2 -1 Signaling in Nucleus Accumbens Is Necessary for Cocaine-Induced Relapse

Relapse to cocaine seeking is associated with potentiated excitatory synapses in nucleus accumbens. α2δ-1 is an auxiliary subunit of voltage-gated calcium channels that affects calcium-channel trafficking and kinetics, initiates extracellular signaling cascades, and promotes excitatory synaptogenesis. Previous data demonstrate that repeated exposure to alcohol, nicotine, methamphetamine, and morphine upregulates α2δ-1 in reward-related brain regions, but it was unclear whether this alteration generalized to cocaine. Here, we show that α2δ-1 protein was increased in nucleus accumbens after cocaine self-administration and extinction compared with saline controls. Furthermore, the endogenous ligand thrombospondin-1, responsible for the synaptogenic properties of the α2δ-1 receptor, was likewise elevated. Using whole-cell patch-clamp recordings of EPSCs in nucleus accumbens, we demonstrated that gabapentin, a specific α2δ-1 antagonist, preferentially reduced the amplitude and increased the paired-pulse ratio of EPSCs evoked by electrical stimulation in slices from cocaine-experienced rats compared with controls. In vivo, gabapentin microinjected in the nucleus accumbens core attenuated cocaine-primed but not cue-induced reinstatement. Importantly, gabapentin's effects on drug seeking were not due to a general depression of spontaneous or cocaine-induced locomotor activity. Moreover, gabapentin had no effect on reinstatement of sucrose seeking. These data indicate that α2δ-1 contributes specifically to cocaine-reinstated drug seeking, and identifies this protein as a target for the development of cocaine relapse medications. These results also inform ongoing discussion in the literature regarding efficacy of gabapentin as a candidate addiction therapy

Caldendrin–Jacob: A Protein Liaison That Couples NMDA Receptor Signalling to the Nucleus

NMDA (N-methyl-D-aspartate) receptors and calcium can exert multiple and very divergent effects within neuronal cells, thereby impacting opposing occurrences such as synaptic plasticity and neuronal degeneration. The neuronal Ca2+ sensor Caldendrin is a postsynaptic density component with high similarity to calmodulin. Jacob, a recently identified Caldendrin binding partner, is a novel protein abundantly expressed in limbic brain and cerebral cortex. Strictly depending upon activation of NMDA-type glutamate receptors, Jacob is recruited to neuronal nuclei, resulting in a rapid stripping of synaptic contacts and in a drastically altered morphology of the dendritic tree. Jacob's nuclear trafficking from distal dendrites crucially requires the classical Importin pathway. Caldendrin binds to Jacob's nuclear localization signal in a Ca2+-dependent manner, thereby controlling Jacob's extranuclear localization by competing with the binding of Importin-α to Jacob's nuclear localization signal. This competition requires sustained synapto-dendritic Ca2+ levels, which presumably cannot be achieved by activation of extrasynaptic NMDA receptors, but are confined to Ca2+ microdomains such as postsynaptic spines. Extrasynaptic NMDA receptors, as opposed to their synaptic counterparts, trigger the cAMP response element-binding protein (CREB) shut-off pathway, and cell death. We found that nuclear knockdown of Jacob prevents CREB shut-off after extrasynaptic NMDA receptor activation, whereas its nuclear overexpression induces CREB shut-off without NMDA receptor stimulation. Importantly, nuclear knockdown of Jacob attenuates NMDA-induced loss of synaptic contacts, and neuronal degeneration. This defines a novel mechanism of synapse-to-nucleus communication via a synaptic Ca2+-sensor protein, which links the activity of NMDA receptors to nuclear signalling events involved in modelling synapto-dendritic input and NMDA receptor–induced cellular degeneration

Toll-like receptor signaling and stages of addiction

Athina Markou and her colleagues discovered persistent changes in adult behavior following adolescent exposure to ethanol or nicotine consistent with increased risk for developing addiction. Building on Dr. Markou's important work and that of others in the field, researchers at the Bowles Center for Alcohol Studies have found that persistent changes in behavior following adolescent stress or alcohol exposure may be linked to induction of immune signaling in brain. This study aims to illuminate the critical interrelationship of the innate immune system (e.g., toll-like receptors [TLRs], high-mobility group box 1 [HMGB1]) in the neurobiology of addiction. This study reviews the relevant research regarding the relationship between the innate immune system and addiction. Emerging evidence indicates that TLRs in brain, particularly those on microglia, respond to endogenous innate immune agonists such as HMGB1 and microRNAs (miRNAs). Multiple TLRs, HMGB1, and miRNAs are induced in the brain by stress, alcohol, and other drugs of abuse and are increased in the postmortem human alcoholic brain. Enhanced TLR-innate immune signaling in brain leads to epigenetic modifications, alterations in synaptic plasticity, and loss of neuronal cell populations, which contribute to cognitive and emotive dysfunctions. Addiction involves progressive stages of drug binges and intoxication, withdrawal-negative affect, and ultimately compulsive drug use and abuse. Toll-like receptor signaling within cortical-limbic circuits is modified by alcohol and stress in a manner consistent with promoting progression through the stages of addiction

DMFC as Battery-Extender in solar-boat application

For special applications Direct Methanol Fuel Cells (DMFC) are close to commercial application or already commercialized today. However for the step from laboratory to a broader market of fuel cells, a significant cost reduction, as well as a lifetime and power density improvement of the systems is needed. The Goals of the BZ-BattExt Project should be reached by applying new knowledge in alternative materials, improved operation strategies and enhanced sub systems. In the project a 100 W DMFC compact system as battery extender was successfully developed and operated. The reduction of the number of components and the simplification of the system led to a high reduction in price, weight and volume. The feasibility of a micro-DMFC system was evaluated which enables a minimised system periphery due to an improved System Architecture. For this, alternative materials and functional components were developed and investigated leading to new membranes with reduced water and methanol permeation allowing a low air stoich operation and higher system efficiency. Gas diffusion layers of various compositions were tested and optimised materials were selected. New sealing materials with good methanol stability and optimized processibility in commercial production Processes were developed and the MEA preparation was adapted to the new materials. The use of a simple, cost-effective way of stack production was demonstrated for DMFC use. Using this new components and materials, coupled with the enhanced subsystem architectures and enhanced operation strategies, the build up and start-up of an improved micro DMFC System was achieved. The technical feasibility of the Results was investigated in the real application. The micro DMFC System was used as a battery range extender in a 6m solar boat. The DMFC fuel cell system serves as a basis for an efficient, compact and cost effective alternative for battery- or battery-extender systems and can fulfil a broad variety of applications

BZ-BattExt – DMFC as Battery-Extender in solar-boat application

For special applications Direct Methanol Fuel Cells (DMFC) are close to commercial application or already commercialized today. However for the step from laboratory to a broader market of fuel cells, a significant cost reduction, as well as an improvement in life time and power density of the systems is needed. These items were the focus of the project BZ-BattExt, to be reached by new knowledge in alternative materials, operation strategies as also the realisation of enhanced sub systems. This project is funded by the German Federal Ministry of Education and Research in the program of Micro fuel cells. In the project the feasibility of a micro-DMFC system is evaluated which enables a minimised system periphery due to an improved system architecture. For this, alternative materials and functional components were developed and investigated. New membranes with reduced water and methanol permeation allow operation at low air stoichiometry and favourable system efficiency. Gas diffusion layers of various compositions were tested and optimised material was selected. New sealing materials with good methanol stability and optimized processibility in commercial production process were developed. MEA preparation was adapted to the new materials. The use of a simple, cost-effective way of stack production was demonstrated for DMFC use. The investigation and construction of enhanced subsystems and operation strategies, which enable and optimise the use of new components and materials, as also the realisation of the micro-DMFC system is a focus of the project. The technical feasibility of the results is investigated in the application, which means it is tested as battery extender of a solar boat. The DMFC fuel cell system serves as a basis for an efficient, compact and cost effective alternative for battery- or battery-extender systems and can fulfil a broad variety of applications

Implementation of the chronic care model in small medical practices improves cardiovascular risk but not glycemic control

OBJECTIVE To test whether the implementation of elements of the Chronic Care Model (CCM) via a specially trained practice nurse leads to an improved cardiovascular risk profile among type 2 diabetes patients. RESEARCH DESIGN AND METHODS This cluster randomized controlled trial with primary care physicians as the unit of randomization was conducted in the German part of Switzerland. Three hundred twenty-six type 2 diabetes patients (age >18 years; at least one glycosylated hemoglobin [HbA1c] level of ≥7.0% [53 mmol/mol] in the preceding year) from 30 primary care practices participated. The intervention included implementation of CCM elements and involvement of practice nurses in the care of type 2 diabetes patients. Primary outcome was HbA1c levels. The secondary outcomes were blood pressure (BP), LDL cholesterol, accordance with CCM (assessed by Patient Assessment of Chronic Illness Care [PACIC] questionnaire), and quality of life (assessed by the 36-item short-form health survey [SF-36]). RESULTS After 1 year, HbA1c levels decreased significantly in both groups with no significant difference between groups (-0.05% [-0.60 mmol/mol]; P = 0.708). Among intervention group patients, systolic BP (-3.63; P = 0.050), diastolic BP (-4.01; P < 0.001), LDL cholesterol (-0.21; P = 0.033), and PACIC subscores (P < 0.001 to 0.048) significantly improved compared with control group patients. No differences between groups were shown in the SF-36 subscales. CONCLUSIONS A chronic care approach according to the CCM and involving practice nurses in diabetes care improved the cardiovascular risk profile and is experienced by patients as a better structured care. Our study showed that care according to the CCM can be implemented even in small primary care practices, which still represent the usual structure in most European health care systems