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

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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.

Materials and methods

Rats were treated with one of the two regimens: one based on the typical neurotoxic regimen (4 × 10 mg/kg every 2 h) and one based on pharmacokinetic modeling (Cho AK, Melega WP, Kuczenski R, Segal DS Synapse 39:161–166, 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 dopamine (DA) and 5-HT, increased glial fibrillary acidic protein, and increased corticosterone levels regardless of dosing regimen 3 days post-treatment. 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.

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Acknowledgments

Portions of these data were presented at the 15th Annual Meeting of the International Behavioral Neuroscience Society meeting (May, 2006) in Whistler, BC and at the 7th International Brain Research Organization meeting (July, 2007) in Melbourne, Australia. Research supported by the Scottish Rite Schizophrenia Fellowship and grants from the National Institutes of Health: DA 006733 and DA014269.

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Authors and Affiliations

  1. Division of Neurology (MLC 7044), Cincinnati Children’s Research Foundation, 3333 Burnet Ave., Cincinnati, OH, 45229-3039, USA

    Nicole R. Herring, Tori L. Schaefer, Charles V. Vorhees & Michael T. Williams

  2. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Nicole R. Herring, Tori L. Schaefer, Charles V. Vorhees & Michael T. Williams

  3. James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA

    Gary A. Gudelsky

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  1. Nicole R. Herring
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  2. Tori L. Schaefer
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  3. Gary A. Gudelsky
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  4. Charles V. Vorhees
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  5. Michael T. Williams
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Corresponding authors

Correspondence to Charles V. Vorhees or Michael T. Williams.

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Herring, N.R., Schaefer, T.L., Gudelsky, G.A. et al. Effect of (+)-methamphetamine on path integration learning, novel object recognition, and neurotoxicity in rats. Psychopharmacology 199, 637–650 (2008). https://doi.org/10.1007/s00213-008-1183-y

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  • DOI: https://doi.org/10.1007/s00213-008-1183-y

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