Circadian modulation of reward via the MT1 and MT 2 melatonin receptors
Clough, Shannon Jean
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The goal of our research was to investigate the underlying connections between the reward and circadian systems. Diurnal variation in reinforcement-related process has been described in models of place preference, self-administration, and sensitization. This variation hints at modulation by a hormone and/or molecule under circadian control. We utilized a two-step approach, first examining the role of endogenous melatonin and its receptors in the modulation of reinforcement-related behaviors and secondly examining the contributions of the reinforcing stimuli of methamphetamine (METH) and running wheel to induce rhythmicity. METH and palatable snack food have been extensively studied for their ability to produce reinforcement. Studies have suggested a circadian variation in both drug and natural reinforcement, with each following its own time course. The pineal hormone melatonin is synthesized following a circadian rhythm, with low levels during the day and high levels at night. The reinforcing properties of METH and snack food were measured by the conditioned place preference paradigm, which relies on the association of a reinforcing substance with a distinct set of contextual cues. During the day (Zeitgeber Time [ZT] 6 - 8; 12h: 12h light-dark cycle, ZT 0 = lights on), when melatonin is low, METH (1.2 mg/kg, i.p.) induces a strong place preference in C3H/HeN wild-type mice. However, during the dark phase (ZT 19 - 21), when melatonin is high, mice exhibited a similar preference score regardless of receiving METH or vehicle. This profile is similar to that observed with palatable snack food, with a strong place preference for snack food at ZT 6 - 8 and no preference exhibited at ZT 19 - 21. In addition to displaying a diurnal variation, METH and snack food reinforcement also appear to be dependent on the presence of the melatonin receptors as deletion of either the MT 1 (MT 1 KO) or MT 2 (MT 2 KO) receptor results in complete abrogation of place preference. The conditioned place preference paradigm requires reinforcement-related learning and memory to occur, a process, which relies on long-term potentiation, which is inhibited by melatonin through the MT 2 receptor. Mice lacking the MT 2 receptor performed poorly in a novel object recognition task, while mice lacking the MT 1 receptor performed poorly in discrimination learning, reversal learning and retention memory tasks as part of an attentional set shift paradigm. Taken together these data suggests that mice lacking either melatonin receptor may have deficits in hippocampal-independent (MT 2 ) and hippocampal-dependent (MT 1 ) learning and memory. We suggest that this deficit in memory could be responsible for the lack of preference observed during a conditioned place preference task in C3H/HeN mice. METH reconstitutes rhythmicity in mice rendered arrhythmic by electrolytic lesions of the suprachiasmatic nucleus (SCNX). This is cited as evidence for an extra-SCN circadian oscillator sensitive to METH. Running wheel activity, which is also known to have reinforcing properties, is frequently used to measure the output of the circadian system. We demonstrated an integral role for running wheel in the induction and maintenance of rhythmic behavior in SCNX mice. Our results suggest the entrainment observed in SCNX mice is due to an extra-SCN oscillator and occurs as a result of the combined reinforcing properties from both the METH and running wheel. We conclude there is a critical role for circadian rhythms in reinforcement-related process, particularly those governed by a learning and memory component. Melatonin and its receptors represent an integral part of the connection between these systems. We propose melatonin, its receptors and the circadian pathway as a potential target for therapeutics addressing the addictive behavior underlying drug abuse and obesity.