title: Sensitivity to Chronic Methamphetamine Administration and Withdrawal in Mice with Relaxin-3/RXFP3 Deficiency.
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.
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, Victoria, 3052, Australia.|Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Mouna
authors.initials: M
authors.lastname: Haidar
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, Victoria, 3052, Australia.|Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Victoria, Australia.|Faculty of Health Sciences, La Trobe University, Bundoora, Victoria, Australia.
authors.forename: Monica
authors.initials: M
authors.lastname: Lam
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, Victoria, 3052, Australia.|INC Research, Oakleigh, Victoria, Australia.
authors.forename: Berenice E
authors.initials: BE
authors.lastname: Chua
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, Victoria, 3052, Australia.|Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Smith
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, Victoria, 3052, Australia. andrew.gundlach@florey.edu.au.|Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia. andrew.gundlach@florey.edu.au.|Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Victoria, Australia. andrew.gundlach@florey.edu.au.
authors.forename: Andrew L
authors.identifier: http://orcid.org/0000-0002-6066-9692
authors.initials: AL
authors.lastname: Gundlach
mesh_terms: D059445:Anhedonia / Q000187:drug effects; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000523:psychology; D001835:Body Weight / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D008694:Methamphetamine / Q000009:adverse effects*; D051379:Mice; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D012065:Relaxin / Q000235:genetics*; D012919:Social Behavior; D013375:Substance Withdrawal Syndrome / Q000235:genetics / Q000523:psychology*
chemical_list: D000697:Central Nervous System Stimulants; D043562:Receptors, G-Protein-Coupled; C505050:SALPR protein, mouse; C512898:relaxin-3 protein, mouse; D008694:Methamphetamine; D012065:Relaxin
keywords: Arousal; Knockout mice; Methamphetamine; Monoamines; Relaxin-3; Rxfp3