Human Methamphetamine Pharmacokinetics Simulated in the Rat: Single Daily Intravenous Administration Reveals Elements of Sensitization and Tolerance

Abstract

We developed a computer-controlled intravenous methamphetamine (METH) administration procedure (dynamic infusion), which enables us to compensate for an important pharmacokinetic difference between rats and humans by imposing a 12-h half-life for the drug in rats. Dynamic infusion of 0.5 mg/kg METH produced a pharmacokinetic profile that closely simulates the METH exposure pattern in humans, including an apparent half-life of 11.671.3 h, and an area under the concentration vs time curve of 9.4 mM h, about 20-fold larger than results obtained with typical rat pharmacokinetics. Using this procedure, METH produced a prolonged behavioral stimulation and elevation in caudate extracellular dopamine (DA). Both the behavioral and the DA effects exhibited tolerance to the sustained plasma METH exposure. Single daily dynamic infusion of 0.5 mg/kg METH for 15 days resulted in a progressive enhancement of the behavioral response until about Day 10. On subsequent days, in addition to continued evidence of sensitization, tolerance in the form of a marked decrease in the duration of the behavioral activation became a prominent feature of the response. Qualitative changes in the behavior also emerged. Resumption of METH treatment following 4 days of withdrawal revealed that sensitization was apparent during the first dynamic infusion, and that tolerance re-emerged within two additional days of drug administration. These results showed that a humanlike METH exposure pattern produced behavioral and striatal DA response profiles that are both quantitatively and qualitatively different from the effects typically observed with single daily METH injections in rats. Thus, simulation of human METH exposure patterns may be a critical prerequisite to identifying mechanisms relevant to the chronic use of this drug in humans. Neuropsychopharmacology (2006) 31, 941-955.

Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation

“…Nevertheless, the present results for MA-injected B6 mice are qualitatively similar to results from relatively recent studies, in which rats with a history of behavior-contingent vs. non-contingent intravenous MA exposure displayed MA-induced DA sensitization that manifested early in withdrawal (Lominac et al, 2012; Laćan et al, 2013; Le Cozannet et al, 2013). While requiring further study, particularly with respect to MA pharmacokinetics (see Segal and Kuczenski, 2006 for Discussion), the capacity of repeated MA to elicit time-independent DA sensitization within the NAC (and perhaps also within the mPFC) is qualitatively similar across rodent species, routes of delivery and contingency of delivery, which renders non-contingent models of MA administration well-suited for the study of the psychobiological consequences of subchronic MA exposure of relevance to MA abuse and the development of addiction (see also Laćan et al, 2013). …”

“…The majority of extant pre-clinical data has been derived using very high-dose MA treatment regimens (10–100 mg/kg acutely or binge administration of 4–10 mg/kg given multiple times within a day) that elicit neurotoxicity within dorsal striatal regions (for recent reviews on the subject: Kuhn et al, 2011; Carvalho et al, 2012; Ares-Santos et al, 2013; Halpin et al, 2014). While we have gained tremendous molecular and cellular insight into how high-dose MA experience produces forebrain damage of relevance to late-stage addiction, to the best of our knowledge, less than 15 reports exist pertaining to the interactions between forebrain dopamine systems and low-dose, subchronic exposure to MA (e.g., Zhang et al, 2001; Broom and Yamamoto, 2005; Ago et al, 2006, 2007, 2012; Segal and Kuczenski, 2006; Fukakusa et al, 2008; Schwendt et al, 2009; Lominac et al, 2012; Laćan et al, 2013; Le Cozannet et al, 2013). Also, whereas it is generally held that repeated MA exposure elicits a sensitization of forebrain dopamine release that contributes to the development of behavioral sensitization and/or underpins this drug's positive-reinforcing or rewarding properties (e.g., Ujike et al, 1989; Yang et al, 2008a,b), discrepancies exist regarding the relative roles played by DA within different forebrain terminal regions, most notably the NAC vs. mPFC (see Ago et al, 2006, 2007, 2012).…”

Chronic wheel running-induced reduction of extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats is associated with reduced number of periaqueductal gray dopamine neurons

“…16 hours after the end of their last self-administration session to label progenitors in the S phase of the cell cycle and were killed 5 weeks later (Figure 1a). This time point was chosen to prevent labeling cells during peak withdrawal manifestation and high brain and plasma methamphetamine levels after methamphetamine self-administration (Cryan et al, 2003; Segal and Kuczenski, 2006; McFadden et al, 2012b). …”

Methamphetamine Increases Brain Viral Load and Activates Natural Killer Cells in Simian Immunodeficiency Virus-Infected Monkeys

“…34 -36 However, the markedly different Meth pharmacokinetics in rodents as opposed to primates (approximately a 10-fold shorter half-life in rodents) complicates interpretation of rodent studies. 37 Furthermore, these are largely acute studies, and chronic administration studies such as ours have not been performed to examine the effects of Meth on immune parameters.…”