Sensitivity to chronic methamphetamine administration and withdrawal in mice with relaxin-3/RXFP3 deficiency

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.