Role of [MT.sub.1] melatonin receptors in methamphetamine-induced locomotor sensitization in C57BL/6 mice

• Published in: Psychopharmacology 2014-01, Vol.231 (1), p.257
• Main Authors: Hutchinson, Anthony J, Ma, Jason, Liu, Jiabei, Hudson, Randall L, Dubocovich, Margarita L
• Format: Article
• Language: English
• Subjects: Complications and side effects; Dosage and administration; Drug abuse; Drug therapy; Genetic aspects; Melatonin; Methamphetamine; Physiological aspects
• ISSN: 0033-3158
• DOI: 10.1007/s00213-013-3228-0

Rationale Melatonin modifies physiological and behavioral responses to psychostimulants, with the [MT.sub.1] and [MT.sub.2] melatonin receptors specifically implicated in facilitating methamphetamine (METH)-induced sensitization in melatonin-proficient mice. Objective The objective of the study is to assess differences in locomotor sensitization after a single dose of methamphetamine in low-melatonin-expressing C57BL/6 wild-type and [MT.sub.1] receptor knockout ([MT.sub.1]KO) mice, comparing with melatonin-expressing C3H/HeN mice. Methods Mice received a vehicle or methamphetamine (1.2 mg/kg, i.p.) pretreatment (day 1) during the light (ZT5-9) or dark (ZT 19-21) periods in novel test arenas. Locomotor sensitization was assessed by methamphetamine challenge after an eight-day abstinence (day 9). TH protein expression was evaluated by immunofluorescence and Western blot analysis. Results Methamphetamine pretreatment induced statistically significant locomotor sensitization upon challenge after eight-day abstinence in C3H and C57 wild-type mice during the light period. The magnitude of sensitization in C57 mice was diminished in the dark period and completely abrogated in [MT.sub.1]KO mice. No differences were observed in tyrosine hydroxylase immunoreactivity in the mesolimbic dopamine system. Additional exposures to the test arenas after methamphetamine pretreatment (nights 2-6) enhanced sensitization. Conclusions Deletion of the [MT.sub.1] melatonin receptor abolishes sensitization induced by a single METH pretreatment. The magnitude of sensitization is also altered by time of day and contextual cues. We conclude that the [MT.sub.1] melatonin receptor is emerging as a novel target of therapeutic intervention for drug abuse disorders. Keywords Melatonin * [MT.sub.1] melatonin receptor * Methamphetamine * Sensitization * C57BL/6 mouse