Regulation of clock and clock-controlled genes during morphine reward and reinforcement: Involvement of the period 2 circadian clock

Abstract

Background: Morphine abuse is a devastating disorder that affects millions of people worldwide, and literature evidence indicates a relationship between opioid abuse and the circadian clock. Aim: We explored morphine reward and reinforcement using mouse models with Per2 gene modifications (knockout (KO); overexpression (OE)). Methods: Mice were exposed to various behavioral, electroencephalographic, pharmacological, and molecular tests to assess the effects of morphine and identify the underlying mechanisms with a focus on reward and reinforcement and the corresponding involvement of circadian and clock-controlled gene regulation. Results: Per2 deletion enhances morphine-induced analgesia, locomotor sensitization, conditioned place preference (CPP), and self-administration (SA) in mice, whereas its overexpression attenuated these effects. In addition, reduced withdrawal was observed in Per2 KO mice, whereas an augmented withdrawal response was observed in Per2 OE mice. Moreover, naloxone and SCH 23390 blocked morphine CPP in Per2 KO and wild-type (WT) mice. The rewarding (CPP) and reinforcing effects (SA) observed in morphine-conditioned and morphine self-administered Per2 KO and WT mice were accompanied by activated μ-opioid and dopamine D1 receptors and TH in the mesolimbic (VTA/NAcc) system. Furthermore, genetic modifications of Per2 in mice innately altered some clock genes in response to morphine. Conclusion: These findings improve our understanding of the role of Per2 in morphine-induced psychoactive effects. Our data and those obtained in previous studies indicate that targeting Per2 may have applicability in the treatment of substance abuse.

The circadian neurobiology of reward

“…In absence of Per1 cocaine sensitization and reward is missing whereas a lack of Per2 leads to hypersensitized cocaine 51 . Similar effects were observed after morphine intake where a loss of Per2 increased morphine self‐administration 87 …”

“…51 Similar effects were observed after morphine intake where a loss of Per2 increased morphine self-administration. 87 While the dopamine receptor D2 is activated by tonic extracellular dopamine levels, the D1 receptor is activated by higher-amplitude, phasic-stimulated dopamine release. 88 Differences in postsynaptic dopamine receptor activation occur throughout the day, whereby the ratio of the D2 and D1 receptor is important: during high extracellular dopamine concentrations, as during the dark phase, more DRD2 and less DRD1 activation is described whereas the opposite-less DRD2 and more DRD1 activation is observed during low extracellular dopamine concentrations, as during the light phase.…”

Deletion of Cryab increases the vulnerability of mice to the addiction-like effects of the cannabinoid JWH-018 via upregulation of striatal NF-κB expression

“…The SA test was performed as reported previously ( Custodio et al, 2022 ). Lever pressing training, which was based on food pellet reward under continuous reinforcement, was performed for three consecutive days [30 min per session (AM and PM sessions)].…”

Hippocampal dentate gyri proteomics reveals Wnt signaling involvement in the behavioral impairment in the THRSP-overexpressing ADHD mouse model

“…Briefly, 5-BrdU-injected mice (n = 6/group) were sacrificed immediately after the last day of the respective experiments. Standard protocols for brain fixation were followed 63 . Briefly, mice were anesthetized using tiletamine/ zolazepam (50 mg mL −1 ); Zoletil; Vibrac Laboratories, Carros, France) and xylazine (100 mg mL −1 ).…”

“…The prepared slides were then covered with 24 × 50 mm microscope cover glasses (Marienfield Laboratory Glassware, Germany; catalog number:0101222) and observed under a confocal laser-scanning microscope (Leica TCS SP8). The number of cells expressing BrdU in the DG was counted, and corrected cell fluorescence levels for NEU-N and GFAP in the DG were analyzed using ImageJ software (RRID: SCR_003070), as described previously 63,65,66 (Fig. 6a, b).…”