Increased plasma concentration and brain penetration of methamphetamine in behaviorally sensitized rats

doi:10.1016/S0014-2999(03)01321-9

European Journal of Pharmacology

Volume 464, Issue 1, 7 March 2003, Pages 39-48

https://doi.org/10.1016/S0014-2999(03)01321-9 Get rights and content

Abstract

Exposure to methamphetamine causes behavioral sensitization in experimental animals. However, the precise mechanism of this behavioral sensitization has not yet been fully elucidated. Accordingly, we evaluated the pharmacokinetic properties of methamphetamine in rats behaviorally sensitized to methamphetamine following its repeated administration (6 mg/kg, i.p., once a day for 5 days followed by a 21-day drug abstinence period). In the sensitized rats, methamphetamine (0.8 mg/kg)-induced locomotor activity was significantly enhanced, suggesting the successful establishment of behavioral sensitization to methamphetamine. Significant increases in the concentrations of methamphetamine in plasma and brain dialysate, as well as the delayed disappearance of methamphetamine from plasma, were observed in the sensitized rats after intravenous injection of methamphetamine (5 mg/kg). The tissue to plasma concentration ratio (Kp) of methamphetamine in lung and heart decreased in the sensitized rats. The renal excretion of methamphetamine, which is sensitive to several cations, was also decreased in the sensitized rats. Moreover, in the sensitized rats, the expression of organic cation transporter 3 (OCT3) mRNA was decreased in kidney, brain and heart as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Taken together, these results suggest that the behavioral outcome of sensitization to methamphetamine might, in part, be due to the increased levels of methamphetamine in plasma and brain extracellular areas, as well as an altered tissue distribution of methamphetamine associated with changes in the cation transport system.

Introduction

Repeated exposure to drugs of abuse, including amphetamine and methamphetamine, results in a progressive and persistent enhancement of their psychomotor and positive reinforcing effects. This phenomenon, termed behavioral sensitization (Pierce and Kalivas, 1997;Sato, 1986, Stewart and Badiani, 1993), is thought to underlie certain aspects of the development of addiction to drugs and to drug-induced psychosis Robinson and Becker, 1986, Robinson and Berridge, 1993.

Thus far, the expression of behavioral sensitization is believed to result from neuroplastic changes in the brain circuitry involved in motivational behavior, such as long-lasting hyperreactivity of dopaminergic and glutamatergic neurons, as well as altered activity of monoamine transporters Ellinwood et al., 1995, Pierce and Kalivas, 1997. For example, Vanderschuren et al. (1999) have recently demonstrated that even a single injection of amphetamine causes behavioral, neuroendocrine and neurochemical sensitization to amphetamine. In addition, behavioral sensitization was also found after administration of a dopamine D1 receptor agonist (SKF-82958), a dopamine D2 receptor agonist (quinpirole) and cocaine to rats pretreated with amphetamine. These results suggest that the neuro-functional changes of the dopaminergic system associated with exposure to drugs of abuse are important for altering neuronal functions, subsequently causing behavioral sensitization.

The effects of dopamine receptor antagonists on methamphetamine/amphetamine-induced behavioral sensitization are limited; dopamine receptor antagonists do not reverse the established behavioral sensitization to methamphetamine Ellinwood et al., 1995, Hamamura et al., 1991, Sato, 1983, Ujike, 1989. Moreover, amphetamine induces behavioral sensitization even in postsynaptic dopamine receptor-knockout mice Crawford et al., 1997, Xu et al., 2000. In the light of these discrepancies, an alternative explanation for the behavioral sensitization to psychostimulants should be considered.

There are few data available concerning drug pharmacokinetics in animals behaviorally sensitized to methamphetamine/amphetamine Cho et al., 2001, Mizugaki et al., 1993, Numachi et al., 1992, Riviere et al., 1999, Riviere et al., 2000. This might also to be an important factor contributing to altered behavior in sensitized animals. Regarding this, inconsistent data have been reported for psychostimulant-abusing subjects, with pharmacokinetics being either changed (Änggård et al., 1970, Beckett and Rowland, 1965a, Beckett and Rowland, 1965b; also see review of Busto et al., 1989) or unchanged (Cook et al., 1992).

In the present study, we investigated the pharmacokinetics and brain penetration of methamphetamine in rats behaviorally sensitized to methamphetamine. Our results revealed that the concentration–time profiles of methamphetamine in plasma and brain dialysates are increased in rats that are behaviorally sensitized to methamphetamine. Our data also suggest that the altered tissue distribution and renal excretion of methamphetamine possibly result from decreased cation transport.

Section snippets

Animals

Male Wistar rats (260–330 g) were purchased from Japan SLC (Hamamatsu, Japan). Animals were kept in a temperature (22–24 °C)-, humidity (55±5%)- and light (12-h light–dark cycle, lights on at 07:00)-regulated room with food and water ad libitum for at least 3 days before experiments. The procedures involving animals and their care conformed to the international guidelines Principles of Laboratory Animal Care (NIH publication no. 85-23, revised 1985) and Guiding Principles for the Care and Use

Methamphetamine-induced locomotor activity

Repeated methamphetamine treatment, followed by a 21-day drug abstinence period (sensitized), did not affect habituation and/or basal locomotor activity [control rats: 1817±135; sensitized rats: 1619±302; F(1,8)=0.354; NS]. One-way ANOVA with repeated measures showed a significant difference for methamphetamine-induced locomotor activity between control and sensitized rats [F(1,88)=13.07, p<0.01] (Fig. 1). Scheffe's post hoc test indicated significant differences between groups at 0–10, 30–40,

Discussion

There are no reports in which methamphetamine levels were measured in plasma, brain and other tissues of methamphetamine-sensitized animals, except for those using positron emission tomography (PET) in experimental animals Mizugaki et al., 1993, Numachi et al., 1992. These PET studies have demonstrated that ¹¹C-methamphetamine activity in the brain is increased in methamphetamine-sensitized animals, suggesting the importance of increased methamphetamine level in behavioral sensitization.

Acknowledgements

This work was supported by a grant-in-aid from the Ministry of Health and Welfare, Japan to T.K.

Preliminary data were presented at the Annual Meeting of the Society for Neuroscience, San Diego, 2001 and the 2001 CINP regional meeting, Hiroshima, Japan.

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Increased plasma concentration and brain penetration of methamphetamine in behaviorally sensitized rats

Abstract

Introduction

Section snippets

Animals

Methamphetamine-induced locomotor activity

Discussion

Acknowledgements

Methods

Biochim. Biophys. Acta

J. Biol. Chem.

Brain Res.

J. Pharm. Sci.

Life Sci.

Life Sci.

Brain Res., Mol. Brain Res.

Nucl. Med. Biol.

Brain Res., Brain Res. Rev.

Brain Res.

Brain Res., Brain Res. Rev.

Prog. Neuro-psychopharmacol. Biol. Psychiatry

J. Biol. Chem.

Life Sci.

J. Biol. Chem.

Brain Res.

Pharmacokinetic and clinical studies on amphetamine dependent subjects

Eur. J. Clin. Pharmacol.

Effect of short-term cyclosporine A administration on urinary acidification

Clin. Nephrol.

Urinary excretion kinetics of amphetamine in man

J. Pharm. Pharmacol.

Urinary excretion of methylamphetamine in man

Nature

Disposition and pharmacodynamics of methamphetamine in pregnant sheep

JAMA

Structure of renal organic anion and cation transporters

Am. J. Physiol., Renal Physiol.

Clinical pharmacokinetics of non-opiate abused drugs

Clin. Pharmacokinet.

Relevance of pharmacokinetic parameters in animal models of methamphetamine abuse

Synapse