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Sensitivity to Chronic Methamphetamine Administration and Withdrawal in Mice with Relaxin-3/RXFP3 Deficiency

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Abstract

Methamphetamine (METH) is a highly addictive psychostimulant, and cessation of use is associated with reduced monoamine signalling, and increased anxiety/depressive states. Neurons expressing the neuropeptide, relaxin-3 (RLN3), and its cognate receptor, RXFP3, constitute a putative ‘ascending arousal system’, which shares neuroanatomical and functional similarities with serotonin (5-HT)/dorsal raphe and noradrenaline (NA)/locus coeruleus monoamine systems. In light of possible synergistic roles of RLN3 and 5-HT/NA, endogenous RLN3/RXFP3 signalling may compensate for the temporary reduction in monoamine signalling associated with chronic METH withdrawal, which could alter the profile of ‘behavioural despair’, bodyweight reductions, and increases in anhedonia and anxiety-like behaviours observed following chronic METH administration. In studies to test this theory, Rln3 and Rxfp3 knockout (KO) mice and their wildtype (WT) littermates were injected once daily with saline or escalating doses of METH (2 mg/kg, i.p. on day 1, 4 mg/kg, i.p. on day 2 and 6 mg/kg, i.p. on day 3–10). WT and Rln3 and Rxfp3 KO mice displayed an equivalent sensitivity to behavioural despair (Porsolt swim) during the 2-day METH withdrawal and similar bodyweight reductions on day 3 of METH treatment. Furthermore, during a 3-week period after the cessation of chronic METH exposure, Rln3 KO, Rxfp3 KO and corresponding WT mice displayed similar behavioural responses in paradigms that measured anxiety (light/dark box, elevated plus maze), anhedonia (saccharin preference), and social interaction. These findings indicate that a whole-of-life deficiency in endogenous RLN3/RXFP3 signalling does not markedly alter behavioural sensitivity to chronic METH treatment or withdrawal, but leave open the possibility of a more significant interaction with global or localised manipulations of this peptide system in the adult brain.

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Acknowledgments

This research was supported by National Health and Medical Research Council of Australia Project Grants 1005988 and 1024885 (ALG), grants from the Pratt and Besen Family Foundation (ALG), a Brain & Behavior Research Foundation (USA) NARSAD Independent Investigator Award (ALG), and the Victorian Government Operational Infrastructure Support Programme. MH is the recipient of a postgraduate scholarship from the Alzheimer’s Australia Dementia Research Foundation. The authors thank Timothy Lovenberg and Steve Sutton (Janssen Companies of Johnson & Johnson, San Diego, CA, USA) for commissioning and providing the original Rln3 and Rxfp3 knockout mice.

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The authors declare that they have no conflict of interest.

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Correspondence to Andrew L. Gundlach.

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Special Issue: In Honor of Dr. Philip Beart.

Craig M. Smith and Andrew L. Gundlach jointly supervised this research.

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Haidar, M., Lam, M., Chua, B.E. et al. Sensitivity to Chronic Methamphetamine Administration and Withdrawal in Mice with Relaxin-3/RXFP3 Deficiency. Neurochem Res 41, 481–491 (2016). https://doi.org/10.1007/s11064-015-1621-2

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  • DOI: https://doi.org/10.1007/s11064-015-1621-2

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