ABSTRACT
A healthy, balanced diet is essential for both physical and mental well-being. Such a diet must include an adequate intake of micronutrients, essential fatty acids, amino acids and antioxidants. The monoamine neurotransmitters, serotonin, dopamine and noradrenaline, are derived from dietary amino acids and are involved in the modulation of mood, anxiety, cognition, sleep regulation and appetite. The capacity of nutritional interventions to elevate brain monoamine concentrations and, as a consequence, with the potential for mood enhancement, has not been extensively evaluated. The present study investigated an extract from oregano leaves, with a specified range of active constituents, identified via an unbiased, high-throughput screening programme. The oregano extract was demonstrated to inhibit the reuptake and degradation of the monoamine neurotransmitters in a dose-dependent manner, and microdialysis experiments in rats revealed an elevation of extracellular serotonin levels in the brain. Furthermore, following administration of oregano extract, behavioural responses were observed in mice that parallel the beneficial effects exhibited by monoamine-enhancing compounds when used in human subjects. In conclusion, these data show that an extract prepared from leaves of oregano, a major constituent of the Mediterranean diet, is brain-active, with moderate triple reuptake inhibitory activity, and exhibits positive behavioural effects in animal models. We postulate that such an extract may be effective in enhancing mental well-being in humans.
Subject(s)
Anti-Anxiety Agents/therapeutic use , Antidepressive Agents/therapeutic use , Biogenic Monoamines/physiology , Dietary Supplements , Neurotransmitter Uptake Inhibitors/therapeutic use , Origanum/chemistry , Plant Extracts/therapeutic use , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/metabolism , Antidepressive Agents/chemistry , Antidepressive Agents/metabolism , Anxiety/prevention & control , Behavior, Animal , Benzoquinones/analysis , Benzoquinones/pharmacology , Brain/metabolism , Cymenes , Depression/prevention & control , Dietary Supplements/analysis , Drug Discovery/methods , HEK293 Cells , Humans , Male , Mice , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/metabolism , Monoamine Oxidase Inhibitors/therapeutic use , Monoterpenes/analysis , Monoterpenes/blood , Monoterpenes/pharmacology , Neurotransmitter Uptake Inhibitors/chemistry , Neurotransmitter Uptake Inhibitors/metabolism , Neurotransmitter Uptake Inhibitors/pharmacology , Plant Extracts/chemistry , Plant Extracts/metabolism , Plant Leaves/chemistry , Random Allocation , Rats , Serotonin Plasma Membrane Transport Proteins/genetics , Serotonin Plasma Membrane Transport Proteins/metabolismABSTRACT
Methylphenidate, a drug widely used for attention deficit hyperactivity disorder in children, may affect neuronal function differently in young and adult subjects, particularly in the prefrontal cortex, a brain structure that does not fully develop until adulthood. We compared the impact of development on the effects of methylphenidate on single unit electrical activity and mRNA expression of the effector immediate early gene activity-regulated cytoskeletal-associated protein (Arc) following methylphenidate in the prefrontal cortex in adult (more than 60 days old) and juvenile (25-35 days old) rats. Methylphenidate, administered under urethane anaesthesia to adult rats, at doses ranging from 1 mg/kg to 3 mg/kg intravenously, exerts a progressive activation of firing of prefrontal cortex neurones (30% to 84% from baseline). This activation was significantly lower in the juvenile rats, reaching only 37% of baseline levels at the highest dose (3 mg/kg, intravenous). In adults, methylphenidate (4 mg/kg intraperitoneal) produced marked increases in Arc mRNA levels compared with saline controls by 123% and 164% in cingulated and orbital cortex, respectively. Corresponding values for the juvenile rats were significantly lower (42% and 79%). In summary, this multi-approach investigation showed that the reactivity of prefrontal cortex neurones to methylphenidate differs markedly in juvenile and adult rats.
Subject(s)
Central Nervous System Stimulants/pharmacology , Cytoskeletal Proteins/genetics , Methylphenidate/pharmacology , Nerve Tissue Proteins/genetics , Prefrontal Cortex/drug effects , Age Factors , Animals , Central Nervous System Stimulants/administration & dosage , Dose-Response Relationship, Drug , Electrophysiological Phenomena , Gene Expression Regulation/drug effects , Male , Methylphenidate/administration & dosage , Neurons/drug effects , Neurons/metabolism , Prefrontal Cortex/metabolism , RNA, Messenger/drug effects , RNA, Messenger/metabolism , RatsABSTRACT
Psychostimulant drugs are widely used in children for the treatment of attention-deficit/hyperactivity disorder. Recent animal studies have suggested that exposure to these agents in early life could be detrimental to brain development. Here, for the first time, the effect of methylphenidate (MPH) and D-amphetamine (AMPH) on the expression of two key genes for neuronal development and plasticity, brain-derived neurotrophic factor (bdnf) and the effector immediate early gene activity-regulated, cytoskeletal-associated protein (Arc), was examined in both juvenile and adult rats. Both MPH [2 mg/kg, intraperitoneal (i.p.)] and AMPH (0.5 mg/kg, i.p.) induced marked decreases of bdnf mRNA in hippocampal and cortical brain regions of juveniles, whereas effects in adults were significantly less (hippocampus) or opposite (frontal cortex). In comparison, Arc mRNA was decreased (hippocampus and parietal cortex), largely unaffected (frontal cortex) or increased (striatum) in juveniles, whereas in adults, Arc mRNA increased in most brain regions. MPH-induced locomotion was also measured, and showed a much smaller increase in juveniles than in adults. In summary, our data show that the effects of MPH and AMPH on expression of the neurodevelopmentally important genes, bdnf and Arc, differ markedly in juvenile and adult rats, with juveniles showing evidence of brain region-specific decreases in both genes. These age-dependent effects on gene expression may be linked with the reported long-term harmful effects of psychostimulants in animal models.
