Theobromine improves hyperactivity, inattention, and working memory modulation of dopaminergic neural function in the frontal cortex of spontaneously hypertensive rats. Food & function Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder and dopaminergic dysfunction in the prefrontal cortex (PFC) may play a role. Our previous research indicated that theobromine (TB), a methylxanthine, enhances cognitive function in rodents the PFC. This study investigates TB's effects on hyperactivity and cognitive function in stroke-prone spontaneously hypertensive rats (SHR), an ADHD animal model. Male SHRs (6-week old) received a diet containing 0.05% TB for 40 days, while control rats received normal diets. Age-matched male Wistar-Kyoto rats (WKY) served as genetic controls. During the TB administration period, we conducted open-field tests and Y-maze tasks to evaluate hyperactivity and cognitive function, then assessed dopamine concentrations and tyrosine hydroxylase (TH), dopamine receptor D1-5 (DRD1-5), dopamine transporter (DAT), vesicular monoamine transporter-2 (VMAT-2), synaptosome-associated protein-25 (SNAP-25), and brain-derived neurotrophic factor (BDNF) expressions in the PFC. Additionally, the binding affinity of TB for the adenosine receptors (ARs) was evaluated. Compared to WKY, SHR exhibited hyperactivity, inattention and working memory deficits. However, chronic TB administration significantly improved these ADHD-like behaviors in SHR. TB administration also normalized dopamine concentrations and expression levels of TH, DRD2, DRD4, SNAP-25, and BDNF in the PFC of SHR. No changes were observed in DRD1, DRD3, DRD5, DAT, and VMAT-2 expression between SHR and WKY rats, and TB intake had minimal effects. TB was found to have affinity binding to ARs. These results indicate that long-term TB supplementation mitigates hyperactivity, inattention and cognitive deficits in SHR by modulating dopaminergic nervous function and BDNF levels in the PFC, representing a potential adjunctive treatment for ADHD. 10.1039/d4fo00683f

Dopaminergic system and neurons: Role in multiple neurological diseases. Neuropharmacology The dopaminergic system is a complex and powerful neurotransmitter system in the brain. It plays an important regulatory role in motivation, reward, cognition, and motor control. In recent decades, research in the field of the dopaminergic system and neurons has increased exponentially and is gradually becoming a point of intervention in the study and understanding of a wide range of neurological diseases related to human health. Studies have shown that the dopaminergic system and neurons are involved in the development of many neurological diseases (including, but not limited to Parkinson's disease, schizophrenia, depression, attention deficit hyperactivity disorder, etc.) and that dopaminergic neurons either have too much stress or too weak function in the dopaminergic system can lead to disease. Therefore, targeting dopaminergic neurons is considered key to treating these diseases. This article provides a comprehensive review of the dopaminergic system and neurons in terms of brain region distribution, physiological function and subtypes of dopaminergic neurons, as well as the role of the dopaminergic system and neurons in a variety of diseases. 10.1016/j.neuropharm.2024.110133

Aberrant extracellular dopamine clearance in the prefrontal cortex exhibits ADHD-like behavior in NCX3 heterozygous mice. The FEBS journal Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that involves dopaminergic dysfunction in the prefrontal cortex (PFC), manifesting hyperactivity, inattention, and cognitive deficits. However, the ADHD-associated candidate genes underlying dopaminergic neurotransmission alterations remain poorly defined. Here, we identified the abundant localization of sodium-calcium exchanger 3 (NCX3) levels in the dopaminergic neurons of the ventral tegmental area, a major source of dopaminergic innervation to the PFC. We confirmed that NCX3 knockdown in N27 cells caused aberrant dopamine influx through the strong interaction between calcium/calmodulin-dependent protein kinase II alpha and dopamine transporter. In addition, we assessed behavioral changes and underlying molecular properties in NCX3 heterozygous (NCX3) mice. NCX3 mice exhibited hyperactivity, cognitive deficits, and social dysfunction which were alleviated by treating with methylphenidate. Furthermore, NCX3 mice displayed a persistent elevation of basal dopamine levels and decreased extracellular levels of dopamine triggered by social stimuli in the PFC of NCX3 mice. In agreement with the rise in extracellular dopamine levels in the PFC, NCX3 mice showed activation of dopamine D1 receptor signaling pathways in the PFC compared to wild-type mice. Thus, deficiency of NCX3 leads to impaired dopaminergic neurotransmission in the PFC, which likely accounts for the ADHD-like behavior in NCX3 mice. 10.1111/febs.17339