Methamphetamine-induced dopaminergic deficits and refractoriness to subsequent treatment

Abstract

Repeated high-dose methamphetamine administrations can cause persistent dopaminergic deficits. As individuals abusing methamphetamine are often exposed to recurrent high-dose administration, the impact of its repeated exposure merits investigation. Accordingly, rats were pretreated with repeated high-dose injections of methamphetamine, and subsequently “challenged” with the same neurotoxic regimen 7 or 30 days later. Results revealed that the initial methamphetamine treatment caused persistent deficits in striatal dopamine levels, dopamine transporter function, and vesicular monoamine transporter-2 function. The subsequent methamphetamine challenge treatment was without further persistent effects on these parameters, as assessed 7 days after the challenge, regardless of the interval (7 or 30 days) between the initial and challenge drug exposures. Similarly, a methamphetamine challenge treatment administered 7 days after the initial drug treatment was without further acute effect on dopamine transporter or VMAT-2 function, as assessed 1 h later. Thus, this study describes a model of resistance, possibly explained by: 1) the existence of dopaminergic neurons that are a priori refractory to deficits caused by methamphetamine; 2) the existence of dopaminergic neurons made persistently resistant consequent to a neurotoxic methamphetamine exposure; and/or 3) altered activation of post-synaptic basal ganglia systems necessary for the elaboration of methamphetamine-induced dopamine neurotoxicity.

Introduction

Previous studies have demonstrated that repeated high-dose administrations of methamphetamine cause persistent dopaminergic neuronal deficits in rodents, non-human primates and humans. For example, high-dose methamphetamine administration is associated with long-term striatal reduction in: 1) dopamine levels (Kogan et al., 1976, Ricaurte et al., 1980, Wagner et al., 1980, Woolverton et al., 1989); 2) dopamine transporter (Wagner et al., 1980, Guilarte et al., 2003) and vesicular monoamine transporter-2 (VMAT-2) levels (Guilarte et al., 2003); and 3) tyrosine hydroxylase activity (Kogan et al., 1976, Hotchkiss et al., 1979). In addition to these persistent deficits, repeated methamphetamine administrations rapidly (within 1 h) reduce striatal dopamine transporter activity, as measured in synaptosomes obtained from treated rats (Fleckenstein et al., 1997, Kokoshka et al., 1998). Methamphetamine treatment also decreases striatal VMAT-2 activity acutely, as measured ex vivo in a cytoplasmic (non-membrane associated) vesicular subcellular fraction prepared from treated rats (Brown et al., 2000); an outcome presumptively linked with a redistribution of VMAT-2 protein within nerve terminals (Riddle et al., 2002; for review, see also Fleckenstein et al., 2007 and references contained therein).

Many laboratories have investigated the impact of repeated methamphetamine injections in rodent models. However, relatively few studies have investigated the impact of repeated “binge-like” methamphetamine treatments. This is an important clinical issue since many individuals who abuse methamphetamine are subjected to multiple “binge” episodes, each of which includes exposure to several high-dose administrations of drug. Noteworthy, one study by Thomas and Kuhn (2005) has investigated this issue. In particular, mice were treated with a high-dose, “neurotoxic” methamphetamine regimen and “challenged” 7 days later with a second “binge-like” exposure. Results revealed that the first methamphetamine treatment decreased striatal dopamine tissue content, and dopamine levels were not further depleted by the second methamphetamine exposure. In addition, the second methamphetamine treatment did not provoke a subsequent microglial response when the mice were pretreated with the first “neurotoxic” methamphetamine regimen, regardless of the interval between methamphetamine exposures (7 vs. 30 days). Importantly, dopamine levels and microglial assessments in those studies were assessed 2 days after the second methamphetamine exposure, and these investigators suggested that the microglial activation “precedes and contributes to methamphetamine-induced nerve ending damage.”

Given the importance of understanding the impact of repeated methamphetamine exposures, the purpose of the present study, like that of Thomas and Kuhn (2005), was to assess the effect of pretreatment with a “binge-like” methamphetamine regimen on subsequent responses of striatal dopaminergic systems to a second “challenge” with multiple high-dose administrations of the stimulant. In contrast to this previous report, the current study focused on the response of the dopamine transporter and VMAT-2 both acutely (1 h) after the second treatment and 7 days later (i.e., a time point typically used to assess the expression of toxicity because dopamine terminals have presumably been severely damaged or lost by this time). Results revealed that the first treatment regimen caused persistent deficits in dopamine levels, as well as in dopamine transporter and VMAT-2 function. However, a subsequent methamphetamine challenge treatment was without further persistent effects on these parameters, regardless of the interval between exposures. Similarly, a subsequent methamphetamine challenge treatment administered 7 days after the initial drug treatment was without further acute effects on dopamine transporter or VMAT-2 function, as assessed 1 h later. This model of resistance is unique relative to at least one other model wherein apparent tolerance to the effects of a neurotoxic methamphetamine regimen is transient (e.g., Danaceau et al., 2007), and can be explained by either: 1) the existence of a population of dopaminergic neurons that is a priori resistant to the persistent deficits caused by methamphetamine; 2) the existence of a population of dopaminergic neurons made resistant as a consequence of exposure to a neurotoxic regimen of methamphetamine; and/or 3) altered activation of post-synaptic basal ganglia systems necessary for the elaboration of methamphetamine-induced monoamine neurotoxicity. Identification of this phenomenon may facilitate understanding the neurobiological mechanisms underlying persistently altered behaviors observed as a consequence of methamphetamine-induced monoamine neurotoxicity.