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Differential neurochemical consequences of an escalating dose-binge regimen followed by single-day multiple-dose methamphetamine challenges

Molecular Neuropsychiatry Branch, DHHS/NIH/NIDA Intramural Research Program, Baltimore, Maryland 21224, USA.
Journal of Neurochemistry (Impact Factor: 4.24). 07/2008; 105(5):1873-85. DOI: 10.1111/j.1471-4159.2008.05269.x
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ABSTRACT 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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    • "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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    • "Following habituation, rats were injected intraperitoneally with either (±)-METH-hydrochloride (NIDA, Baltimore, MD) or an equivalent volume of 0.9% saline for a period of three weeks as described elsewhere (Graham et al. 2008; Cadet et al. 2009a). The saline-or METH-pretreated animals received either saline or METH (5 mg/kg x 8 at 1 h intervals) challenges 72 hours after the preconditioning period. "
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    • "Generalizations from this research may have limited applicability to this study, which was concerned with the impact of widely spaced administrations on longer-term effects. For example, when administrations are closely spaced, as dose increases, the rate of tolerance can increase (Fernstrom and Choi, 2008; Graham et al, 2008). This dose-tolerance relationship may result, in part, because higher doses produce larger impairments in the mechanisms that underlie normal responsiveness, and with closely spaced administrations these mechanisms may not have sufficient time to normalize before the next administration. "
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