Effect of (+)-methamphetamine on path integration learning, novel object recognition, and neurotoxicity in rats

Abstract

Rationale-Methamphetamine (MA) has been implicated in cognitive deficits in humans after chronic use. Animal models of neurotoxic MA exposure reveal persistent damage to monoaminergic systems, but few associated cognitive effects.Objectives-Since, questions have been raised about the typical neurotoxic dosing regimen used in animals and whether it adequately models human cumulative drug exposure, these experiments examined two different dosing regimens.Methods-Rats were treated with one of two regimens, one the typical neurotoxic regimen (4 × 10 mg/kg every 2 h) and one based on pharmacokinetic modeling (Cho et al. 2001) designed to better represent accumulating plasma concentrations of MA as seen in human users (24 ×1.67 mg/kg once every 15 min); matched for total daily dose. In two separate experiments, dosing regimens were compared for their effects on markers of neurotoxicity or on behavior.Results-On markers of neurotoxicity, MA showed decreased DA and 5-HT, and increased glial fibrillary acidic protein and increased corticosterone levels regardless of dosing regimen 3 days posttreatment. Behaviorally, MA-treated groups, regardless of dosing regimen, showed hypoactivity, increased initial hyperactivity to a subsequent MA challenge, impaired novel object recognition, impaired learning in a multiple-T water maze test of path integration, and no differences on spatial navigation or reference memory in the Morris water maze. After behavioral testing, reductions of DA and 5-HT remained.Conclusions-MA treatment induces an effect on path integration learning not previously reported. Dosing regimen had no differential effects on behavior or neurotoxicity.

The Effect of Prenatal Methamphetamine Exposure on Recognition Memory in Adult Rats

“…As matter of cognitive functions, our studies showed that prenatal MA exposure alone does not affect cognitive functions and that MA application in adulthood impairs learning in the Morris water maze regardless of prenatal exposure, which did not support the assumption of prenatal sensitization to drugs in adulthood (Schutová et al, 2008(Schutová et al, , 2009b. On the contrary, studies of others found impairing effects in learning and memory of prenatally MA-exposed adult offspring (Acuff-Smith et al, 1996;Williams et al, 2003;Herring et al, 2008). As the opinions on the sensitization of prenatal MA exposure vary, the present study focused on two aims.…”

An Evaluation of the Evidence that Methamphetamine Abuse Causes Cognitive Decline in Humans

“…When assessed at least 1 week after MA administration, rats and mice that are administered large, binge doses of MA (X4 mg/kg per dose, often multiple times per day) exhibit deficits in several cognitive domains, including object recognition memory (Belcher et al, 2005;Siegel et al, 2010), odor recognition memory (O'Dell et al, 2011), spatial learning (Acevedo et al, 2007;Vorhees et al, 2009), sequential learning (Chapman et al, 2001;Daberkow et al, 2005), path integration learning (Herring et al, 2008), working memory (Mizoguchi et al, 2011), effort discounting (similar to delay discounting) (Kosheleff et al, 2012), and reversal learning (Izquierdo et al, 2010).…”

Spontaneous object recognition and its relevance to schizophrenia: a review of findings from pharmacological, genetic, lesion and developmental rodent models

“…In rodents, methamphetamine consistently impairs SOR (Table 1). An acute dose reduced novel object exploration with delays ranging across studies from 1 h to 24 h (1 h, Herring et al 2008;1.5 h and 24 h, Schroder et al 2003;1.5 h, Belcher et al 2008;2 h, Camarasa et al 2010). However, subchronic methamphetamine impaired SOR with a 24-h delay (Kamei et al 2006;Noda et al 2010) but had no effect with a 1-h delay (Kamei et al 2006).…”

“…Methamphetamine has been shown to reduce radioligand binding of dopamine and the dopamine reporter DAT in the striatum, as well as serotonin and the serotonin transporter SERT in the hippocampus and perirhinal cortex (Schroder et al 2003;Herring et al 2008;Belcher et al 2008). The effects of methamphetamine may also impinge upon the glutamatergic and cholinergic systems: a methamphetamineinduced deficit could be rescued by pretreatment with the NMDA and α7-nicotinic acetylcholine receptor (α7-nAChR) antagonist, memantine (2 h, Camarasa et al 2010), although the mechanism behind this effect is unknown.…”