Distinct roles of presynaptic dopamine receptors in the differential modulation of the intrinsic synapses of medium-spiny neurons in the nucleus accumbens

Background: In both schizophrenia and addiction, pathological changes in dopamine release appear to induce alterations in the circuitry of the nucleus accumbens that affect coordinated thought and motivation. Dopamine acts principally on medium-spiny GABA neurons, which comprise 95% of accumbens neurons and give rise to the majority of inhibitory synapses in the nucleus. To examine dopamine action at single medium-spiny neuron synapses, we imaged Ca2+ levels in their presynaptic varicosities in the acute brain slice using two-photon microscopy. Results: Presynaptic Ca2+ rises were differentially modulated by dopamine. The D1/D5 selective agonist SKF81297 was exclusively facilitatory. The D2/D3 selective agonist quinpirole was predominantly inhibitory, but in some instances it was facilitatory. Studies using D2 and D3 receptor knockout mice revealed that quinpirole inhibition was either D2 or D3 receptor-mediated, while facilitation was mainly D3 receptor-mediated. Subsets of varicosities responded to both D1 and D2 agonists, showing that there was significant co-expression of these receptor families in single medium-spiny neurons. Neighboring presynaptic varicosities showed strikingly heterogeneous responses to DA agonists, suggesting that DA receptors may be differentially trafficked to individual varicosities on the same medium-spiny neuron axon. Conclusion: Dopamine receptors are present on the presynaptic varicosities of medium-spiny neurons, where they potently control GABAergic synaptic transmission. While there is significant coexpression of D1 and D2 family dopamine receptors in individual neurons, at the subcellular level, these receptors appear to be heterogeneously distributed, potentially explaining the considerable controversy regarding dopamine action in the striatum, and in particular the degree of dopamine receptor segregation on these neurons. Assuming that post-receptor signaling is restricted to the microdomains of medium-spiny neuron varicosities, the heterogeneous distribution of dopamine receptors on individual varicosities is likely to encode patterns in striatal information processing

State space analysis of sleep after traumatic brain injury in rats

Objectives: Sleep-wake disturbances occur frequently after traumatic brain injury (TBI). Therefore, we aimed at studying the dynamic features of sleep after severe TBI in a rat model of traumatic brain injury. Methods: We obtained 24 h encephalographic recordings at different time points after TBI and analyzed the signal using a novel frequency based EEG analysis technique (state space analysis). In this quantitative sleep analysis approach, velocity in state space represents behavioral state instability. Results: We found a significantly higher mean velocity of slow wave sleep 7 days after TBI as compared to the control group (p=0.04, 2-sided t-test). This transient effect was no longer seen after 28 days and was not observed in the control group. Conclusions: The observed short-lasting elevation of state space velocity can be interpreted as a transient sleep state instability after TBI. These results shed a new light into the dynamics of pathological changes of sleep architecture after TBI that are not identified by conventional scoring and analysis techniques

Increased Sleep Need and Reduction of Tuberomammillary Histamine Neurons after Rodent Traumatic Brain Injury

Although sleep-wake disturbances are prevalent and well described after traumatic brain injury, their pathophysiology remains unclear, most likely because human traumatic brain injury is a highly heterogeneous entity that makes the systematic study of sleep-wake disturbances in relation to trauma-induced histological changes a challenging task. Despite increasing interest, specific and effective treatment strategies for post-traumatic sleep-wake disturbances are still missing. With the present work, therefore, we aimed at studying acute and chronic sleep-wake disturbances by electrophysiological means, and at assessing their histological correlates after closed diffuse traumatic brain injury in rats with the ultimate goal of generating a model of post-traumatic sleep-wake disturbances and associated histopathological findings that accurately represents the human condition. We assessed sleep-wake behavior by means of standard electrophysiological recordings before and 1, 7, and 28 days after sham or traumatic brain injury procedures. Sleep-wake findings were then correlated to immunohistochemically labeled and stereologically quantified neuronal arousal systems. Compared with control animals, we found that closed diffuse traumatic brain injury caused increased sleep need one month after trauma, and sleep was more consolidated. As histological correlate, we found a reduced number of histamine immunoreactive cells in the tuberomammillary nucleus, potentially related to increased neuroinflammation. Monoaminergic and hypocretinergic neurotransmitter systems in the hypothalamus and rostral brainstem were not affected, however. These results suggest that our rat traumatic brain injury model reflects human post-traumatic sleep-wake disturbances and associated histopathological findings very accurately, thus providing a study platform for novel treatment strategies for affected patients

Sleep Modulation Alleviates Axonal Damage and Cognitive Decline after Rodent Traumatic Brain Injury

UNLABELLED Traumatic brain injury (TBI) is a major cause of death and disability worldwide. It produces diffuse axonal injury (DAI), which contributes to cognitive impairment, but effective disease-modifying treatment strategies are missing. We have recently developed a rat model of closed skull TBI that reproduces human TBI consequences, including DAI and clinical sequelae such as memory impairment. Here, we investigated whether sleep modulation after trauma has an impact on DAI and memory outcome. We assessed cognition with the novel object recognition test and stained for amyloid precursor protein, a DAI marker. We found that both sleep induction and restriction acutely after TBI enhanced encephalographic slow-wave activity, markedly reduced diffuse axonal damage in the cortex and hippocampus, and improved memory impairment 2 weeks after trauma. These results suggest that enhancing slow-wave sleep acutely after trauma may have a beneficial disease-modifying effect in subjects with acute TBI. SIGNIFICANCE STATEMENT Traumatic brain injury (TBI) is a clinically important entity. Cognitive deficits belong to the most prevalent chronic posttraumatic symptoms, most likely due to diffuse axonal injury (DAI). A growing body of evidence suggests a role of sleep in the clearance of waste products in the brain, possibly including amyloid precursor protein (APP), a marker of DAI. In this study, we provide evidence that enhancement of slow-wave oscillatory activity in the delta-frequency range decreases the APP-immunoreactivity and preserves cognitive abilities after trauma, potentially offering novel, noninvasive treatment options for traumatic injury

Cost analysis for the implementation of a medication review with follow-up service in Spain

© 2017, Springer International Publishing. Background Medication review with follow-up (MRF) is a professional pharmacy service proven to be cost-effective. Its broader implementation is limited, mainly due to the lack of evidence-based implementation programs that include economic and financial analysis. Objective To analyse the costs and estimate the price of providing and implementing MRF. Setting Community pharmacy in Spain. Method Elderly patients using poly-pharmacy received a community pharmacist-led MRF for 6 months. The cost analysis was based on the time-driven activity based costing model and included the provider costs, initial investment costs and maintenance expenses. The service price was estimated using the labour costs, costs associated with service provision, potential number of patients receiving the service and mark-up. Main outcome measures Costs and potential price of MRF. Results A mean time of 404.4 (SD 232.2) was spent on service provision and was extrapolated to annual costs. Service provider cost per patient ranged from €196 (SD 90.5) to €310 (SD 164.4). The mean initial investment per pharmacy was €4594 and the mean annual maintenance costs €3,068. Largest items contributing to cost were initial staff training, continuing education and renting of the patient counselling area. The potential service price ranged from €237 to €628 per patient a year. Conclusion Time spent by the service provider accounted for 75–95% of the final cost, followed by initial investment costs and maintenance costs. Remuneration for professional pharmacy services provision must cover service costs and appropriate profit, allowing for their long-term sustainability