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Dissociations between cognitive and motor effects of psychostimulants and atomoxetine in hyperactive DAT-KO mice

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Abstract

Rationale

Psychostimulants such as amphetamine and methylphenidate, which target the dopamine transporter (DAT), are the most frequently used drugs for the treatment of hyperactivity and cognitive deficits in humans with attention deficit hyperactivity disorder (ADHD). While psychostimulants can increase activity in healthy subjects, they exert a “paradoxical” calming effect in humans with ADHD as well as in hyperactive mice lacking the dopamine transporter (DAT-KO mice). However, the mechanism of action of these drugs and their impact on cognition in the absence of DAT remain poorly understood.

Objectives

This study was conducted to investigate the effects of psychostimulants and noradrenergic and serotonergic drugs on cognition in DAT-KO mice and normal (WT) littermates.

Methods

We used a recently developed behavioral apparatus, the automated H-maze. The H-maze involves the consecutive learning of three different rules: delayed alternation, nonalternation, and reversal tasks.

Results

Treatment of WT animals with the psychostimulants replicated the behavior observed in untreated DAT-KO mice while “paradoxically” restoring cognitive performances in DAT-KO mice. Further investigation of the potential involvement of other monoamine systems in the regulation of cognitive functions showed that the norepinephrine transporter blocker atomoxetine restored cognitive performances in DAT-KO mice without affecting hyperactivity. In contrast, the nonselective serotonin receptor agonist 5CT, which antagonizes hyperactivity in DAT-KO mice, had no effect on cognitive functions.

Conclusions

Taken together, these data allow dissociation of the locomotor and cognitive effects of ADHD drugs and suggest that the combination of DAT-KO mice with the automated H-maze can constitute a powerful experimental paradigm for the preclinical development of therapeutic approaches for ADHD.

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Acknowledgments

We thank Nathalie Bouchard and Kathye Aubé for assistance maintaining mouse colonies, Hugues Dufour for assembling the H-maze, and Francis Lemay for his corrections of the manuscript. T.D. is a recipient of fellowships from the CRCN. M.L. and S. M. are recipients of Fonds de la Recherche en Santé du Québec (FRSQ) postdoctoral fellowships. L.A.V.M is a postdoctoral fellow of The Brazilian National Council of Scientific and Technological Development (CNPq). J.M.B. is NARSAD Vital Projects Fund, Inc. investigator and Canada Research Chair in Molecular Psychiatry. This work was supported by a Canadian Institute of Health Research (CIHR) operating grant (NSA 93798) to J.M.B and a FRSQ project for innovative strategic development.

Conflict of interest

The authors declare no competing interests.

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Authors and Affiliations

  1. Département de psychiatrie et de neurosciences, Faculté de médecine, Université Laval, Pavillon Ferdinand-Vandry, 1050, avenue de la Médecine, Québec City, QC, Canada

    Thomas Del’Guidice, Morgane Lemasson, Adeline Etiévant, Stella Manta, Luiz Alexandre V. Magno & Jean-Martin Beaulieu

  2. Institut universitaire en santé mentale de Québec, 2601, chemin de la canardière, Suite F-6500, Québec City, QC, G1J 2G3, Canada

    Thomas Del’Guidice, Morgane Lemasson, Adeline Etiévant, Stella Manta, Luiz Alexandre V. Magno & Jean-Martin Beaulieu

  3. Aix-Marseille Université/CNRS UMR7259–NICN–Neurobiologie des Processus Mnésiques, Centre Saint Charles, 13344, Marseille, France

    Guy Escoffier & François S. Roman

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  1. Thomas Del’Guidice
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Correspondence to Jean-Martin Beaulieu.

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Figure S1

The lack of the DA transporter in DAT-KO mice does not affect olfactory perception. (A-B) Comparison of the odor detection threshold of WT and HO DAT-KO mice for the two odors isoamyl acetate and octanol. Normalized values are expressed as the mean ratio of the time spent investigating the odor and the total sniffing time (i.e., odor plus mineral oil). Data are presented as mean ± SEM (n = 8 mice per group). (JPEG 73 kb)

High resolution image (TIFF 4396 kb)

Figure S2

Cognitive effect of different AMPH doses in WT mice. (A-E) Trials-to-reach the success criterion in (A) the ALT, (C) N-ALT and (E) REV task after treatment with vehicle, 0.2 mg/kg, 1 mg/kg or 2 mg/kg, i.p. amphetamine (AMPH). (B-F) Proportion (across trials) of successful animals in (B) the ALT, (D) N-ALT and (F) REV task. Data are presented as means ± SEM. Fractions below each bars indicate the proportion of mice that completed each task. *, **, p ≤ 0.05, p ≤ 0.01. One-way ANOVA test with Newman’s Keuls post-hoc tests. (JPEG 73 kb)

High resolution image (TIFF 634 kb)

Figure S3

CP809.101 did not improve cognitive functions in DAT-KO mice and did not abolish hyperactivity. (A-B) Example of the representative performance of a CP809.101-treated (1 mg/kg, i.p.) (A) WT (B) HO mice that reached the three criteria of 4 consecutive correct trials for each rule. (C-D) Trials-to-criterion and time performed by WT and HO mice in the alternation (ALT), the non-alternation (N-ALT) and the reversal (REV) tasks after acute treatments with CP809,101. (E-F) Proportion (across trials) of successful WT and HO animals in the three tasks after CP809.101 treatment. Data are presented as means ± SEM. Fractions below each bars indicate the proportion of mice that completed each task. *, ** and ***p ≤ 0.05, p ≤ 0.01 and p ≤ 0.001. Two Way ANOVA followed by Bonferroni post-hoc tests. (JPEG 97 kb)

High resolution image (TIFF 661 kb)

Figure S4

ATX does not change locomotor activity of DAT-KO mice. Novelty-induced locomotor activity of DAT-KO mice in an open field after one injection of saline (0,9 % of NaCl solution) or ATX treatment (1 mg/kg, i.p.) 30 min after the test begins. Locomotor activity was measured as the horizontal activity performed for 90 min. (JPEG 61 kb)

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Del’Guidice, T., Lemasson, M., Etiévant, A. et al. Dissociations between cognitive and motor effects of psychostimulants and atomoxetine in hyperactive DAT-KO mice. Psychopharmacology 231, 109–122 (2014). https://doi.org/10.1007/s00213-013-3212-8

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