Genetic Deletion of the MT2 Melatonin Receptor Induces an Alternating Pattern of Locomotor Activity in Methamphetamine‐Sensitized C3H‐HeN mice

Repeated psychostimulant exposures cause locomotor sensitization, a long‐term enhancement of locomotor responses. This project probed the roles of the MT 1 and MT 2 melatonin receptors on the activity of methamphetamine (MTA)‐sensitized mice at slow (0–20 mm/s), intermediate (20–100 mm/s), and fast (>100 mm/s) speeds. Wild‐type (WT) C3H‐HeN mice and knockouts (KO) lacking the MT 1 and/or MT 2 receptors (MT 1 KO, MT 2 KO and MT 1 /MT 2 KO) were sensitized by 6 daily MTA treatments, 1.2 mg/kg i.p.), then tested for sensitization by measuring distance traveled following a MTA challenge. WT mice expressed most of their activity within the intermediate speed range (136.9±28.8 m traveled) when compared to slow (62.1±2.3 m) and fast (13.4±3.8 m) ranges during the day (ZT 5–7, ZT 0=lights on). In contrast, MT 2 KO mice expressed significantly higher activity in the slow (148.5±16.9 m, n=5, p <0.05) and fast (34.7±13.5 m, n=5, p <0.05) ranges than did the WT, MT 1 KO (slow: 63.9±2.9 m; fast: 16.1±3.9 m, n=8) and MT 1 /MT 2 KO (slow: 56.8±4.6 m; fast: 10.8±3.8 m, n=7) mice. In WT mice, activity patterns were not altered at night (ZT 19–21) or by melatonin co‐treatments. The data indicate that the MT 1 receptor causes the mice to alternate between bursts of high‐speed motion and periods of little or no motion at all. In contrast, the MT 2 receptor may favor a locomotor response to MTA at sustained intermediate speeds. Supported by DA 021870 to MLD.