Melatonin, or 5-methoxy-N-acetyltryptamine, is synthesized and released by the pineal gland and locally in the retina following a circadian rhythm, with low levels during the day and elevated levels at night. Melatonin activates two high-affinity G protein–coupled receptors, termed MT1 and MT2, to exert beneficial actions in sleep and circadian abnormality, mood disorders, learning and memory, neuroprotection, drug abuse, and cancer. Progress in understanding the role of melatonin receptors in the modulation of sleep and circadian rhythms has led to the discovery of a novel class of melatonin agonists for treating insomnia, circadian rhythms, mood disorders, and cancer. This review describes the pharmacological properties of a slow-release melatonin preparation (i.e., Circadin®) and synthetic ligands (i.e., agomelatine, ramelteon, tasimelteon), with emphasis on identifying specific therapeutic effects mediated through MT1 and MT2 receptor activation. Discovery of selective ligands targeting the MT1 or the MT2 melatonin receptors may promote the development of novel and more efficacious therapeutic agents.

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Prostaglandin E 2 (PGE 2 ) is produced at high levels in the injured central nervous system, where it is generally considered a cytotoxic mediator of inflammation. The cellular actions of PGE 2 are mediated by G-protein signaling activated by prostanoid receptors termed EP 1 , EP 2 , EP 3 and EP 4 . Recent studies have implicated the EP 2 prostanoid receptor in apparently conflicting roles promoting neuronal death in some model systems and the survival of neurons in others. Here we show that treatment of immortalized human microglia and CCF-STTG1 astrocytes with either PGE 2 or the EP 2 selective agonist butaprost stimulates the release of brain-derived neurotrophic factor (BDNF). Both cell lines express mRNA for the EP 2 receptor, whereas transcripts for the other subtypes are not detected. Pharmacological studies using PGE 2 and modulators of cyclic AMP signaling implicate this pathway in PGE 2 -stimulated BDNF release. These results indicate that EP 2 prostanoid receptor activation induces BDNF secretion through stimulation of cyclic AMP dependent signaling. Our findings provide a mechanism by which endogenous PGE 2 might contribute to either neurotoxicity or neuroprotection in the injured brain via the induction of BDNF release from microglial cells and astrocytes. KeywordsProstaglandin E 2 ; microglia; astrocytes; BDNF; G-protein coupled receptor; brain derived neurotrophic factor; cyclic AMP Prostaglandin E 2 (PGE 2 ) is a prominent lipid autocrine/paracrine signaling mediator produced by the sequential metabolism of arachidonic acid by cyclooxygenase (COX) and PGE 2 synthase. PGE 2 is a major agent in local intercellular signaling associated with inflammation, pain, fever and immune responses (reviewed by Matsuoka & Narumiya, 2007;Khanapure et al., 2007;Harris et al., 2002). The cellular actions of PGE 2 are mediated by the activation of a group of G-protein coupled receptors that includes subtypes termed the EP 1 , EP 2 , EP 3 and EP 4 prostanoid receptors. These receptor subtypes are distinguished from one another by their selectivity for different ligands and by their unique coupling to intracellular signaling #Corresponding author (E-mail: regan@pharmacy.arizona.edu). * These authors contributed equally to this work Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Funk et al., 1993) while stimulation of the EP 2 receptor promotes the production of intracellular cyclic AMP (Regan et al., 1994a). Activation of the EP 3 receptor, which is expressed as multiple isoforms through alternative mRNA splicing, inhibits cyclic AMP signaling (Regan et al., 1994b) ...

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.

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.