Distinct 5-HT receptor subtypes regulate claustrum excitability by serotonin and the psychedelic, DOI.

Recent evidence indicates that neuronal activity within the claustrum (CLA) may be central to cellular and behavioral responses to psychedelic hallucinogens. The CLA prominently innervates many cortical targets and displays exceptionally high levels of serotonin (5-HT) binding. However, the influence of serotonin receptors, prime targets of psychedelic drug action, on CLA activity remains unexplored. We characterize the CLA expression of all known 5-HT subtypes and contrast the effects of 5-HT and the psychedelic hallucinogen, 2,5-dimethoxy-4-iodoamphetamine (DOI), on excitability of cortical-projecting CLA neurons. We find that the CLA is particularly enriched with 5-HT2C receptors, expressed predominantly on glutamatergic neurons. Electrophysiological recordings from CLA neurons that project to the anterior cingulate cortex (ACC) indicate that application of 5-HT inhibits glutamate receptor-mediated excitatory postsynaptic currents (EPSCs). In contrast, application of DOI stimulates EPSCs. We find that the opposite effects of 5-HT and DOI on synaptic signaling can both be reversed by inhibition of the 5-HT2C, but not 5-HT2A, receptors. We identify specific 5-HT receptor subtypes as serotonergic regulators of the CLA excitability and argue against the canonical role of 5-HT2A in glutamatergic synapse response to psychedelics within the CLA-ACC circuit.

Astrocyte Ca2+ in the dorsal striatum suppresses neuronal activity to oppose cue-induced reinstatement of cocaine seeking.

Recent literature supports a prominent role for astrocytes in regulation of drug-seeking behaviors. The dorsal striatum, specifically, is known to play a role in reward processing with neuronal activity that can be influenced by astrocyte Ca2+. However, the manner in which Ca2+ in dorsal striatum astrocytes impacts neuronal signaling after exposure to self-administered cocaine remains unclear. We addressed this question following over-expression of the Ca2+ extrusion pump, hPMCA2w/b, in dorsal striatum astrocytes and the Ca2+ indicator, GCaMP6f, in dorsal striatum neurons of rats that were trained to self-administer cocaine. Following extinction of cocaine-seeking behavior, the rats over-expressing hMPCA2w/b showed a significant increase in cue-induced reinstatement of cocaine seeking. Suppression of astrocyte Ca2+ increased the amplitude of neuronal Ca2+ transients in brain slices, but only after cocaine self-administration. This was accompanied by decreased duration of neuronal Ca2+ events in the cocaine group and no changes in Ca2+ event frequency. Acute administration of cocaine to brain slices decreased amplitude of neuronal Ca2+ in both the control and cocaine self-administration groups regardless of hPMCA2w/b expression. These results indicated that astrocyte Ca2+ control over neuronal Ca2+ transients was enhanced by cocaine self-administration experience, although sensitivity to acutely applied cocaine remained comparable across all groups. To explore this further, we found that neither the hMPCA2w/b expression nor the cocaine self-administration experience altered regulation of neuronal Ca2+ events by NPS-2143, a Ca2+ sensing receptor (CaSR) antagonist, suggesting that plasticity of neuronal signaling after hPMCA2w/b over-expression was unlikely to result from elevated extracellular Ca2+. We conclude that astrocyte Ca2+ in the dorsal striatum impacts neurons via cell-intrinsic mechanisms (e.g., gliotransmission, metabolic coupling, etc.) and impacts long-term neuronal plasticity after cocaine self-administration differently from neuronal response to acute cocaine. Overall, astrocyte Ca2+ influences neuronal output in the dorsal striatum to promote resistance to cue-induced reinstatement of cocaine seeking.

Combination of spironolactone and DPP-4 inhibitors for treatment of SARS-CoV-2 infection: a literature review.

Coronavirus disease 2019 (COVID-19) is still causing hospitalization and death, and vaccination appears to become less effective with each emerging variant. Spike, non-spike, and other possible unrecognized mutations have reduced the efficacy of recommended therapeutic approaches, including monoclonal antibodies, plasma transfusion, and antivirals. SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) and probably dipeptidyl peptidase 4 (DPP-4) to initiate the process of endocytosis by employing host proteases such as transmembrane serine protease-2 (TMPRSS-2) and ADAM metallopeptidase domain 17 (ADAM17). Spironolactone reduces the amount of soluble ACE2 and antagonizes TMPRSS-2 and ADAM17. DPP-4 inhibitors play immunomodulatory roles and may block viral entry. The efficacy of treatment with a combination of spironolactone and DPP-4 inhibitors does not appear to be affected by viral mutations. Therefore, the combination of spironolactone and DPP-4 inhibitors might improve the clinical outcome for COVID-19 patients by decreasing the efficiency of SARS-CoV-2 entry into cells and providing better anti-inflammatory, antiproliferative, and antifibrotic effects than those achieved using current therapeutic approaches such as antivirals and monoclonal antibodies.

Type 1 Diabetes and COVID-19: A Literature Review and Possible Management.

Context: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection normally damages the respiratory system but might likewise impair endocrine organs' function. Thyroid dysfunction and hyperglycemia are common endocrine complications of SARS-CoV-2 infection. The onset of type 1 diabetes (T1D) and associated complications, including diabetic ketoacidosis (DKA), hospitalization, and death, are thought to have increased during the coronavirus disease 2019 (COVID-19) pandemic. The aim of this study was to review the available data about the incidence rate of T1D and accompanying complications since the beginning of the COVID-19 pandemic. Evidence Acquisition: A literature review was conducted using the electronic databases PubMed and Google Scholar. The keywords "T1D, T1DM, Type 1 DM or Type 1 Diabetes", "Coronavirus, SARS-CoV-2 or COVID-19" were used to search these databases. Titles and abstracts were screened for selection, and then relevant studies were reviewed in full text. Results: A total of 25 manuscripts out of 304 identified studies were selected. There were 15 (60%) multicenter or nationwide studies. The data about the incidence rate of T1D, hospitalization, and death are not consistent across countries; however, DKA incidence and severity seem to be higher during the COVID-19 pandemic. The present study's data collection demonstrated that COVID-19 might or might not increase the incidence of T1D. Nevertheless, it is associated with the higher incidence and severity of DKA in T1D patients. This finding might indicate that antivirals are not fully protective against the endocrine complications of SARS-CoV-2 infection, which promotes the application of an alternative approach. Conclusions: Combining medications that reduce SARS-CoV-2 entry into the cells and modulate the immune response to infection is an alternative practical approach to treating COVID-19.