Mechanism of an exaggerated locomotor response to a low-dose challenge of methamphetamine

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Abstract

Previous studies using phenylethylamine psychostimulants such as amphetamine (AMPH) have demonstrated that pretreatment with a high-dose of drug followed by a low-dose challenge injection (3 h later) results in an exaggerated behavioral response. In order to explore the mechanism of this exaggerated or what has been suggested to be a “sensitized” response, we investigated the effects of methamphetamine (METH) in a similar treatment paradigm. The current study found that, as suggested by previous studies, a low-dose challenge with METH substantially increased the locomotor response in animals that received a high-dose pretreatment (3.5 h prior to challenge). We also observed that rats displayed an increase in the concentrations of METH and its metabolite AMPH in the striatum following the low-dose challenge of METH if they were pretreated with METH versus saline. A similar pattern for METH and AMPH levels was measured in the plasma. Taken together, these results suggest that the accumulation of drug in animals pretreated with high-dose METH contributes to the overall enhanced behavioral response following challenges with low-doses of METH.

Introduction

Administration of psychostimulants (e.g. amphetamine (AMPH), methamphetamine (METH)) increases locomotor and stereotypic behaviors likely modulated by elevated extracellular dopamine (DA) in the basal ganglia and limbic regions (Kuczenski et al., 1991, Robinson and Camp, 1990, Sharp et al., 1987). Such changes in DA function have been associated with not only motor control, but control of cognitive, emotional and motivational functions as well (DiChiara et al., 2004, Gulley et al., 2004, Nordahl et al., 2003, Volkow et al., 2002).

Using a high-dose of AMPH (4.0 mg/kg) followed by a challenge with a low-dose of AMPH (0.5 mg/kg) 3 h later, appears to alter the pattern and duration of locomotor responses (Kuczenski and Segal, 1999a, Kuczenski and Segal, 1999b). Interestingly, this altered pattern of locomotor activity has been speculated to reflect changes in DA release (Kuczenski and Segal, 1989, Kuczenski and Segal, 1999a, Kuczenski and Segal, 1999b, Kuczenski et al., 1997) or brain tissue levels of AMPH (Kuczenski and Segal, 1994, Kuczenski et al., 1997). Of interest, the “typical” locomotor activity pattern following a low-dose challenge by AMPH returns if the time between the injections is increased from 3 to 5 h suggesting that DA response to the drug has returned to “normal” (Kuczenski and Segal, 1999a). Thus, Kuczenski and Segal, 1999a, Kuczenski and Segal, 1999b propose that the exaggerated response of DA systems to AMPH low-dose challenge is due to increased sensitivity of DA receptors. According to this hypothesis, the priming dose of the AMPH pretreatment temporarily sensitizes DA receptors such that locomotor responses to the concentrations of DA released following the low-dose challenge by AMPH are exaggerated (Kuczenski and Segal, 1999a, Kuczenski and Segal, 1999b).

Similar to the effects of AMPH, METH produces a dramatic increase in extracellular levels of DA in limbic and basal ganglia structures contributing to a constellation of locomotor behavioral effects. Using a similar dosing paradigm to Kuczenski and Segal, the current study tested whether a low-dose challenge of METH resulted in exaggerated locomotor responses in animals receiving a high-dose METH pretreatment 3.5 h earlier. Preliminary studies determined that METH doses of 4.0 mg/kg and a challenge of 0.4 mg/kg produced similar exaggerated levels of locomotor activity as the previous studies by Kuczenski and Segal using AMPH. In order to investigate a possible pharmacokinetic role in this phenomenon, striatal and plasma drug level of METH and its metabolite AMPH were measured at multiple time points following the challenge injection. Time points were chosen to correspond with different “phases” of locomotor activation as determined by preliminary studies in our lab and others (e.g. Kuczenski and Segal, 1999a, Kuczenski and Segal, 1999b). Our data suggest that the pharmacokinetic responses to this METH dosing paradigm may be the principal explanation for the enhanced locomotor response following a METH challenge injection administered 3.5 h after high-dose METH pretreatment.

Section snippets

Animals

Male Sprague–Dawley rats (Charles River Laboratories, Raleigh, NC) weighing between 260 to 320 g were used for the experiments. They were allowed to acclimate to the colony room for at least 2 weeks prior to experiments and were maintained in a temperature-controlled room with a 12-h light/dark cycle and were given free access to food and water. All experiments were approved by the University of Utah Institutional Animal Care and Use Committee and adhered to the National Academy of Sciences

Locomotor activity

Saline injections alone had little impact on horizontal or vertical activity (Fig. 1A and B). The three-way ANOVA yielded a significant interaction (pretreatment × challenge treatment × time) for both horizontal [F(20,669) = 2.22, p < 0.05] and vertical activity [F(20,669) = 2.00, p < 0.05]. Individual one-way ANOVAs performed at each 10-min time point indicated significant differences for horizontal activity at 20 min [F(3,31) = 14.58, p < 0.01], 30 min [F(3,31) = 15.78, p < 0.01], 40 min [F(3,31) = 14.84, p < 0.01],

Discussion

Unlike the earlier work with AMPH (Kuczenski and Segal, 1999a, Kuczenski and Segal, 1999b), the current study investigated the contribution of pharmacokinetics to the locomotor response following repeated METH treatment. Our results demonstrated an amplified locomotor response in rats pretreated by a high-dose and then challenged with a low-dose of METH such that these rats expressed a greater amount of motor activity for a longer duration. Thus, following the challenge injection of METH

Acknowledgements

This work was supported by PHS grants from NIDA, DA09407, and DA00378.

References (13)

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