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Netrin-1 receptor-deficient mice show age-specific impairment in drug-induced locomotor hyperactivity but still self-administer methamphetamine

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Abstract

Rationale

The mesocorticolimbic dopamine system undergoes significant reorganization of neuronal connectivity and functional refinement during adolescence. Deleted in colorectal cancer (DCC), a receptor for the guidance cue netrin-1, is involved in this reorganization. Previous studies have shown that adult mice with a heterozygous (het) loss-of-function mutation in DCC exhibit impairments in sensitization and conditioned place preference (CPP) to psychostimulants. However, the commonly abused psychostimulant methamphetamine (METH) has not been assessed, and the role of DCC in drug self-administration remains to be established.

Objectives

Using dcc het mice and wildtype (WT) littermates, we extended previous findings on dcc haplodeficiency by examining self-administration of METH in adult mice, including cue-induced drug seeking following abstinence. We also examined hyperactivity, sensitization, and CPP to a METH-paired context in adult and adolescent mice.

Results

While adult dcc het mice expressed largely similar METH self-administration and cue-induced drug seeking as WT littermates, they failed to modulate responding according to dose of METH. Compared to WT, both adult and adolescent dcc het mice expressed impaired locomotor hyperactivity to acute METH but nevertheless showed comparable behavioral sensitization. Conditioned hyperactivity increased with age in WT but not in dcc het mice.

Conclusions

Impaired METH-induced hyperactivity and dose-related responding in adult dcc het mice suggest that reduced DCC alters METH-related behaviors. Adolescence is identified as a vulnerable period during which impairment in hyperactivity due to reduced DCC can be overcome with repeated METH injections. Nevertheless, DCC appears to have a somewhat limited role in METH-consumption and seeking following abstinence.

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Authors and Affiliations

  1. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, 3010, VIC, Australia

    Jee Hyun Kim, Doron Lavan, Nicola Chen & Andrew J. Lawrence

  2. Department of Psychiatry, McGill University, Montreal, Quebec, H3A 1A1, Canada

    Cecilia Flores

  3. Queensland Brain Institute, The University of Queensland, Brisbane, 4072, QLD, Australia

    Helen Cooper

Authors
  1. Jee Hyun Kim
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  2. Doron Lavan
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  3. Nicola Chen
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  4. Cecilia Flores
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  5. Helen Cooper
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  6. Andrew J. Lawrence
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Corresponding author

Correspondence to Andrew J. Lawrence.

Additional information

Jee Hyun Kim and Doron Lavan contributed equally to this work.

Funded by National Health and Medical Research Council (NHMRC) Project Grant APP1022201 to AJL and JHK. AJL is an NHMRC PRF while JHK is an Australian Research Council DECRA Fellow. The Victorian Government’s Operational Infrastructure Support Program is gratefully acknowledged. HMC was supported by a Queensland Government Smart Futures Fellowship.

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Kim, J.H., Lavan, D., Chen, N. et al. Netrin-1 receptor-deficient mice show age-specific impairment in drug-induced locomotor hyperactivity but still self-administer methamphetamine. Psychopharmacology 230, 607–616 (2013). https://doi.org/10.1007/s00213-013-3187-5

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  • DOI: https://doi.org/10.1007/s00213-013-3187-5

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