Differential neurochemical consequences of an escalating dose-binge regimen followed by single-day multiple-dose methamphetamine challenges. Journal of Neurochemistry, 105(5), 1873-1885

Molecular Neuropsychiatry Branch, DHHS/NIH/NIDA Intramural Research Program, Baltimore, Maryland 21224, USA.
Journal of Neurochemistry (Impact Factor: 4.28). 07/2008; 105(5):1873-85. DOI: 10.1111/j.1471-4159.2008.05269.x
Source: PubMed


Chronic intake of methamphetamine (METH) causes tolerance to its behavioral and subjective effects. To better mimic human patterns of drug abuse, the present study used a rodent model that took into account various facets of human drug administration and measured METH-induced effects on brain monoamine levels. Adult male Sprague-Dawley rats were injected with METH or saline according to an escalating dose schedule for 2 weeks. This was followed by a challenge regimen of either saline or one of two doses of METH (3 x 10 mg/kg every 2 h or 6 x 5 mg/kg given every hour, both given within a single day). Both challenge doses of METH caused significant degrees of depletion of dopamine in the striatum and norepinephrine and serotonin in the striatum, cortex, and hippocampus. Animals pre-treated with METH showed significant attenuation of METH-induced striatal dopamine depletion but not consistent attenuation of norepinephrine and serotonin depletion. Unexpectedly, METH pre-treated animals that received the 3 x 10 mg/kg challenge showed less increases in tympanic temperatures than saline pre-treated rats whereas METH pre-treated animals that received the 6 x 5 mg/kg METH challenge showed comparable increases in temperatures to saline pre-treated rats. Therefore, pre-treatment-induced partial protection against monoamine depletion is probably not because of attenuated METH-induced hyperthermia in those rats.

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Available from: Jean Lud Cadet, Sep 22, 2014
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    • "Histamine and its receptors are also altered by Meth use and is involved in the cognitive deficits following both developmental and adult exposure to the drug (Acevedo & Raber, 2011 ; Noda et al. 2010). The GABAergic (Zhu et al. 2006) and norepinephrine (Graham et al. 2008) systems are also vulnerable to Meth toxicity. However, research has focused primarily upon dopamine (DA), serotonin (5-HT) and glutamate in adult animals. "
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    ABSTRACT: Neonatal exposure to (+)-methamphetamine (Meth) results in long-term behavioural abnormalities but its developmental mechanisms are unknown. In a series of experiments, rats were treated from post-natal days (PD) 11-20 (stage that approximates human development from the second to third trimester) with Meth or saline and assessed using locomotor activity as the readout following pharmacological challenge doses with dopamine, serotonin and glutamate agonists or antagonists during adulthood. Exposure to Meth early in life resulted in an exaggerated adult locomotor hyperactivity response to the dopamine D1 agonist SKF-82958 at multiple doses, a high dose only under-response activating effect of the D2 agonist quinpirole, and an exaggerated under-response to the activating effect of the N-methyl-d-aspartic acid (NMDA) receptor antagonist, MK-801. No change in locomotor response was seen following challenge with the 5-HT releaser p-chloroamphetamine or the 5-HT2/3 receptor agonist, quipazine. These are the first data to show that PD 11-20 Meth exposure induces long-lasting alterations to dopamine D1, D2 and glutamate NMDA receptor function and may suggest how developmental Meth exposure leads to many of its long-term adverse effects.
    The International Journal of Neuropsychopharmacology 03/2012; 16(2):1-15. DOI:10.1017/S1461145712000144 · 4.01 Impact Factor
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    • "The exact neurobiological mechanisms by which meth SA decreased cortical NET remain unknown. One possibility could be a generalized degradative effect on monoamine terminals (Graham et al., 2008). However, this notion is inconsistent with the lack of overt toxicity in the meth SA animals and the lack of a similar NET downregulation in the non-contingent meth rats. "
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    ABSTRACT: Chronic methamphetamine (meth) can lead to persisting cognitive deficits in human addicts and animal models of meth addiction. Here, we examined the impact of either contingent or non-contingent meth on memory performance using an object-in-place (OIP) task, which measures the ability to detect an object relative to its location and surrounding objects. Further, we quantified monoamine transporter levels and markers of neurotoxicity within the OIP circuitry and striatum. Male Long-Evans rats received an acute meth binge (4 × 4 mg/kg i.p., 2 h intervals) or self-administered meth (0.02 mg/infusion, i.v.; 7 days for 1 h/day, followed by 14 days for 6 h/day). Rats were tested for OIP recognition memory following one week of withdrawal. Subsequently, transporters for serotonin (SERT) and norepinephrine (NET) were quantified using Western blot in tissue obtained from the hippocampus, perirhinal cortex, and prefrontal cortex. In addition, striatal dopamine transporters, tyrosine hydroxylase, and glial fibrillary acidic protein were measured to assess potential neurotoxicity. Control (saline-treated) rats spent more time interacting with the objects in the changed locations. In contrast, contingent or non-contingent meth resulted in disrupted OIP performance as seen by similar amounts of time spent with all objects, regardless of location. While only acute meth binge produced signs of neurotoxicity, both meth regimens decreased SERT in the perirhinal cortex and hippocampus. Only meth self-administration resulted in a selective decrease in NET. Meth-induced changes in SERT function in the OIP circuitry may underlie memory deficits independently of overt neurotoxic effects. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
    Neuropharmacology 11/2011; 62(2):1119-26. DOI:10.1016/j.neuropharm.2011.11.003 · 5.11 Impact Factor
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    • "This finding is consistent with many previous reports. For example, METH has also been shown to induce a tolerance to the neurotoxic effects of MDMA [58], other amphetamines [59], [60], [61], [62], [63], methamphetamine [64] and MPTP oxidation products [65], [66] as well as to 6-OHDA in an animal model of PD [67]. Moreover, preconditioning and cross-tolerance using several different drugs have been shown in various in vitro models of the DA deficiency seen in PD [19], [20], [53]. "
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    ABSTRACT: Mild stress can protect against a larger insult, a phenomenon termed preconditioning or tolerance. To determine if a low intensity stressor could also protect cells against intense oxidative stress in a model of dopamine deficiency associated with Parkinson disease, we used methamphetamine to provide a mild, preconditioning stress, 6-hydroxydopamine (6-OHDA) as a source of potentially toxic oxidative stress, and MN9D cells as a model of dopamine neurons. We observed that prior exposure to subtoxic concentrations of methamphetamine protected these cells against 6-OHDA toxicity, whereas higher concentrations of methamphetamine exacerbated it. The protection by methamphetamine was accompanied by decreased uptake of both [(3)H] dopamine and 6-OHDA into the cells, which may have accounted for some of the apparent protection. However, a number of other effects of methamphetamine exposure suggest that the drug also affected basic cellular survival mechanisms. First, although methamphetamine preconditioning decreased basal pERK1/2 and pAkt levels, it enhanced the 6-OHDA-induced increase in these phosphokinases. Second, the apparent increase in pERK1/2 activity was accompanied by increased pMEK1/2 levels and decreased activity of protein phosphatase 2. Third, methamphetamine upregulated the pro-survival protein Bcl-2. Our results suggest that exposure to low concentrations of methamphetamine cause a number of changes in dopamine cells, some of which result in a decrease in their vulnerability to subsequent oxidative stress. These observations may provide insights into the development of new therapies for prevention or treatment of PD.
    PLoS ONE 10/2011; 6(10):e24722. DOI:10.1371/journal.pone.0024722 · 3.23 Impact Factor
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