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

Abstract

The drug of abuse methamphetamine (METH) is known for its ability to enhance reward responses. The rewarding properties of psychostimulants have been shown to vary across time of day in mice. The goal of this study was to determine the role of the MT1 and MT2 melatonin receptors in METH-induced reward, as measured by the conditioned place preference (CPP) paradigm during the light and dark phases. C3H/HeN wild-type mice were trained for METH-induced CPP at either ZT 6–8 (ZT: Zeitgeber time; ZT 0 = lights on), when endogenous melatonin levels are low, or ZT 19–21, when melatonin levels are high. These time points also correspond to the high and low points for expression of the circadian gene Period1, respectively. The locomotor response to METH (1.2 mg/kg, ip) treatment was of similar magnitude at both times, however only C3H/HeN mice conditioned to METH at ZT 6–8 developed a place preference. C3H/HeN mice with a genetic deletion of either the MT1 (MT1KO) or MT2 (MT2KO) receptor tested at ZT 6–8 or ZT 19–21 did not develop a place preference for METH, though both showed a similar increase in locomotor activity following METH treatment when compared to wild-type mice. We conclude that in our mouse model METH-induced conditioned place preference is dependent on time of day and the presence of the MT1 or MT2 receptors, suggesting a role for melatonin in METH-induced reward.

MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective

“…Melatonin has been linked to modulation of drug-induced sensitization and reward (124–128). Recent evidence, including data from our laboratory and others, suggests that melatonin receptors modulate responses to drugs of abuse in two well-established models of addictive liability, i.e., locomotor sensitization (124, 125, 127) and conditioned place preference (126, 128). …”

“…Together, these results suggest that melatonin abrogates the rewarding properties of morphine through the MT 2 receptor (132). Results from our laboratory revealed a strong place preference in methamphetamine-treated wild-type C3H/HeN mice during the mid-light phase, which was abrogated during the peak melatonin period of the mid-dark phase (126). Knockout mice lacking either the MT 1 or MT 2 receptor exhibited sharply reduced place preference for methamphetamine at both times of day (126).…”

“…Results from our laboratory revealed a strong place preference in methamphetamine-treated wild-type C3H/HeN mice during the mid-light phase, which was abrogated during the peak melatonin period of the mid-dark phase (126). Knockout mice lacking either the MT 1 or MT 2 receptor exhibited sharply reduced place preference for methamphetamine at both times of day (126). Thus, melatonin appears to act through its receptors to inhibit methamphetamine-induced reward, and antagonists of the MT 1 and MT 2 receptors may have the capacity to block the induction of the methamphetamine-induced reward sensation.…”

Learned motivation drives circadian physiology in the absence of the master circadian clock

“…The highly addictive psychostimulant Meth exerts its primary actions within the mesolimbic dopamine pathway, where its actions result in increased dopamine release and reward sensation (60). Meth is considered to be highly reinforcing in rodents as demonstrated by selfadministration, sensitization, and conditioned place preference studies (44, 46, 61). Meth alters synaptic plasticity within the reward pathway in a manner similar to RW.…”

“…(+)-Methamphetamine hydrochloride (Sigma-Aldrich) was dissolved in 0.9% saline and administered at a dose of 1.2 mg/kg via intraperitoneal injections in a volume of 0.01 ml/g. This dose was chosen on the basis of previous studies in our laboratory (44)(45)(46). Mice were randomly assigned to groups that received either Veh (0.9% saline, i.p.)…”