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.

Children with attention-deficit/hyperactivity disorder (ADHD) often struggle with impaired executive function, temporal processing, and visuospatial memory, hallmarks of the predominantly inattentive presentation (ADHD-PI), subserved by the hippocampus. However, the specific genes/proteins involved and how they shape hippocampal structures to influence ADHD behavior remain poorly understood. As an exploratory tool, hippocampal dentate gyri tissues from thyroid hormone-responsive protein overexpressing (THRSP OE) mice with defining characteristics of ADHD-PI were utilized in proteomics. Integrated proteomics and network analysis revealed an altered protein network involved in Wnt signaling. Compared with THRSP knockout (KO) mice, THRSP OE mice showed impaired attention and memory, accompanied by dysregulated Wnt signaling affecting hippocampal dentate gyrus cell proliferation and expression of markers for neural stem cell (NSC) activity. Also, combined exposure to an enriched environment and treadmill exercise could improve behavioral deficits in THRSP OE mice and Wnt signaling and NSC activity. These findings show new markers specific to the ADHD-PI presentation, converging with the ancient and evolutionary Wnt signaling pathways crucial for cell fate determination, migration, polarity, and neural patterning during neurodevelopment. These findings from THRSP OE mice support the role of Wnt signaling in neurological disorders, particularly ADHD-PI presentation.

There are three presentations of attention-deficit/hyperactivity disorder (ADHD): the predominantly inattention (ADHD-PI), predominantly hyperactive–impulsive (ADHD-HI), and combined (ADHD-C) presentations of ADHD. These may represent distinct childhood-onset neurobehavioral disorders with separate etiologies. ADHD diagnoses are behaviorally based, so investigations into potential etiologies should be founded on behavior. Animal models of ADHD demonstrate face, predictive, and construct validity when they accurately reproduce elements of the symptoms, etiology, biochemistry, and disorder treatment. Spontaneously hypertensive rats (SHR/NCrl) fulfill many validation criteria and compare well with clinical cases of ADHD-C. Compounding the difficulty of selecting an ideal model to study specific presentations of ADHD is a simple fact that our knowledge regarding ADHD neurobiology is insufficient. Accordingly, the current review has explored a potential animal model for a specific presentation, ADHD-PI, with acceptable face, predictive, and construct validity. The Thrsp gene could be a biomarker for ADHD-PI presentation, and THRSP OE mice could represent an animal model for studying this distinct ADHD presentation.