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Restless legs syndrome (RLS) is a chronic sensorimotor disorder diagnosed by clinical symptoms. It is challenging to translate the diagnostic self-reported features of RLS to animals. To help researchers design their experiments, a task force was convened to develop consensus guidelines for experimental readouts in RLS animal models. The RLS clinical diagnostic criteria were used as a starting point. After soliciting additional important clinical features of RLS, a consensus set of methods and outcome measures intent on capturing these features-in the absence of a face-to-face interview-was generated and subsequently prioritized by the task force. These were, in turn, translated into corresponding methods and outcome measures for research on laboratory rats and mice and used to generate the final recommendations. The task force recommended activity monitoring and polysomnography as principal tools in assessing RLS-like behavior in rodents. Data derived from these methods were determined to be the preferred surrogate measures for the urge to move, the principal defining feature of RLS. The same tools may be used to objectively demonstrate sleep-state features highly associated with RLS, such as sleep disturbance and number and periodicity of limb movements. Pharmacological challenges and dietary or other manipulations that affect iron availability are desirable to aggravate or improve RLS-like behavior and lend greater confidence that the animal model being proffered replicates key clinical features of RLS. These guidelines provide the first consensus experimental framework for researchers to use when developing new rodent models of RLS. © 2020 International Parkinson and Movement Disorder Society.

Morphine is routinely used for pain management in heart failure patients. However, extended morphine exposure associates with major adverse cardiovascular events. Reports link the dopamine receptor D2-family with morphine-induced nociception modulation. This study first assessed whether morphine induces cardiac remodeling in healthy mice, then whether DRD3 agonist (DRD3ag, D2-family member) adjunct therapy prevents morphine-induced cardiac remodeling. Mice received morphine (2 mg/kg/day i. p.) for 7 days (D7) and were either euthanized at D7 or kept 7 more days without morphine (i.e. withdrawal period, D8-D14): G1, morphine; G2, morphine/DRD3ag; G3, morphine + withdrawal; G4, morphine/DRD3ag + withdrawal; G5, morphine + withdrawal/DRD3ag. A separate cohort of animals were used as naïve tissues. We evaluated functional and molecular parameters of cardiac remodeling. Although we did not observe significant differences in systolic function, morphine induced both interstitial fibrosis and cardiomyocyte hypertrophy. Interestingly, DRD3ag abolished these effects. Compared to naïve tissues, collagen 1 increased after withdrawal in G3 and G4 and collagen 3 increased in G1-G4 but at higher levels in G1 and G2. Only G5 did not show collagen differences compared to naïve, suggesting DRD3ag treatment during withdrawal may be beneficial and prevent morphine-induced fibrosis. Smad2/3 phosphorylation increased during withdrawal, indicating a likely upstream pathway for the observed morphine-induced fibrosis. Overall, our data suggest that DRD3ag adjunct therapy decreases morphine-induced adverse cardiac remodeling.

Restless Legs Syndrome (RLS) is characterized by an urge to move the legs, usually accompanied by uncomfortable sensations. RLS symptoms generally happen at night and can be relieved by movements. Genetic studies have linked polymorphisms in BTBD9 to a higher risk of RLS. Knockout of BTBD9 homolog in mice (Btbd9) and fly results in RLS-like phenotypes. A dysfunctional dopaminergic system is associated with RLS. However, the function of BTBD9 in the dopaminergic system and RLS is not clear. Here, we made use of the simple Caenorhabditis elegans nervous system. Loss of hpo-9, the worm homolog of BTBD9, resulted in hyperactive egg-laying behavior. Analysis of genetic interactions between hpo-9 and genes for dopamine receptors (dop-1, dop-3) indicated that hpo-9 and dop-1 worked similarly. Reporter assays of dop-1 and dop-3 revealed that hpo-9 knockout led to a significant increase of DOP-3 expression. This appears to be evolutionarily conserved in mice with an increased D(2) receptor (D(2)R) mRNA in the striatum of the Btbd9 knockout mice. Furthermore, the striatal D(2)R protein was significantly decreased and the dynamin I was increased. Overall, activities of DA neurons in the substantia nigra were not altered, but the peripheral D(1)R pathway was potentiated in the Btbd9 knockout mice. Finally, we generated and characterized dopamine neuron-specific Btbd9 knockout mice and detected active-phase sleepiness, suggesting that dopamine neuron-specific loss of Btbd9 is sufficient to disturb the sleep. Our results suggest that increased activities in the D(1)R pathway, decreased activities in the D(2)R pathway, or both may contribute to RLS.

Restless Legs Syndrome (RLS) is a sensorimotor disorder that severely affects sleep. It is characterized by an urge to move the legs that is often accompanied by periodic limb movements during sleep (PLMS). RLS has a high prevalence in the population and is usually a life-long condition. While its origins remain unclear, RLS is initially highly responsive to treatment with dopaminergics that target the D3 receptor. However, over time patients often develop a gradual tolerance that can lead to the emergence of adverse effects and the augmentation of the symptoms. While the basal ganglia and the striatum control leg movements, the lumbar spinal cord is the gateway for the sensory processing of the symptoms and critical for the associated leg movements. D3 receptors are highly expressed in nucleus accumbens (NAc) of the striatum and the sensory-processing areas of the spinal dorsal horn. In contrast, D1 receptors are strongly expressed throughout the entire striatum and in the ventral horn of the spinal cord. Long-term treatment with D3 receptor full agonists is associated with an upregulation of the D1 receptor subtype, and D3 and D1 receptors can form functional heteromers, in which the D3R controls the D1R function. It is conceivable that the switch from beneficial treatment to augmentation observed in RLS patients after prolonged D3R agonist exposure may be the result of unmasked D1-like receptor actions.

Restless legs syndrome (RLS) is a sensorimotor disorder that severely affects sleep. It is characterized by an urge to move the legs, which is often accompanied by periodic limb movements during sleep. RLS has a high prevalence in the population and is usually a life-long condition. While its origins remain unclear, RLS is initially highly responsive to treatment with dopaminergic agonists that target D2-like receptors, in particular D2 and D3, but the long-term response is often unsatisfactory. Over the years, several putative animal models for RLS have been developed, mainly based on the epidemiological and neurochemical link with iron deficiency, treatment efficacy of D2-like dopaminergic agonists, or genome-wide association studies that identified risk factors in the patient population. Here, we present the first systematic review of putative animal models of RLS, provide information about their face and construct validity, and report their role in deciphering the underlying pathophysiological mechanisms that may cause or contribute to RLS. We propose that identifying the causal links between genetic risk factors, altered organ functions, and changes to molecular pathways in neural circuitry will eventually lead to more effective new treatment options that bypass the side effects of the currently used therapeutics in RLS, especially for long-term therapy.

Opioids are not universally effective for treating neuropathic pain following spinal cord injury (SCI), a finding that we previously demonstrated in a rat model of SCI. The aim of this study was to determine analgesic response of morphine-responsive and nonresponsive SCI rats to adjunct treatment with dopamine modulators and to establish if the animal groups expressed distinct metabolomic profiles. Thermal thresholds were tested in female Long Evans rats (N = 45) prior to contusion SCI, after SCI and following injection of morphine, morphine combined with dopamine modulators, or dopamine modulators alone. Spinal cord and striatum samples were processed for metabolomics and targeted mass spectrometry. Morphine provided analgesia in 1 of 3 of SCI animals. All animals showed improved analgesia with morphine + pramipexole (D3 receptor agonist). Only morphine nonresponsive animals showed improved analgesia with the addition of SCH 39166 (D1 receptor antagonist). Metabolomic analysis identified 3 distinct clusters related to the tyrosine pathway that corresponded to uninjured, SCI morphine-responsive and SCI morphine-nonresponsive groups. Mass spectrometry showed matching differences in dopamine levels in striatum and spinal cord between these groups. The data suggest an overall benefit of the D3 receptor system in improving analgesia, and an association between morphine responsiveness and metabolomic changes in the tyrosine/dopamine pathways in striatum and spinal cord. PERSPECTIVE: Spinal cord injury (SCI) leads to opioid-resistant neuropathic pain that is associated with changes in dopamine metabolomics in the spinal cord and striatum of rats. We present evidence that adjuvant targeting of the dopamine system may be a novel pain treatment approach to overcome opioid desensitization and tolerance after SCI.

A secondary consequence of spinal cord injury (SCI) is debilitating chronic neuropathic pain, which is commonly morphine resistant and inadequately managed by current treatment options. Consequently, new pain management therapies are desperately needed. We previously reported that dopamine D3 receptor (D3R) dysfunction was associated with opioid resistance and increases in D1 receptor (D1R) protein expression in the spinal cord. Here, we demonstrate that in a model of SCI neuropathic pain, adjuvant therapy with a D3R agonist (pramipexole) or D1R antagonist (SCH 39166) can restore the analgesic effects of morphine and reduce reward potential. Prior to surgery thermal and mechanical thresholds were tested in three groups of female rats (naïve, sham, SCI). After surgery, testing was repeated under the following drug conditions: 1) saline, 2) morphine, 3) pramipexole, 4) SCH 39166, 5) morphine + pramipexole, and 6) morphine + SCH 39166. Reward potential of morphine and both combinations was assessed using conditioned place preference. Following SCI, morphine + pramipexole and morphine + SCH 39166 significantly increased both thermal and mechanical thresholds. Morphine alone induced conditioned place preference, but when combined with either the D3R agonist or D1R antagonist preference was not induced. The data suggest that adjunct therapy with receptor-specific dopamine modulators can restore morphine analgesia and decrease reward potential and thus, represents a new target for pain management therapy after SCI.

Sleep-related movements comprise a broad spectrum of simple and usually stereotyped movements that are sometimes associated with sleep disturbance (insomnia, sleep fragmentation, and non-restorative sleep). They may represent a physiological variant or a sleep disorder, depending on their intensity, frequency, and associated sleep disruption degree. Sleep-related movements involve usually the lower limbs; they can be idiopathic or associated with other sleep disorders, neurological disease, and medical condition or occur as a consequence of drug use. Several pathophysiological hypotheses have been proposed, but for the majority of these disorders, the neurobiological mechanism is far from being completely understood. Further studies are needed to elucidate the pathophysiology of sleep-related movements in order to better appreciate their clinical significance. This chapter describes the neurobiology of sleep-related movements, namely, periodic limb movements, alternating leg muscle activation, hypnagogic foot tremor, high-frequency myoclonus, excessive fragmentary myoclonus, propriospinal myoclonus at sleep onset, neck myoclonus during sleep, sleep bruxism, sleep-related rhythmic movement disorder, sleep-related leg cramps, and sleep starts. We also present a mechanistic model of the potential role of the spinal central pattern generator for locomotion in generating the leg movements.

Restless legs syndrome (RLS) is a common disorder. The population prevalence is 1.5% to 2.7% in a subgroup of patients having more severe RLS with symptoms occurring 2 or more times a week and causing at least moderate distress. It is important for primary care physicians to be familiar with the disorder and its management. Much has changed in the management of RLS since our previous revised algorithm was published in 2013. This updated algorithm was written by members of the Scientific and Medical Advisory Board of the RLS Foundation based on scientific evidence and expert opinion. A literature search was performed using PubMed identifying all articles on RLS from 2012 to 2020. The management of RLS is considered under the following headings: General Considerations; Intermittent RLS; Chronic Persistent RLS; Refractory RLS; Special Circumstances; and Alternative, Investigative, and Potential Future Therapies. Nonpharmacologic approaches, including mental alerting activities, avoidance of substances or medications that may exacerbate RLS, and oral and intravenous iron supplementation, are outlined. The choice of an alpha2-delta ligand as first-line therapy for chronic persistent RLS with dopamine agonists as a second-line option is explained. We discuss the available drugs, the factors determining which to use, and their adverse effects. We define refractory RLS and describe management approaches, including combination therapy and the use of high-potency opioids. Treatment of RLS in pregnancy and childhood is discussed.

The spinal cord contains a highly collateralized network of descending dopamine (DA) fibers that stem from the dorso-posterior hypothalamic A11 region in the brain, however, the modulatory actions of DA have generally only been assessed in lumbar segments L2-L5. In contrast to these exclusively sensorimotor segments, spinal cords segments T1-L2 and, in mouse, L6-S2, additionally contain the intermediolateral (IML) nucleus, the origin of autonomic nervous system (ANS). Here, we tested if the different spinal circuits in sensorimotor and IML-containing segments react differently to the modulation of the monosynaptic reflex (MSR) by DA. Bath-application of DA (1 μM) led to a decrease of MSR amplitude in L3-L5 segments; however, in IML-containing segments (T10-L2, and S1/2) the MSR response was facilitated. We did not observe any difference in the response between thoracic (sympathetic) and lumbosacral (parasympathetic) segments. Application of the D2-receptor agonists bromocriptine or quinpirole mimicked the effects of DA, while blocking D2 receptor pathways with raclopride or application with the D1-receptor agonist SKF 38393 led to an increase of the MSR in L3-L5 segments and a decrease of the MSR in IML-containing segments. In contrast, in the presence of the gap-junction blockers, carbenoloxone and quinine, DA modulatory actions in IML-containing segments were similar to those of sensorimotor L3-L5 segments. We suggest that DA modulates MSR amplitudes in the spinal cord in a segment-specific manner, and that the differential outcome observed in ANS segments may be a result of gap junctions in the IML.

While the role of the ascending dopaminergic system in brain function and dysfunction has been a subject of extensive research, the role of the descending dopaminergic system in spinal cord function and dysfunction is just beginning to be understood. Adenosine plays a key role in the inhibitory control of the ascending dopaminergic system, largely dependent on functional complexes of specific subtypes of adenosine and dopamine receptors. Combining a selective destabilizing peptide strategy with a proximity ligation assay and patch-clamp electrophysiology in slices from male mouse lumbar spinal cord, the present study demonstrates the existence of adenosine A1-dopamine D1 receptor heteromers in the spinal motoneuron by which adenosine tonically inhibits D1 receptor-mediated signaling. A1-D1 receptor heteromers play a significant control of the motoneuron excitability, represent main targets for the excitatory effects of caffeine in the spinal cord and can constitute new targets for the pharmacological therapy after spinal cord injury, motor aging-associated disorders and restless legs syndrome.

OBJECTIVEIn tuberculum sellae meningioma (TSM) surgery, endonasal approaches are claimed to have a superior visual outcome compared with transcranial approaches. The authors question whether this is always true and analyze their series of cases of endoscope-assisted transcranial TSM surgery with special regard to the postoperative visual outcome in order to explore this issue.METHODSAll surgical procedures for TSM performed between 2003 and 2015 in the Department of Neurosurgery, University Medicine Greifswald, were retrospectively analyzed. Special attention was paid to the postoperative visual outcome.RESULTSDuring the study period, 15 patients (12 female and 3 male) underwent surgery for TSM. Gross-total resection was achieved in 14 cases (93.3%) and near-total resection in 1. One patient suffered from a major stroke during surgery and had to be excluded from further analyses. No other complications occurred. Preoperatively, visual acuity was disturbed in 12 patients (80%) and visual field deficits were present in 11 patients (73.3%). In 3 patients (20%), the TSM was an incidental finding. Postoperatively, ophthalmological examination revealed an improvement of visual acuity in 10 (90.9%) of 11 patients and improvement of visual field deficits in 9 (90%) of 10 patients; no deterioration of visual acuity or visual field was seen in any patient. Visual acuity and visual field improvement was observed in all patients who had surgery within 3 years after the onset of visual disturbances. No tumor recurrence was observed during follow-up (mean 32 months, range 3–134 months). TSMs were approached via a frontolateral craniotomy in 7 patients and via a supraorbital craniotomy in 8. The use of the endoscope as an assistive device led to improved tumor visualization and consequent removal in areas that were hidden in the microscopic view in 6 patients (40%).CONCLUSIONSThe present series confirms a favorable visual outcome after TSM surgery via supraorbital or frontolateral endoscope-assisted approaches. With endoscopic visualization, major manipulation of the optic apparatus could be avoided, perhaps affecting the favorable visual outcome.

In the European Union, and Germany in particular, the transport of livestock is an essential step in the meat production process. Pig transport especially, has frequently been the focus of public interest. In the last several decades, awareness for animal welfare has grown in society, which has often led to negative attitudes from the public towards farm animal husbandry and transportation. It is a well-known fact that a person’s knowledge and his/her attitude are strongly linked. Thus far, the connection between knowledge and attitude with regards to the transport of farm animals, especially pigs, has not been scientifically examined. In an online survey taken by 272 German consumers the effect that additional information in the form of written texts and pictures on public perception was examined. The results of this study reveal that this additional information does have a positive effect on the respondents’ attitudes, yet consumer attitudes remain rather negative.

Restless legs syndrome (RLS) is primarily treated with levodopa and dopaminergics that target the inhibitory dopamine receptor subtypes D3 and D2. The initial success of this therapy led to the idea of a hypodopaminergic state as the mechanism underlying RLS. However, multiple lines of evidence suggest that this simplified concept of a reduced dopamine function as the basis of RLS is incomplete. Moreover, long-term medication with the D2/D3 agonists leads to a reversal of the initial benefits of dopamine agonists and augmentation, which is a worsening of symptoms under therapy. The recent findings on the state of the dopamine system in RLS that support the notion that a dysfunction in the dopamine system may in fact induce a hyperdopaminergic state are summarized. On the basis of these data, the concept of a dynamic nature of the dopamine effects in a circadian context is presented. The possible interactions of cell adhesion molecules expressed by the dopaminergic systems and their possible effects on RLS and augmentation are discussed. Genome-wide association studies (GWAS) indicate a significantly increased risk for RLS in populations with genomic variants of the cell adhesion molecule receptor type protein tyrosine phosphatase D (PTPRD), and PTPRD is abundantly expressed by dopamine neurons. PTPRD may play a role in the reconfiguration of neural circuits, including shaping the interplay of G protein-coupled receptor (GPCR) homomers and heteromers that mediate dopaminergic modulation. Recent animal model data support the concept that interactions between functionally distinct dopamine receptor subtypes can reshape behavioral outcomes and change with normal aging. Additionally, long-term activation of one dopamine receptor subtype can increase the receptor expression of a different receptor subtype with opposite modulatory actions. Such dopamine receptor interactions at both spinal and supraspinal levels appear to play important roles in RLS. In addition, these interactions can extend to the adenosine A1 and A2A receptors, which are also prominently expressed in the striatum. Interactions between adenosine and dopamine receptors and dopaminergic cell adhesion molecules, including PTPRD, may provide new pharmacological targets for treating RLS. In summary, new treatment options for RLS that include recovery from augmentation will have to consider dynamic changes in the dopamine system that occur during the circadian cycle, plastic changes that can develop as a function of treatment or with aging, changes in the connectome based on alterations in cell adhesion molecules, and receptor interactions that may extend beyond the dopamine system itself.

The long-term treatment of chronic pain by opioids is limited by tolerance and risk of addiction/dependence. Previously, we have shown that combination treatment of morphine with a dopamine D

Dopaminergic treatments targeting the D3 receptor subtype to reduce the symptoms of RLS show substantial initial clinical benefits but fail to maintain their efficacy over time. Sensorimotor circuits in the spinal cord are the gateway for the sensory processing of the symptoms and critical for the associated leg movements that relieve the symptoms and the periodic limb movements that often develop during sleep. There is a high preponderance of the inhibitory D3 receptor in the sensory-processing areas of the spinal cord (dorsal horn), whereas the motor areas in the ventral horn more strongly express the excitatory D1 receptor subtype. D3 and D1 receptors can form functional heteromeric ensembles that influence each other. In the spinal cord, long-term treatment with D3 receptor agonists is associated with the upregulation of the D1 receptor subtype and block of D1 receptor function at this stage can restore the D3 receptor effect. Alternate scenarios for a role of dopamine involve a role for the D5 receptor in regulating motor excitability and for the D4 receptor subtype in controlling D3-like effects. A model emerges that proposes that the behavioral changes in RLS, while responsive to D3 receptor agonists, may be ultimately be the result of unmasked increased D1-like receptor activities.

Die Direktvermarktung von Lebensmitteln kann eine Einkommensalternative zur Produktion von cash crops f��r Landwirte darstellen. Sie hat sich vom einfachen Ab-Hof-Verkauf oder Wochenm��rkten zu einer professionellen Vermarktungsform mit vielseitigen Auspr��gungen entwickelt. Dabei unterscheiden sich die einzelnen Betriebe durch z.B. verschiedene Absatzwege, das Sortiment oder auch die Anzahl an Arbeitskr��ften. Obwohl die Direktvermarktung in der deutschen Landwirtschaft f��r einige Betriebe einen wichtigen Einkommensfaktor darstellt, existieren nur wenige Studien zur detaillierten Beschreibung von Direktvermarktungsbetrieben. An dieser Stelle setzt die hier durchgef��hrte empirische Studie mit 39 Direktvermarktungsbetrieben an. Durch die Bildung einer Typologie k��nnen vier unterschiedliche Betriebstypen identifiziert werden. Die Ergebnisse zeigen, dass ein Teil der Betriebe als Vollsortimenter auftritt, ��hnlich wie der Lebensmitteleinzelhandel. Ein anderer Teil hat sich auf den Verkauf an Wiederverk��ufer, bspw. direkt an den Lebensmitteleinzelhandel, spezialisiert. Aber auch der klassische Verkauf ��ber Hofl��den mit dem Schwerpunkt auf eigenen Produkten ist weiterhin pr��sent am Markt. Die Typologie kann landwirtschaftlichen Direktvermarktern oder Neueinsteigern erfolgreiche Produktions- und Vermarktungsperspektiven abseits des landwirtschaftlichen Mainstreams aufzeigen. Direct marketing of food may enable farmers to generate higher incomes. Originally, direct marketing comprised on farm sales and weekly markets, but it has recently developed into a professionalized marketing approach of various forms. Hereby, the direct marketers differ by marketing channel, the range of products or the number of labour used. Although direct marketing is an important source of income for some farms, only a few studies have addressed a detailed description of direct marketers so far. This research gap is tackled with by an empirical study of 39 direct marketers. A cluster analysis identified 4 types of direct marketers. Some direct marketers try to offer a full range of products, similar to a retail strategy. Others are specialized in selling to specific actors in the value chain, e.g. the retail. Also the results confirm the classic on farm shop to sell mainly its own produce. The typology may provide a useful guidance for direct marketers or regular farmers when structuring their future farm business.

Dopaminergic treatments targeting the D3 receptor subtype to reduce the symptoms of RLS show substantial initial clinical benefits but fail to maintain their efficacy over time. Sensorimotor circuits in the spinal cord are the gateway for the sensory processing of the symptoms and critical for the associated leg movements that relieve the symptoms and the periodic limb movements that often develop during sleep. There is a high preponderance of the inhibitory D3 receptor in the sensory-processing areas of the spinal cord (dorsal horn), whereas the motor areas in the ventral horn more strongly express the excitatory D1 receptor subtype. D3 and D1 receptors can form functional heteromeric ensembles that influence each other. In the spinal cord, long-term treatment with D3 receptor agonists is associated with the upregulation of the D1 receptor subtype and block of D1 receptor function at this stage can restore the D3 receptor effect. Alternate scenarios for a role of dopamine involve a role for the D5 receptor in regulating motor excitability and for the D4 receptor subtype in controlling D3-like effects. A model emerges that proposes that the behavioral changes in RLS, while responsive to D3 receptor agonists, may be ultimately be the result of unmasked increased D1-like receptor activities.

Restless legs syndrome, also known as Willis-Ekbom disease, is a common neurological condition whose manifestation is affected by complex environmental and genetic interactions. Restless legs syndrome can occur on its own, mostly at a young age, or with comorbidities such as cardiovascular disease, diabetes, and arterial hypertension, making it a difficult condition to properly diagnose. However, the concept of restless legs syndrome as being two entities, primary or secondary to another condition, has been challenged with genetic data providing further insight into the pathophysiology of the condition. Although dopaminergic treatment was formerly the first-line therapy, prolonged use can result in a serious worsening of symptoms known as augmentation. Clinical studies on pregabalin, gabapentin enacarbil, oxycodone-naloxone, and iron preparations have provided new treatment options, but most patients still report inadequate long-term management of symptoms. Studies of the hypoxic pathway activation and iron deficiency have provided valuable information about the pathophysiology of restless legs syndrome that should now be translated into new, more effective treatments for restless legs syndrome.

While the role of the ascending dopaminergic system in brain function and dysfunction has been a subject of extensive research, the role of the descending dopaminergic system in spinal cord function and dysfunction is just beginning to be understood. Adenosine plays a key role in the inhibitory control of the ascending dopaminergic system, largely dependent on functional complexes of specific subtypes of adenosine and dopamine receptors. Combining a selective destabilizing-peptide strategy with a proximity ligation assay and patch-clamp electrophysiology in slices from male mouse lumbar spinal cord, the present study demonstrates the existence of adenosine A(1)-dopamine D(1) receptor heteromers in the spinal motoneuron by which adenosine tonically inhibits D(1) receptor-mediated signaling. A(1)-D(1) receptor heteromers play a significant control of the motoneuron excitability, represent main targets for the excitatory effects of caffeine in the spinal cord and can constitute new targets for the pharmacological therapy after spinal cord injury, motor aging-associated disorders and Restless Legs Syndrome.

Farmer-to-consumer direct marketing provides an alternative marketing strategy for farmers, ensuring their income while also meeting consumers' increasing demand for local food. This study evaluates the challenging factors of this marketing channel from the farmers' viewpoint. A CAPI survey was carried out among 121 German livestock owners. The results of a cluster analysis demonstrate that the location of the farm represents the most challenging requirement for the interviewed farmers. The cluster analysis additionally reveals that most of the livestock owners see problems with the implementation of requirements concerning the personal challenges of direct farm marketing (especially hygiene regulations, self-motivation and customer contact).

The symptomatology of Restless Legs Syndrome (RLS) includes periodic leg movements during sleep (PLMS), dysesthesias, and hyperarousal. Alterations in the dopaminergic system, a presynaptic hyperdopaminergic state, seem to be involved in PLMS, while alterations in glutamatergic neurotransmission, a presynaptic hyperglutamatergic state, seem to be involved in hyperarousal and also PLMS. Brain iron deficiency (BID) is well-recognized as a main initial pathophysiological mechanism of RLS. BID in rodents have provided a pathogenetic model of RLS that recapitulates the biochemical alterations of the dopaminergic system of RLS, although without PLMS-like motor abnormalities. On the other hand, BID in rodents reproduces the circadian sleep architecture of RLS, indicating the model could provide clues for the hyperglutamatergic state in RLS. We recently showed that BID in rodents is associated with changes in adenosinergic transmission, with downregulation of adenosine A1 receptors (A1R) as the most sensitive biochemical finding. It was hypothesized that A1R downregulation leads to hypersensitive striatal glutamatergic terminals and facilitation of striatal dopamine release. Hypersensitivity of striatal glutamatergic terminals was demonstrated by an optogenetic-microdialysis approach in the rodent with BID, indicating that it could represent a main pathogenetic factor that leads to PLMS in RLS. In fact, the dopaminergic agonists pramipexole and ropinirole and the α2δ ligand gabapentin, used in the initial symptomatic treatment of RLS, completely counteracted optogenetically-induced glutamate release from both normal and BID-induced hypersensitive corticostriatal glutamatergic terminals. It is a main tenet of this essay that, in RLS, a single alteration in the adenosinergic system, downregulation of A1R, disrupts the adenosine-dopamine-glutamate balance uniquely controlled by adenosine and dopamine receptor heteromers in the striatum and also the A1R-mediated inhibitory control of glutamatergic neurotransmission in the cortex and other non-striatal brain areas, which altogether determine both PLMS and hyperarousal. Since A1R agonists would be associated with severe cardiovascular effects, it was hypothesized that inhibitors of nucleoside equilibrative transporters, such as dipyridamole, by increasing the tonic A1R activation mediated by endogenous adenosine, could represent a new alternative therapeutic strategy for RLS. In fact, preliminary clinical data indicate that dipyridamole can significantly improve the symptomatology of RLS.

Für viele Landwirte ist bei der landwirtschaftlichen Direktvermarktung von Lebensmitteln der Standort einer der einflussreichsten Faktoren bezogen auf den Erfolg der Unternehmung. Die hier vorgestellte multi-methoden Studie untersucht den Erfolgsfaktor "Standort" bei der landwirtschaftlichen Direktvermarktung unter Berücksichtigung verschiedener Vermarktungswege. Die Analyse der qualitativen und quantitativen Daten bestätigt die Annahme vieler Landwirte, dass ein guter Standort einen positiven Einfluss auf die Direktvermarktung hat. Gleichzeitigt wird jedoch deutlich, dass ein schlechter Standort nicht automatisch ein Ausschlusskriterium für eine erfolgreiche Direktvermarktung sein muss. Durch die Ausnutzung unterschiedlicher Absatzwege an den Endkunden, wie z.B. Markstände oder Onlinehandel, aber auch durch eine Belieferung von Wiederverkäufern lässt sich auch an vermeidlich schwierigen Standorten in ländlicher Lage erfolgreich Direktvermarktung betreiben.

Restless legs syndrome (RLS) is commonly treated with the dopamine agonists pramipexole, and rotigotine, which target the inhibitory dopamine receptor subtype D3R. While initially highly effective, these compounds lose their efficacy in treating RLS over time, and long-term therapy regularly leads to a worsening of the symptoms (augmentation). This dopamine agonist-induced augmentation has become a prime concern in the treatment of RLS, and while alternate therapies are being proposed, the mechanisms leading to augmentation remain opaque. Evidence suggests that the prolonged D3R treatment may lead to a hyper-dopaminergic state and involve the excitatory dopamine D1 receptor (D1R) subtype. We here present an animal model in which we can test acute and long-term effects of dopamine D3R agonists in a behavior setting relevant to RLS and in which we can induce a switch of the drug effect similar to the one observed in RLS patients under chronic therapy. We also present evidence that we can reverse this long-term effect by blocking the D1R. Together, data from our new animal model indicate that the mechanisms leading to augmentation in RLS patients after long-term use of the currently used dopamine receptor agonists may be related to a D3R-induced upregulation of the D1R system. As such, our model can be used to assess the interactions between D3R and D1R and unravel the mechanisms that lead to augmentation, and it has the potential to serve as a Launchpad for the development of new pharmacological strategies for the treatment of both RLS and augmentation.

Opioids have a prominent role in managing acute pain. However, long-term management of pain with opioids is complicated, as tolerance for the drug develops, increasing the risk for misuse and abuse. The need exists for chronically effective treatments that minimize the rewarding component. Our data shows that, in animal models, combining low-dose morphine with a dopamine 3 receptor (DR3) agonist or dopamine 1 receptor (D1R) antagonist provides superior analgesia against acute painful stimuli compared to morphine alone. The current study examined if adjuvant treatment with D3R agonists or D1R antagonists can also prevent the development of tolerance to and reduce the addictive potential of morphine. Thermal and mechanical thresholds were tested in 16, female Long-Evans rats before and after a single subcutaneous dose of morphine (2mg/kg). Rats were then randomized to 1 of 4 chronic drug conditions: saline; morphine (5mg/kg/day); morphine + pramipexole (D3R agonist, 0.1mg/kg/day); morphine + SCH39166 (D1R antagonist, 0.1mg/kg/day). Drugs were delivered for 14 days via subcutaneous osmotic pump. Analgesia provided by an acute dose of morphine was re-assessed at 7 and 14 days after initiation of drug delivery. Addictive potential of each drug combination was determined using conditioned place preference (CPP). Prior to drug delivery, acute morphine injection increased thermal and mechanical thresholds in all animals. Fourteen days after chronic administration of morphine, sensory thresholds did not change in response to acute morphine (i.e. animals were tolerant). In contrast, sensory thresholds were increased in animals that had received morphine in combination with either dopamine receptor modulator. The addition of either dopamine receptor modulator to morphine also reduced the preference for the drug compared to morphine alone. Adjuvant therapy with clinically-available dopamine receptor agonists or antagonists can prevent the development of morphine tolerance and reduce the rewarding effect of morphine alone.

Resistance characteristics were determined for a total of 27 wood-based materials containing native soft- and hardwoods, differently modified timbers and preservative treated timbers. A functional relation between measured electrical resistance and gravimetrical wood moisture content (MC) was established in a range between 15 and 50 % MC. Most precise MC estimation was found for salt-treated timber (±2.5 %), followed by native timber (±3.5 %) and modified timber (±7 %) in the hygroscopic range. As expected, preciseness decreased above fiber saturation, but was still sufficient for native timber (±8 %) and preservative treated wood (±5 %) at approx. 50 % MC.

Der Roggenanbau ist besonders auf leichten Böden attraktiv. Durch klimatische Veränderungen und eine zukünftig stärkere Reglementierung der Düngung wird er zunehmend auch auf besseren Stand-orten interessant. Damit eine Erweiterung des Roggenanbaus auch ökonomisch attraktiv wird, müssen die Absatzwege ausgebaut werden. Dafür bietet die Schweinefütterung noch erhebliches Potenzial. Roggen spielt als Getreidekomponente in der Schweinefütterung, trotz ökonomischer Vorteile gegenüber anderen Getreidearten, wie zum Beispiel Weizen, noch immer eine untergeordnete Rolle. Die folgende Arbeit untersucht, welche Faktoren den Roggeneinsatz und die Höhe der Roggeneinsatzmenge in der Schweinefütterung beeinflussen. Die Ergebnisse einer Umfrage unter Schweinehaltern in Deutschland weisen persönliche, externe/soziale und betriebsinterne Faktoren auf. Ein zwei-stufiges ökonometrisches Modell erlaubt dabei eine getrennte Betrachtung der Faktoren, die im Zusammenhang mit der Roggeneinsatzmenge stehen und jener Faktoren, die mit gänzlichem Verzicht auf Roggen in der Fütterung in Verbindung gebracht werden können. Bei persönlichen Einstellungen zeigt sich, dass die negativere Einschätzung von Roggenvermeidern bereits beim Anbau beginnt. Bei betriebsinternen Faktoren sticht der Roggenanbau auf dem eigenen Betrieb hervor. Informationskampagnen sollten sich daher auf beide Aspekte beziehen, Anbau und Fütterungseinsatz. Ähnlich verhält es sich mit den Einstellungen zur Mutterkornbelastung, welche besser eingeordnet werden können, wenn sie in Verbindung mit der Fusarium-Anfälligkeit, relativ zum Weizen, diskutiert werden. Betriebe, die ihr Futter selber mischen, sowie einen betrieblichen Schwerpunkt in der Schweinehaltung haben, stehen dem Roggeneinsatz in der Schweinefütterung positiv gegenüber und helfen bei der Identifikation von Marktsegmenten mit Optimierungspotenzial durch verstärkten Roggeneinsatz.

Tiertransporte sind in der Europäischen Union sowie in Deutschland ein essentieller Produktionsschritt in der Fleischproduktion. Dabei steht der Transport von Schweinen immer wieder im Fokus der öffentlichen Diskussion. Ein wachsendes Tierschutzbewusstsein in einigen Teilen der Gesellschaft führt zu einer kritischen Haltung gegenüber der Tiergerechtigkeit von Tiertransporten. Aus anderen Forschungsarbeiten ist bekannt, dass eine Veränderung des Wissens einer Person durch Informationen, Auswirkungen auf die Einstellung haben kann. Dieser Zusammenhang wurde wissenschaftlich bei dem Transport von Schweinen bisher nicht untersucht und wird in der vorliegenden Arbeit aufgegriffen. In einer Onlinebefragung von 272 deutschen Verbrauchern wird der Einfluss von Informationen in Form von Texten und Bildern auf die Einstellung der Probanden gegenüber Tiertransporten untersucht. Die Ergebnisse zeigen, dass sich die untersuchten Informationen positiv auf die Einstellung der Verbraucher auswirken. Jedoch ist zu beobachten, dass trotz der zusätzlichen Informationen die Einstellung zu Tiertransporten eher ablehnend bleibt. In the European Union, and Germany in particular, the transport of livestock is an essential step in the meat production process. Pig transport especially, has frequently been the focus of public interest. In the last several decades, awareness for animal welfare has grown in society, which has often led to negative attitudes from the public towards farm animal husbandry and transportation. It is a well-known fact that a person’s knowledge and his/her attitude are strongly linked. Thus far, the connection between knowledge and attitude with regards to the transport of farm animals, especially pigs, has not been scientifically examined. In an online survey taken by 272 German consumers the effect that additional information in the form of written texts and pictures on public perception was examined. The results of this study reveal that this additional information does have a positive effect on the respondents’ attitudes, yet consumer attitudes remain rather negative.

Morphine actions involve the dopamine (DA) D1 and D3 receptor systems (D1R and D3R), and the responses to morphine change with age. We here explored in differently aged wild-type (WT) and D3R knockout mice (D3KO) the interactions of the D1R/D3R systems with morphine in vivo at three different times of the animals’ lifespan (2 months, 1 year, and 2 years). We found that: (1) thermal pain withdrawal reflexes follow an aging-associated phenotype, with relatively longer latencies at 2 months and shorter latencies at 1 year, (2) over the same age range, a dysfunction of the D3R subtype decreases reflex latencies more than aging alone, (3) morphine altered reflex responses in a dose-dependent manner in WT animals and changed at its higher dose the phenotype of the D3KO animals from a morphine-resistant state to a morphine-responsive state, (4) block of D1R function had an aging-dependent effect on thermal withdrawal latencies in control animals that, in old animals, was stronger than that of low-dose morphine. Lastly, (5) block of D1R function in young D3KO animals mimicked the behavioral phenotype observed in the aged WT. Our proof-of-concept data from the rodent animal model suggest that, with age, block of D1R function may be considered as an alternative to the use of morphine, to modulate the response to painful stimuli.

Frequency-dependent modulation and dopamine (DA) receptors strongly modulate neural circuits in the spinal cord. Of the five known DA receptor subtypes, the D3 receptor has the highest affinity to DA, and D3-mediated actions are mainly inhibitory. Using an animal model of spinal sensorimotor dysfunction, the D3 receptor knockout mouse (D3KO), we investigated the physiological consequences of D3 receptor dysfunction on pain-associated signaling pathways in the spinal cord, the initial integration site for the processing of pain signaling. In the D3KO spinal cord, inhibitory actions of DA on the proprioceptive monosynaptic stretch reflex are converted from depression to facilitation, but its effects on longer-latency and pain-associated reflex responses and the effects of FM have not been studied. Using behavioral approaches in vivo, we found that D3KO animals exhibit reduced paw withdrawal latencies to thermal pain stimulation (Hargreaves' test) over wild type (WT) controls. Electrophysiological and pharmacological approaches in the isolated spinal cord in vitro showed that constant current stimulation of dorsal roots at a pain-associated frequency was associated with a significant reduction in the frequency-dependent modulation of longer-latency reflex (LLRs) responses but not monosynaptic stretch reflexes (MSRs) in D3KO. Application of the D1 and D2 receptor agonists and the voltage-gated calcium-channel ligand, pregabalin, but not DA, was able to restore the frequency-dependent modulation of the LLR in D3KO to WT levels. Thus we demonstrate that nociception-associated LLRs and proprioceptive MSRs are differentially modulated by frequency, dopaminergics and the Ca(2+) channel ligand, pregabalin. Our data suggest a role for the DA D3 receptor in pain modulation and identify the D3KO as a possible model for increased nociception.