Endogenous Melatonin Decreases Place Preference For Methamphetamine Through A Learning And Memory Independent Mechanism In C57BL/6 Mice
Authors: Clough Shannon J. , Kasahara Takaoki , Veros Kaliana M. , Hudson Randall L. , Dubocovich Margarita L. 
Published: November 2023

The pineal molecule melatonin is synthesized via two key enzymes (AANAT and HIOMT) (Reiter, Mol Cel Endocrinol 1991;79:C153–C158). Melatonin has been linked to an inhibition of conditioned place preference (CPP) for methamphetamine (METH), mediated through its two G protein‐coupled receptors (Clough et al., Physiol Behav 2014,132:79–86) Additionally, CPP for METH has been shown to follow a diurnal variation, with a complete abrogation of CPP occurring during the dark phase when melatonin levels are at their peak. This suggests a potential role for endogenous melatonin in modulating METH‐induced CPP. In order to further examine the role of endogenous melatonin in METH‐induced CPP we utilized a mouse line developed by Kasahara and his team. These congenic C57BL/6J mice were developed through backcrossing with MSM mice, to produce melatonin proficient (Aanat(+/+);Hiomt(+/+): AH+/+) and melatonin deficient (Aanat(−/−);Hiomt(−/−): AH−/−) mice on the same genetic background. AH−/− mice lack any significant production of melatonin, while AH+/+ mice have a constant elevated level of melatonin in the blood (2–5 fold > AH−/−) and pineal gland (10–15 fold > AH−/−). Male AH−/− and AH+/+ mice were conditioned with alternating treatments of METH (1.2mg/kg, ip) or vehicle (VEH) and tested for CPP after the last conditioning session. Testing for all experiments occured during the day (Zeitgeber Time [ZT] 6–8; 12h:12h light‐dark cycle, ZT 0 = lights on). The CPP for METH was significantly higher than VEH in both AH−/− (VEH: −100±42s, n=12; METH: 284±32s, n=16, p<0.05) and AH+/+ (VEH: 14±31s n=13; METH: 181±30s, n=16, p<0.05) mice. However, AH+/+ mice displayed a significantly lower CPP score for METH compared to the AH−/− mice (p<0.05). The CPP paradigm requires reward related learning and memory to occur, a process which relies on long‐term potentiation (Keleta & Martinez, Brain Behav 2012,2:128–141). Melatonin has been linked to an inhibition of long‐term potentiation (Wang et al., Eur J Neurosci 2005,22:2231–7). Therefore we sought to determine whether the decreased CPP observed in AH+/+ mice was due to a learning and memory deficit. To accomplish this we utilized a hippocampal dependent task (attentional set shift) and a hippocampal independent task (novel object recognition). For the attentional set shift task mice were subjected to a series of behavioral tasks to test discrimination and reversal learning. A significant difference between AH−/− and AH+/+ mice was observed in the simple discrimination task (AH−/− [n=6]: 14±3 trials vs. AH+/+ [n=9]: 8±1 trials; p<0.05). No other differences were observed between the two genotypes in terms of compound discrimination, intradimensional shift, extradimensional shift, or reversal tasks. Similarly no significant differences were observed between AH−/− and AH+/+ mice in the novel object recognition task, with both genotypes displaying strong object recognition. Taken together, these data suggest a role for endogenous melatonin in regulating reinforcing behaviors occurring independently of a learning and memory related mechanism. Therefore, suggesting melatonin is exerting its effects independently of its known inhibition of long‐term potentiation and may be acting directly within the reward pathway.

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