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• Triple opioid receptor KO mice showed peripheral iron deficiency and anemia. • Triple opioid receptor KO mice showed diurnal hyperactivity. • Triple opioid receptor KO mice had decreased thermal sensitivity. • Triple opioid receptor KO mice showed decreased dopamine metabolism. Previous studies have uncovered a potential role of the opioid system in iron hemostasis and dopamine metabolism. Abnormalities in both of these systems have been noted in human RLS. Autopsy studies of human RLS have shown an endogenous opioid deficiency in the thalamus. Opioids, particularly prolonged-release oxycodone/naloxone, have been approved in Europe to be a second-line therapy for severe restless legs syndrome (RLS). To study the role of opioid receptors in the pathogenesis of RLS, we used a triple knockout (KO) mouse strain that lack mu, delta, and kappa opioid receptors and explored the behavioral and biochemical parameters relevant to RLS. The triple KO mice showed hyperactivity and a trend of increased probability of waking during the rest period (day) akin to that in human RLS (night). Surprisingly, triple KO mice also exhibit decreased serum iron concentration, evidence of anemia, a significant dysfunction in dopamine metabolism akin to that noted in human RLS, as well as an increased latency in response to thermal stimuli. To our knowledge, this is the first study to demonstrate that the endogenous opioid system may play a role in iron metabolism and subsequently in the pathogenesis of anemia. It is also the first study showing that opioid receptors are involved in the production of motor restlessness with a circadian predominance. Our findings support the role of endogenous opioids in the pathogenesis of RLS, and the triple KO mice can be used to understand the relationship between iron deficiency, anemia, dopaminergic dysfunction, and RLS. [ABSTRACT FROM AUTHOR]

Caffeine is the worldwide most frequently consumed psychostimulant. Its availability is nearly unlimited and in Europe it is not subject to state regulation. Apart from its primary role as an ingredient or additive in numerous beverages it also has medical use in apnea of prematurity, as an adjuvant in pain therapy and has regulatory approval for the short-term treatment of symptoms of fatigue. In doses typically administered caffeine's mechanism of action as a psychostimulant is presumably primarily based on central antagonism at adenosine receptors (A 1 - und A 2A -receptors), which facilitates central inhibition of adenosine-mediated reduction of the activity of the dopaminergic and ascending arousal system. Metabolisation of caffeine mainly depends on cytochrome P450 1A2. Thus, factors that influence the activity of CYP 1A2 (e. g. medication, pregnancy), may induce remarkable changes of pharmacokinetic parameters. Caffeine improves vigilance, attention and reaction time, particularly in sleep-deprived individuals. Moreover, it may improve endurance performances in sports and muscle strength. Intoxications with caffeine are rare, however can be fatal. In general, caffeine use seems not harmful within typical doses of intake. Caffeine features several, however not all characteristics of potentially addictive drugs; withdrawal after termination of a longer period of use and tolerance are known. In the DSM-5 "caffeine use disorder" is categorized as a possible future disorder that currently needs further study. The pattern of caffeine use of patients should be considered in the medical practice., Competing Interests: Der Autor erklärt, dass keine Interessenkonflikte vorliegen,, (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To investigate recent evidence suggesting that social factors are causally related to the development of schizophrenia., Method: I conducted a sytematic review of MEDLINE to identify possibly relevant studies. The search was limited to peer-reviewed studies and review articles appearing in English-language journals since 1996. Studies were included if they used standardized diagnostic criteria for schizophrenia or standardized assessment instruments for psychotic symptoms., Results: Studies of migrants to western Europe provide compelling support for the notion that social factors contribute to the development of schizophrenia. Findings such as excessively high risk for schizophrenia in second-generation immigrants are difficult to explain solely in terms of biological or genetic factors. A growing number of studies implicate childhood exposure to social adversity as a risk factor for schizophrenia, although few studies have used prospective designs. The increased incidence of schizophrenia risk associated with urban birth and (or) urban upbringing suggests possible social causation, but these findings are more ambiguous. Thus far, no studies have explored actual mechanisms by which exposure to social factors might generate psychotic symptoms, although animal experiments suggest that social defeat or social exclusion may cause dopamine dysregulation or sensitization., Conclusions: The accumulating evidence suggesting a role for social factors in the development of schizophrenia arises primarily from studies of migrants conducted in Europe. The mechanisms by which social factors exert their influence remain unknown. Future investigations of social causation should clarify the temporal relation between exposure to social defeat and (or) social adversity and the development of psychotic symptoms.

Major depressive disorder (MDD) is a severe psychiatric disorder with a lifetime prevalence of about 15%.1 The importance of the genetic component is well accepted,2 but the mode of inheritance is complex and non-Mendelian. A line of evidence suggests the involvement of serotonin and dopamine neurotransmitters in the pathophysiology of depression. In the present study, 102 unipolar MDD patients and 172 healthy controls were genotyped for polymorphisms in four serotonergic and three dopaminergic candidate genes [tryptophan hydroxylase (TPH), serotonin receptor 2A (HTR2A), serotonin receptor 2C (HTR2C), serotonin transporter promoter region (5-HTTLPR), dopamine receptor D4 (DRD4), dopamine transporter (DAT1) and catechol-O-methyl transferase (COMT)]. There were no statistical differences between MDD patients and healthy controls in the genotypic and allelic distribution of all polymorphisms investigated. Thus, our study does not support a major role for these polymorphisms in contributing to susceptibility to MDD, although it does not preclude minor effects.

This review focuses on two restorative strategies against Parkinson's disease: (1) intrastriatal implantation of fetal dopamine producing cells and (2) application of neurotrophic factors. (1) Neuronal transplantation of dopaminergic embryonic ventral mesencephalic cells aims at compensating the striatal dopamine deficit in Parkinson's disease. Clinically, dopaminergic ventral mesencephalic grafts have been demonstrated to ameliorate rigidity, bradykinesia, and efficacy of L-DOPA therapy, for instance reduction of L-DOPA-induced dyskinesias and ON-OFF-fluctuations. Future experimental refinements predominantly concern the improvement of survival of the transplanted fetal dopaminergic neurons and the use of genetically modified cells. (2) Neurotrophic factor therapy relates to the prevention and/or restoration of the progressing nigral cell loss in Parkinson's disease. In this regard special emphasis is put on the newly characterized glial cell line-derived neurotrophic factor (GDNF). More recent results and perspectives of this concept are discussed.