Effect of a neurotoxic dose regimen of (+)-methamphetamine on behavior, plasma corticosterone, and brain monoamines in adult C57BL/6 mice

Abstract

Rationale

In rats, neurotoxic doses of methamphetamine (MA) induce astrogliosis, long lasting monoamine reductions, reuptake transporter down-regulation, and learning impairments.

Objective

We tested whether comparable effects occur in C57BL/6 mice.

Method

C57BL/6 mice were treated with 10 mg/kg s.c. × 4 MA on a single day and evaluated at various intervals thereafter.

Results

The neurotoxic dose regimen of MA caused the predicted acute hyperthermia and increased striatal glial fibrillary acidic protein and reduced neostriatal dopamine. The MA-treated mice were hypoactive 24 h later but not 48 h later. MA-treated mice also showed exaggerated initial hyperactivity after a pharmacological dose of MA used to stimulate locomotion followed by a later phase of hypoactivity compared to saline-treated mice. No differences were observed on learning or memory tests (novel object recognition, egocentric, or spatial learning/memory). MA-treated mice showed a trend toward increased prepulse inhibition but not baseline acoustic startle reactivity. After testing, MA-treated mice showed reduced neostriatal dopamine and increased basal plasma corticosterone.

Conclusions

A neurotoxic/binge regimen of MA in mice that produces the typical pattern of neurotoxic changes to those seen in rats, results in few behavioral changes. This may limit the utility of C57BL/6 mice for modeling the cognitive and behavioral effects described in human MA users who show such changes even after prolonged abstinence.

Introduction

Chronic methamphetamine (MA) abuse results in evidence of neurotoxicity and compromised cognition [16]. Magnetic resonance imaging of chronic MA users shows increased globus pallidus and putamen and decreased hippocampal volume [17], [72]. [¹H]-Magnetic resonance spectroscopy of MA users reveals reduced N-acetylaspartate/creatine ratios in the anterior cingulate and reduced creatine in the basal ganglia [54], [63], [67]. Positron emission tomography and autopsy studies show reduced levels of striatal dopamine (DA), tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter type 2 (VMAT-2) [37], [40], [44], [73], [78]. Serotonin transporter (SERT) density is also reduced [68]. In chronic MA users, monoamine transporter changes correlate with cognitive/memory impairments [37], [73], including impairments of recall, manipulation of information, verbal and non-verbal fluency, attention, and executive function [27], [28], [33], [38], [51], [69].

Acute high-dose treatment of rats with MA results in a pattern of neurotoxicity resembling that described in human chronic MA abuse. For example, a so-called neurotoxic/binge dosing paradigm in rats results in hyperthermia [12], [14], [25], [31], neostriatal reactive gliosis based on increased expression of glial fibrillary acidic protein (GFAP) [12], [25], [31], and microgliosis [42] based on increased expression of antibodies against the CD11b receptor. Hyperthermia, increased GFAP, argyrophilia by silver staining, and microgliosis are also seen in MA-treated mice given a neurotoxic dosing regimen [23], [55], [56], [57], [69], [70]. Cell death (via increased TUNEL staining) in the striatum and hippocampus of mice following high dose MA has also been reported [19].

In rats, a neurotoxic MA treatment regimen also causes DA and 5-HT reductions in the striatum and 5-HT reductions in the hippocampus [11], [12], [15], [25], [31], [58], [76] with partial recovery over time [24]. Reductions have been observed in striatal DAT [64], TH activity [41], and VMAT-2 [22], as well as hippocampal reductions in SERT [64] and tryptophan hydroxylase activity [41]. Similarly in mice, a neurotoxic dosing regimen of MA causes reductions in TH, DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and DAT binding in striatum [36], [47] and 5-HT, DA, and HVA reductions in forebrain regions [23].

Binge/neurotoxic MA treatment regimens in rats are reported to also affect behavior. For example, a MA dosing regimen that caused DA, 5-HT, and/or DAT reductions and/or GFAP increases resulted in impaired novel object recognition and egocentric learning, but only minor reductions in locomotor activity [31], [43], [76]. In terms of spatial learning, either no [31], [64] or very small transient deficits [24] are reported.

Much less is known about behavioral effects in mice following a binge/neurotoxic regimen of MA. MA-induced dopaminergic reductions are associated with impaired conditioned place preference to cocaine and MA in Swiss Webster mice; responses which were ameliorated by N-acetylcysteine treatment [1], [2]. Otherwise, there are no studies in mice of the behavioral consequences of neurotoxic/monoamine-depleting dosing regimens of MA. For example, there are no experiments examining the effects of a binge/neurotoxic dosing regimen on spatial, egocentric, or novel object learning in mice, or on the acoustic startle response (ASR), and/or sensory gating using prepulse inhibition (PPI). Nor could experiments be identified of this kind in mice on locomotor activity in response to an acute locomotor-stimulating challenge dose of MA after prior treatment with a neurotoxic dosing regimen of MA.

The objective of the present experiment was to determine whether a binge/neurotoxic regimen of MA given to C57BL/6 mice produces patterns of behavioral changes similar to those in rats, since mice offer advantages in terms of genetic manipulations that might be useful in testing future mechanistic hypotheses if the mouse is similarly sensitive. Our model was the well-established mouse model of O'Callaghan and Miller [56], [57], [70], [71].