Two-Month administration of Methylphenidate improves olfactory sensitivity and suppresses appetite in individuals with obesity

Introduction: Olfaction contributes to feeding behaviour and is modulated by changes in dopamine levels. Methylphenidate (MPH) increases brain dopamine levels and has been shown to reduce appetite and promote weight loss in patients with attention deficit hyperactivity disorder. The objectives of this study were to test the effect of MPH on olfaction, appetite, energy intake and body weight on individuals with obesity. Methods: In a randomized, double-blind study, 12 participants (age 28.9±6.7 yrs) (BMI 36.1±4.5 kg/m2) were assigned to MPH (0.5mg/kg) (n=5) or Placebo (n=7) twice daily for 2 months. Appetite (Visual Analog Scale), odour threshold (Sniffin’ Sticks®), energy intake (food menu), and body weight (DEXA scan) were measured at day 1 and day 60. Results: MPH intake significantly increased odour threshold scores (6.3±1.4 vs. 9.4±2.1 and 7.9±2.3 vs. 7.8±1.9, respectively; p=0.029) vs. Placebo. There was a significantly greater suppression of appetite sensations (desire to eat (p=0.001), hunger (p=0.008), and prospective food consumption (p=0.003)) and an increase in fullness (p=0.028) over time in the MPH vs. Placebo. Conclusions: MPH suppressed appetite and improved olfactory sensitivity in individuals with obesity. These data provide novel findings on the favourable effects of MPH on appetite and weight regulation in individuals living with obesity.

Striatal DAT availability does not change after supraphysiological glucose loading dose in humans

Brain dopamine neurotransmission is regulated by the dopamine transporter (DAT), which drives reuptake of extracellular dopamine into the presynaptic neurons. We hypothesized that the glucose loading dose would affect the striatal DAT availability. An i.v. bolus injection of 18F-FP-CIT was administered after infusion of low-dose glucose (300 mg/kg), high-dose glucose (600 mg/kg) or placebo (normal saline). The emission data were acquired over 90 min in 23 healthy male subjects. Substantial increases of binding potential (BPNDs) from ventral striatum (VST), caudate nucleus, and putamen were observed after low-dose glucose loading (+26.0, +87.0, and +37.8%) and after high-dose glucose loading (+10.4, +51.9, and +22.0%). BPNDs of the caudate nucleus and putamen showed significant differences (P = 0.0472 and 0.0221) after placebo, low-dose glucose, and high-dose glucose loading. BPNDs in the caudate nucleus and putamen after placebo, low-dose glucose, and high-dose glucose loading were positively intercorrelated with each other. In conclusion, striatal DAT changes after physiological glucose loading, but not after supraphysiological glucose loading in humans. DAT availabilities after placebo, low-dose glucose, high-dose glucose loading were correlated to each other in the caudate nucleus and putamen, but not in the VST. Therefore, sub-regional variability in DAT regulatory mechanisms mediated by insulin may exist in humans.

Novel Pathways and Mechanism of Nicotine-Induced Oral Carcinogenesis

Background: Smokeless Tobacco (SLT) contains 9 times more nicotine than Smoked Tobacco (SMT). The carcinogenic effect of nicotine is intensified by converting nicotine-to-nicotine-derived Nitrosamines (NDNs). Methods: A review of the literature was conducted with a tailored search strategy to unravel the novel pathways and mechanisms of nicotine-induced oral carcinogenesis. Results: Nicotine and NDNs act on nicotinic Acetylcholine Receptors (nAChRs) as agonists. Nicotine facilitates cravings through α4β2nAChR and α7nAChR, via enhanced brain dopamine release. Nicotine binding to nAChR promotes proliferation, migration, invasion, chemoresistance, radioresistance, and metastasis of oral cancer cells. Nicotine binding to α7nAChR on keratinocytes triggers Ras/Raf-1/MEK1/ERK cascade promoting anti-apoptosis and pro-proliferative effects. Furthermore, the nicotine-enhanced metastasis is subdued on nAChR blockade through reduced nuclear localization of p-EGFR. Conclusion: Protracted exposure to nicotine/NDN augments cancer-stimulatory α7nAChR and desensitizes cancer inhibitory α4β2nAChR. Since nAChRs dictate both addictive and carcinogenic effects of nicotine, it seems counterintuitive to designate nicotine just as an addictive agent devoid of any carcinogenicity.

Psychostimulant Use Disorder, an Unmet Therapeutic Goal: Can Modafinil Narrow the Gap?

The number of individuals affected by psychostimulant use disorder (PSUD) has increased rapidly over the last few decades resulting in economic, emotional, and physical burdens on our society. Further compounding this issue is the current lack of clinically approved medications to treat this disorder. The dopamine transporter (DAT) is a common target of psychostimulant actions related to their use and dependence, and the recent availability of atypical DAT inhibitors as a potential therapeutic option has garnered popularity in this research field. Modafinil (MOD), which is approved for clinical use for the treatment of narcolepsy and sleep disorders, blocks DAT just like commonly abused psychostimulants. However, preclinical and clinical studies have shown that it lacks the addictive properties (in both behavioral and neurochemical studies) associated with other abused DAT inhibitors. Clinical availability of MOD has facilitated its off-label use for several psychiatric disorders related to alteration of brain dopamine (DA) systems, including PSUD. In this review, we highlight clinical and preclinical research on MOD and its R-enantiomer, R-MOD, as potential medications for PSUD. Given the complexity of PSUD, we have also reported the effects of MOD on psychostimulant-induced appearance of several symptoms that could intensify the severity of the disease (i.e., sleep disorders and impairment of cognitive functions), besides the potential therapeutic effects of MOD on PSUD.

Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson’s disease by regulating gut microbiota

The phenylalanine–tyrosine–dopa–dopamine pathway provides dopamine to the brain. In this process, tyrosine hydroxylase (TH) is the rate-limiting enzyme that hydroxylates tyrosine and generates levodopa (l-dopa) with tetrahydrobiopterin (BH4) as a coenzyme. Here, we show that oral berberine (BBR) might supply H• through dihydroberberine (reduced BBR produced by bacterial nitroreductase) and promote the production of BH4 from dihydrobiopterin; the increased BH4 enhances TH activity, which accelerates the production of l-dopa by the gut bacteria. Oral BBR acts in a way similar to vitamins. The l-dopa produced by the intestinal bacteria enters the brain through the circulation and is transformed to dopamine. To verify the gut–brain dialog activated by BBR’s effect, Enterococcus faecalis or Enterococcus faecium was transplanted into Parkinson’s disease (PD) mice. The bacteria significantly increased brain dopamine and ameliorated PD manifestation in mice; additionally, combination of BBR with bacteria showed better therapeutic effect than that with bacteria alone. Moreover, 2,4,6-trimethyl-pyranylium tetrafluoroborate (TMP-TFB)-derivatized matrix-assisted laser desorption mass spectrometry (MALDI-MS) imaging of dopamine identified elevated striatal dopamine levels in mouse brains with oral Enterococcus, and BBR strengthened the imaging intensity of brain dopamine. These results demonstrated that BBR was an agonist of TH in Enterococcus and could lead to the production of l-dopa in the gut. Furthermore, a study of 28 patients with hyperlipidemia confirmed that oral BBR increased blood/fecal l-dopa by the intestinal bacteria. Hence, BBR might improve the brain function by upregulating the biosynthesis of l-dopa in the gut microbiota through a vitamin-like effect.

Dysregulation of brain dopamine systems in major depressive disorder

Major depressive disorder (MDD or depression) is a debilitating neuropsychiatric syndrome with genetic, epigenetic, and environmental contributions. Depression is one of the largest contributors to chronic disease burden; it affects more than one in six individuals in the United States. A wide array of cellular and molecular modifications distributed across a variety of neuronal processes and circuits underlie the pathophysiology of depression—no established mechanism can explain all aspects of the disease. MDD suffers from a vast treatment gap worldwide, and large numbers of individuals who require treatment do not receive adequate care. This mini-review focuses on dysregulation of brain dopamine (DA) systems in the pathophysiology of MDD and describing new cellular targets for potential medication development focused on DA-modulated micro-circuits. We also explore how neurodevelopmental factors may modify risk for later emergence of MDD, possibly through dopaminergic substrates in the brain.

Effectiveness of Psychostimulant and Non-Psychostimulant Drug Therapy in the Attention Deficit Hyperactivity Disorder

Attention Deficit Hyperkinetic Disorder (ADHD) is a neurobiological behavioral disorder of the child, adolescent, and adult characterized by problems of concentration, hyperactivity, and impulsivity caused by an imbalance of chemical neurotransmitters in the brain—dopamine and noradrenaline. ADHD first-line drugs are divided in psychostimulant, as Methylphenidate and Amphetamines and non-psychostimulant medications-Atomoxetine (the only representative non-psychostimulant medication approved in our country in children and adolescents). The purpose of our research was to assess the clinical evolution of patients with ADHD based on the drug treatment that is administered: psychostimulant or non-psychostimulant. Both psychostimulant—Methylphenidate, and non-psychostimulant therapy—Atomoxetine, proved to significantly improve the symptoms of attention deficit hyperkinetic disorder. There was a significant reduction in the severity of ADHD symptoms at six months and at one year from the start of treatment in the case of the psychostimulant group, whereas in the non-psychostimulant group, the significant reduction in severity of symptomatology occurs only at six months after the start of treatment. We can conclude that both types of drugs are effective in reducing the severity of symptoms and in improving the clinical condition of patients with ADHD, but the comparative analysis of the two groups demonstrated that significantly better results are obtained with psychostimulant treatment.