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Serotonin plays a role in reinforcement learning; however, it is not known which serotonin receptors mediate these effects. Serotonin 6 (5-HT(6)) receptors are abundant in the striatum, a brain area that is involved in reinforcement learning. We previously found that 5-HT(6) receptors in the dorsomedial striatum (DMS) affect reinforcement learning or consolidation over several days. We use viral-mediated gene transfer to discern the role that 5-HT(6) receptors play in mediating post-synaptic responses in anterior versus posterior DMS. Male Long-Evans rats were used to study learning acquisition during a single session of 100 trials on a fixed interval of 20 seconds. In a discrete action-outcome learning task, rats had 10 seconds to press a lever to induce lever retraction and sucrose pellet delivery. In another group of rats, the task had a lever that was continuously extended but only active every 20 seconds, allowing for repetitive, mostly non-reinforced, lever pressing. Results demonstrate that increased expression of 5-HT(6) receptors in the posterior DMS interferes with earning sucrose pellets in only the former task. We take this to indicate that 5-HT(6) receptor signaling in the posterior DMS interferes with acquisition of discrete action-outcome responding. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization's "Coordinated Global Research Roadmap: 2019 Novel Coronavirus" outlined the need for research that focuses on the impact of COVID-19 on pregnant women and children. More than one year after the first reported case significant knowledge gaps remain, highlighting the need for a coordinated approach. To address this need, the Maternal, Newborn and Child Health Working Group (MNCH WG) of the COVID-19 Clinical Research Coalition conducted an international survey to identify global research priorities for COVID-19 in maternal, reproductive and child health., Method: This project was undertaken using a modified Delphi method. An electronic questionnaire was disseminated to clinicians and researchers in three different languages (English, French and Spanish) via MNCH WG affiliated networks. Respondents were asked to select the five most urgent research priorities among a list of 17 identified by the MNCH WG. Analysis of questionnaire data was undertaken to identify key similarities and differences among respondents according to questionnaire language, location and specialty. Following elimination of the seven lowest ranking priorities, the questionnaire was recirculated to the original pool of respondents. Thematic analysis of final questionnaire data was undertaken by the MNCH WG from which four priority research themes emerged., Results: Questionnaire 1 was completed by 225 respondents from 29 countries. Questionnaire 2 was returned by 49 respondents. The four priority research themes which emerged from the analysis were 1) access to healthcare during the COVID-19 pandemic, 2) the direct and 3) indirect effects of COVID-19 on pregnant and breastfeeding women and children and 4) the transmission of COVID-19 and protection from infection., Conclusion: The results of these questionnaires indicated a high level of concordance among continents and specialties regarding priority research themes. This prioritized list of research uncertainties, developed to specifically highlight the most urgent clinical needs as perceived by healthcare professionals and researchers, could help funding organizations and researchers to answer the most pressing questions for clinicians and public health professionals during the pandemic. It is hoped that these identified priority research themes can help focus the discussion regarding the allocation of limited resources to enhance COVID-19 research in MNCH globally., Competing Interests: The authors have declared that no competing interests exist.

Discovered just over 20 years ago, dopamine neurons have the ability to cotransmit both dopamine and glutamate. Yet, the functional roles of dopamine neuron glutamate cotransmission and their implications for therapeutic use are just emerging. This review article encompasses the current body of evidence investigating the functions of dopamine neurons of the ventral midbrain that cotransmit glutamate. Since its discovery in dopamine neuron cultures, further work in vivo confirmed dopamine neuron glutamate cotransmission across species. From there, growing interest has led to research related to neural functioning including roles in synaptic signaling, development, and behavior. Functional connectome mapping reveals robust connections in multiple forebrain regions to various cell types, most notably to cholinergic interneurons in both the medial shell of the nucleus accumbens and the lateral dorsal striatum. Glutamate markers in dopamine neurons reach peak levels during embryonic development and increase in response to various toxins, suggesting dopamine neuron glutamate cotransmission may serve neuroprotective roles. Findings from behavioral analyses reveal prominent roles for dopamine neuron glutamate cotransmission in responses to psychostimulants, in positive valence and cognitive systems and for subtle roles in negative valence systems. Insight into dopamine neuron glutamate cotransmission informs the pathophysiology of neuropsychiatric disorders such as addiction, schizophrenia and Parkinson Disease, with therapeutic implications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Eskenazi, Malave, Mingote, Yetnikoff, Ztaou, Velicu, Rayport and Chuhma.)

Background: Patients with type 2 diabetes present with an accelerated atherosclerotic process. Animal evidence indicates that dipeptidyl peptidase-4 inhibitors (gliptins) have anti-inflammatory and anti-atherosclerotic effects, yet clinical data are scarcely available., Design and Methods: A prospective, randomized, open-label study was performed in 60 patients with coronary artery disease (CAD) and type 2 diabetes, who participated in a cardiac rehabilitation program. After a washout period of 3 weeks, patients were randomized in a 2:1 ratio to receive combined vildagliptin/metformin therapy (intervention group: n = 40) vs. metformin alone (control group: n = 20) for a total of 12 weeks. Blinded assessment of interleukin-1ß (IL-1ß, the primary endpoint), hemoglobin A1c (HbA1c), and high sensitivity C reactive protein (hsCRP), were performed at baseline and after 12 weeks., Results: Mean age of study patients was 67 ± 9 years, 75% were males, and baseline HbA1c and inflammatory markers levels were similar between the two groups. At 12 weeks of follow up, levels of IL-1ß, hsCRP, and HbA1c were significantly lower in the intervention group as compared with the control group. There was a continuous elevation of IL-1ß among the control group, which was not observed in the intervention group (49 vs. 4%, respectively; p < 0.001). The hsCRP was lowered by 60% in the vildagliptin/metformin group vs. 23% in the metformin group (p < 0.01). Moreover, a significant relative reduction of the HbA1c was seen in the intervention group (7% reduction, p < 0.03)., Conclusion: The addition of vildagliptin to metformin treatment in patients with type 2 diabetes and CAD led to a significant suppression of the IL-1ß elevation during follow up. A significant relative reduction of hsCRP and HbA1c in the intervention group was also observed. Trial registration NCT01604213.

Serotonin-6 (5-HT(6)) receptors are densely expressed in the dorsolateral striatum (DLS), a brain region linked to habits. Medications acting on the serotonergic system, including 5-HT(6) receptors, can diminish habitual and repetitive behaviors associated with clinical syndromes such as obsessive-compulsive disorder, and may have implications for addiction as well. To examine the role of 5-HT(6) receptors in the acquisition and persistence of habitual behavior, we manipulated 5-HT(6) receptor expression in the DLS with herpes simplex virus vectors in combination with different behavioral procedures; control rats received a vector expressing enhanced green fluorescent protein. In one set of experiments, rats were tested under conditions that favor the acquisition of either discrete action-outcome responding or repetitive responding; increased 5-HT(6) receptor expression in DLS did not alter learning in either paradigm. In the next experiment, rats were over-trained on fixed- then variable-interval schedules, resulting in an escalation of lever pressing over sessions far in excess of that necessary to receive sucrose pellets. After training, rats received viral vector infusion into the DLS. Subsequently, half of each group underwent an omission contingency training session in which they received reinforcement for refraining from pressing the lever, while the other half served as yoked controls. A probe session under extinction conditions was performed the following day. Only rats that received both the 5-HT(6) vector and omission contingency training showed reduced lever pressing during the probe session. These results suggest that increasing 5-HT(6) receptor signaling in the DLS facilitates behavioral flexibility in the face of changing contingencies., (© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Dorsal striatum is important for the development of drug addiction; however, a precise understanding of the roles of striatopallidal (indirect) and striatonigral (direct) pathway neurons in regulating behaviors remains elusive. Using viral-mediated expression of an engineered G protein-coupled receptor (hM(4)D), we found that activation of hM(4)D receptors with clozapine-N-oxide (CNO) potently reduced striatal neuron excitability. When hM(4)D receptors were selectively expressed in either direct or indirect pathway neurons, CNO did not change acute locomotor responses to amphetamine, but did alter behavioral plasticity associated with repeated drug treatment. Specifically, transiently disrupting striatopallidal neuronal activity facilitated behavioral sensitization, whereas decreasing excitability of striatonigral neurons impaired its persistence. These findings suggest that acute drug effects can be parsed from the behavioral adaptations associated with repeated drug exposure and highlight the utility of this approach for deconstructing neuronal pathway contributions to behavior.