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Role of MT1 melatonin receptors in methamphetamine-induced locomotor sensitization in C57BL/6 mice

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Abstract

Rationale

Melatonin modifies physiological and behavioral responses to psychostimulants, with the MT1 and MT2 melatonin receptors specifically implicated in facilitating methamphetamine (METH)-induced sensitization in melatonin-proficient mice.

Objective

The objective of the study is to assess differences in locomotor sensitization after a single dose of methamphetamine in low-melatonin-expressing C57BL/6 wild-type and MT1 receptor knockout (MT1KO) mice, comparing with melatonin-expressing C3H/HeN mice.

Methods

Mice received a vehicle or methamphetamine (1.2 mg/kg, i.p.) pretreatment (day 1) during the light (ZT5-9) or dark (ZT 19–21) periods in novel test arenas. Locomotor sensitization was assessed by methamphetamine challenge after an eight-day abstinence (day 9). TH protein expression was evaluated by immunofluorescence and Western blot analysis.

Results

Methamphetamine pretreatment induced statistically significant locomotor sensitization upon challenge after eight-day abstinence in C3H and C57 wild-type mice during the light period. The magnitude of sensitization in C57 mice was diminished in the dark period and completely abrogated in MT1KO mice. No differences were observed in tyrosine hydroxylase immunoreactivity in the mesolimbic dopamine system. Additional exposures to the test arenas after methamphetamine pretreatment (nights 2–6) enhanced sensitization.

Conclusions

Deletion of the MT1 melatonin receptor abolishes sensitization induced by a single METH pretreatment. The magnitude of sensitization is also altered by time of day and contextual cues. We conclude that the MT1 melatonin receptor is emerging as a novel target of therapeutic intervention for drug abuse disorders.

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Acknowledgments

The authors would like to thank Iwona Stepien, Kathleen McGowan, and Peter Crombe for their capable assistance with animal management and genotyping, and equipment maintenance.

Author contributions

All authors contributed to the conception, design, planning, data acquisition, and/or analysis of these studies. AJH drafted the manuscript which was revised and edited with substantial feedback from all authors. All authors approved the final version of the manuscript before submission.

Conflict of interest

This work was funded by R01DA021870 to MLD. The authors declare that over the last three years, MLD was a consultant for and received compensation from Takeda Pharmaceutical North America Inc.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, 3435 Main Street (Farber Hall 102), Buffalo, NY, 14221, USA

    Anthony J. Hutchinson, Jason Ma, Jiabei Liu & Margarita L. Dubocovich

  2. Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, University at Buffalo, 3435 Main Street, Buffalo, NY, 14221, USA

    Randall L. Hudson

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  1. Anthony J. Hutchinson
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Corresponding author

Correspondence to Margarita L. Dubocovich.

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Supplemental Figure 1

Locomotor Responses in C57 Mice Subjected to Six Daily VEH or METH Pretreatments. Experimental protocol is shown in Panel A. Ordinates on the line graphs represent distance traveled (mean ± SEM) in 2h tests as a function of Pretreatment Day (B) and in 5 min intervals as a function of time during the challenge test on Day 11 (C). *p < 0.05 when compared to VEH; ns denotes not significant. (JPEG 56 kb)

High resolution image (TIFF 185 kb)

Supplemental Figure 2

TH Immunofluorescence in the Mesolimbic Dopamine System of C57 WT and MT1KO Mice. Representative images show CPu, NAc core, NAc shell and VTA for C57 WT (A–D) and MT1KO mice (E–H). TH protein expression was evaluated by fluorescence intensity (mean gray value, mean ± SEM) in the CPu, NAc core and NAc shell (I–K). Density of TH-positive cell bodies (mean ± SEM) was assessed in the VTA (L). Scale bar in Panel A corresponds to all CPu and NAc images. No significant (ns) differences were found between WT (n = 4) and MT1KO mice (n = 4). (JPEG 63 kb)

High resolution image (TIFF 15615 kb)

Supplemental Figure 3

TH Protein Levels in the Mesolimbic Dopamine System. Western blot analysis of brain homogenates from C57 WT (n = 8) and MT1KO mice (n = 8). Representative blot images are shown for CPu (A), NAc (B) and VTA (C) with corresponding semiquantitative densitometry analyses. Ordinates represent relative mean ± SEM of TH band intensity normalized to corresponding GAPDH values. No significant (ns) differences were observed between genotypes. (JPEG 42 kb)

High resolution image (TIFF 424 kb)

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Hutchinson, A.J., Ma, J., Liu, J. et al. Role of MT1 melatonin receptors in methamphetamine-induced locomotor sensitization in C57BL/6 mice. Psychopharmacology 231, 257–267 (2014). https://doi.org/10.1007/s00213-013-3228-0

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  • DOI: https://doi.org/10.1007/s00213-013-3228-0

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