Genetic deletion of MT₁and MT₂melatonin receptors differentially abrogates the development and expression of methamphetamine‐induced locomotor sensitization during the day and the night in C3H/HeN mice

Abstract

This study explored the role of the melatonin receptors in methamphetamine (METH)-induced locomotor sensitization during the light and dark phases in C3H/HeN mice with genetic deletion of theMT1 and/or MT2 melatonin receptors. Six daily treatments with METH (1.2 mg/kg, i.p.) in a novel environment during the light phase led to the development of locomotor sensitization in wild-type (WT), MT1KO and MT2KO mice. Following four full days of abstinence, METH challenge (1.2 mg/kg, i.p.) triggered the expression of locomotor sensitization in METH-pretreated but not in vehicle (VEH)-pretreated mice. In MT1/MT2KO mice, the development of sensitization during the light phase was significantly reduced and the expression of sensitization was completely abrogated upon METH challenge. During the dark phase the development of locomotor sensitization in METH-pretreated WT, MT1KO and MT2KO mice was statistically different from VEH-treated controls. However, WT and MT2KO, but not MT1KO mice receiving repeated VEH pretreatments during the dark phase expressed a sensitized response to METH challenge that is of an identical magnitude to that observed upon 6 days of METH pretreatment. We conclude that exposure to a novel environment during the dark phase, but not during the light phase, facilitated the expression of sensitization to a METH challenge in a manner dependent on MT1 melatonin receptor activation by endogenous melatonin. We suggest that MT1 and MT2 melatonin receptors are potential targets for pharmacotherapeutic intervention in METH abusers.

Genetic deletion of the MT1 or MT2 melatonin receptors abrogates methamphetamine-induced reward in C3H/HeN mice

“…The trend in all groups showed locomotor activity increasing across trial days, with significant locomotor sensitization observed in WT and MT 1 KO mice at ZT 6–8. This is consistent with our previous finding demonstrating a diurnal variation in METH–induced locomotor sensitization in C3H/HeN mice [12]. Thus we conclude that the effects of melatonin receptor deletion and time of day are specific to METH-induced reinforcing behaviors, as neither of these factors significantly altered the locomotor stimulant properties of METH at the dose tested.…”

“…Assessments were systematically conducted between ZT 6–8 and ZT 19–21, corresponding to the peak and trough of melatonin respectively [10]. Comparisons were made among genotype and between two times of day using a METH dose of 1.2mg/kg, which produces robust sensitization in the C3H/HeN mice [12]. These controls allow for accurate conclusions on the effect of melatonin receptor genotype and time of day at a single dose of METH.…”

“…Wild-type C3H/HeN mice and C3H/HeN mice homozygous for receptor deletions of the MT 1 melatonin receptor (MT 1 KO) were generated in our former laboratory at Northwestern University as previously described [12, 32]. C57Bl/6J MT 1 KO mice (donated by Dr. Steven Reppert; Massachusetts General Hospital, Boston, MA, USA) [33, 34] were backcrossed for seven generations with C3H/HeN mice (Harlan, Indianapolis, IN, USA).…”

“…This dose was chosen based on previous results showing a significant place preference to METH occurred with doses of 1 mg/kg and 2 mg/kg [39]. Furthermore, a dose of 1.2 mg/kg (ip) produced robust sensitization in wild-type C3H/HeN mice in experiments conducted in our laboratory [12]. Mice were randomly assigned to groups receiving either vehicle (VEH: 0.9% saline, ip) or METH (1.2 mg/kg, ip).…”

“…Recent studies in our laboratory have linked deletion of both the MT 1 and MT 2 receptors to a complete abrogation of methamphetamine (METH)-induced locomotor sensitization, suggesting a role for melatonin in sensitizing responses [12]. Melatonin receptors are located in various brain regions including areas of the reward pathway such as the nucleus accumbens (MT 1 ), ventral tegmental area (MT 1 ) [13], substantia nigra reticulata (MT 2 ) [14] and hippocampus (MT 2 ) [15, 16].…”