex. In contrast, meth self-administration caused only transient decreases in norepinephrine and serotonin levels in the two brain regions, with these values returning to normal at seven days after cessation of drug taking. Importantly, meth self-administration was associated with significant dose-dependent increases in glial fibrillary acidic protein in both striatum and cortex, with these changes being of greater magnitude in the striatum. These results suggest that meth self-administration by rats is associated with long-term biochemical changes that are reminiscent of those observed in post-mortem brain tissues of chronic meth abusers.

Partial Text: Methamphetamine (METH) is a highly addictive psychostimulant drug whose abuse has reached epidemic proportions in the USA and worldwide [1]–[4]. This presents a serious public concern because chronic METH abuse is associated with major health problems including anxiety, depression, psychosis and psychomotor dysfunctions in humans [5], [6]. Cognitive studies of chronic METH users have also found deficits consistent with impaired functions of striatal and cortical systems. These include deficits in attention, learning, working memory, and decision making [7]–[11]. The accumulated evidence is compelling that the negative neuropsychiatric consequences of METH abuse are related to drug-induced pathological changes in the brains of METH addicts [12]. Specifically, clinical imaging studies have demonstrated significant reductions in the levels of dopamine transporters (DAT) [8], [11], [13] and reactive gliosis [14], [15] in the brains of METH abusers. Postmortem analyses of brain tissues obtained from METH addicts revealed significant decreases in dopamine (DA) concentrations and in DAT and tyrosine hydroxylase (TH) protein levels [16]–[18]. There is also neuroimaging evidence that these patients suffer from a marked loss of serotonin transporters (5-HTT) in several brain regions [19], although a recent post-mortem report showed that the reductions in 5-HTT might not be as widespread as suggested by the positron emission tomography data [20].

The present experiments demonstrated that (1) extended access to METH self-administration was associated with a progressive escalation of drug intake by rats and significant decreases in their body weights; (2) this pattern of METH intake resulted in persistent dose-dependent depletion of striatal and cortical DA levels measured at various times after cessation of drug treatment; (3) METH self-administration also caused decreases in the expression of striatal and cortical TH and DAT proteins; and (4) METH induced dose-dependent increases in GFAP expression in both, striatum and cortex.



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