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.

Methamphetamine Induces Anhedonic‐Like Behavior and Impairs Frontal Cortical Energetics in Mice

“…Overall, these results are consistent with a recent study suggesting a depressivelike state rather than an anxiety-like state during METH-early withdrawal using a rat self-administration model [32]. Moreover, Haidar et al [33] showed that female C57BL6 mice subjected to chronic METH regimen exhibited behavioral despair during the first 48 h of withdrawal without evident anhedonic-like (SPT) and anxiety-like behaviors (measured by SPT and EPM, respectively). The lack of alterations during the performance of the open field and pole test indicates that the METH-exposed animals have normal motor function; thus, ruling out that putative motor deficits may be responsible for the observed depressive-like behavior.…”

LiCl Pretreatment Ameliorates Adolescent Methamphetamine Exposure-Induced Long-Term Alterations in Behavior and Hippocampal Ultrastructure in Adulthood in Mice

“…Adolescent METH exposure can induce emotional, behavioral, and cognitive deficits, but not all the deficits last for a long time (Hayase et al, 2005; McGregor et al, 2005; Haidar et al, 2016; Fonseca et al, 2017; Thompson et al, 2017). Based on our results, adolescent METH exposure-induced working memory deficits in the Y-maze spontaneous alternation test and anxiety-like behavior in the EPM test spontaneously recovered after long-term METH abstinence; reduced novel spatial exploration was observed both in adolescence and subsequent adulthood; and mild hyperactivity and impaired social recognition memory were found only in subsequent adulthood.…”

Investigating the Role of Serotonin in Methamphetamine Psychosis: Unaltered Behavioral Effects of Chronic Methamphetamine in 5-HT1A Knockout Mice

“…Previously, effects of chronic Meth pretreatment on anxiety have been variable. For example, a 10-day escalating dose protocol in mice induced no changes in anxiety measures in the EPM or light/dark box (48) while studies in rats showed increased anxiety or no change in the EPM depending on the age or extent of Meth exposure or time following exposure (49–51). These results suggest that dosing and testing protocol are very important for long-term effects of Meth on behavior.…”