Role of MT1 melatonin receptors in methamphetamine-induced locomotor sensitization in C57BL/6 mice.
BACKGROUND
Melatonin modifies physiological and behavioral responses to psychostimulants, with the MT₁ and MT₂ 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 MT₁ receptor knockout (MT₁KO) 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 MT₁KO 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 MT₁ 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 MT₁ melatonin receptor is emerging as a novel target of therapeutic intervention for drug abuse disorders.
Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, 3435 Main Street (Farber Hall 102), Buffalo, NY, 14221, USA.
Anthony J
AJ
Hutchinson
Jason
J
Ma
Jiabei
J
Liu
Randall L
RL
Hudson
Margarita L
ML
Dubocovich
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002940:Circadian Rhythm / Q000187:drug effects; D003624:Darkness; D008027:Light; D008297:Male; D008550:Melatonin / Q000235:genetics / Q000378:metabolism; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D044122:Receptor, Melatonin, MT1 / Q000187:drug effects* / Q000235:genetics; D013045:Species Specificity; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000697:Central Nervous System Stimulants; D044122:Receptor, Melatonin, MT1; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase; D008550:Melatonin