Psychopharmacological Analysis of Central Muscarinic and Nicotinic Receptors

Arecoline and nicotine are two psychoactive cholinergic alkaloids. Arecoline is primarily a muscarinic agonist while nicotine, at low doses, is a nicotinic agonist. The experiments in this dissertation investigated two major areas: (1) the role of different factors in the development of tolerance to the behavioral effects of arecoline and nicotine, and (2) the possible mechanism and site of action of the discriminative stimulus (DS) effects of arecoline and nicotine. The role of dispositional and physiological factors comfiared to behavioral factors in the development of tolerance to the effects of arecoline and nicotine on operant behavior was assessed in Experiments I and II, respectively. In part one of Experiment I, rats were trained to respond (M1 a variable-interval 15 second (VI-15) schedule for milk reinforcement. Dose-effect relationships were assessed prior to and during chronic arecoline (1.74 mg/kg/day) treatment. After 21 days Of arecoline administration prior to the session, the dose-effect relationship for total responses was not shifted. However, the dose-effect relationship for total reinforcements was shifted to the right. In part two of Experiment I, rats were trained to respond on a fixed-ratio 20 (FR-ZG) schedule for milk reinforcement. Dose-effect relationships were assessed prior to and during chronic arecoline (0.87 mg/kg/day) administration. One group of rats received daily injections of arecoline prior to the seSsion and a second group received arecoline injections after the session. Daily administration of arecoline resulted in a greater shift to the right of the dose-effect relationship in the pre-session group compared to the post-session group. These data demonstrate the importance cflf behavioral factors in the development of tolerance to arecoline. In Experiment II, rats were trained to respond on a VI-15 second schedule of milk reinforcement. Dose-effect relationships were determined prior to and during chronic nicotine (2.28 mg/kg/day) administration. One group of rats received daily injections Of nicotine prior to the session, another group received nicotine injections after the session. After 36 days of chronic treatment, similar degrees of tolerance were observed in both groups, however the group receiving post-session nicotine developed tolerance at a faster rate. The data suggested that 21 complex interaction of nicotine and the experimental environment affected the rate of tolerance development. Experiment III characterized the DS effect of arecoline. Using a two-lever operant paradigm, rats were trained to discriminate arecoline from saline on a VI-12 second schedule of milk reinforcement. Rats could learn to discriminate 1.74 mg/kg arecoline from saline, but not 0.58 mg/kg from saline. Agonist and antagonist studies demonStrated that the DS effect of arecoline is mediated through central muscarinic receptors. In Experiment IV, the ability of physostigmine to interact fiith the DS effect of nicotine (1.14 mg/kg) and arecoline (1.74 mg/kg) was assessed. Physostigmine (0.125 mg/kg) pretreatment shifted the dose-effect relationship for arecoline to the left but did not affect that of nicotine. Physostigmine (0.25 mg/kg) almost completely generalized to the DS effect of arecoline but not to the DS effect of nicotine. These data suggest an interaction of endogenous acetylcholine with muscarinic receptors but not with nicotinic receptors. In Experiment V, the ability hf arecoline and nicotine injected directly into the dorsal hippocampus (DH) and mesencephalic reticular formation (MRF) to generalize to the DS effect of peripherally administered arecoline (1.74 mg/kg) and nicotine (1.14 mg/kg) was assessed; Nicotine injected into these sites generalized in a dose-related manner to nicotine. The MRF was slightly more sensitive than the DH. Arecoline injected into either site did not generalize to the DS effect of, peripherally administered arecoline. However, a decrease in response rates was observed

Asenapine effects in animal models of psychosis and cognitive function

Asenapine, a novel psychopharmacologic agent in the development for schizophrenia and bipolar disorder, has high affinity for serotonergic, α-adrenergic, and dopaminergic receptors, suggesting potential for antipsychotic and cognitive-enhancing properties. The effects of asenapine in rat models of antipsychotic efficacy and cognition were examined and compared with those of olanzapine and risperidone. Amphetamine-stimulated locomotor activity (Amp-LMA; 1.0 or 3.0 mg/kg s.c.) and apomorphine-disrupted prepulse inhibition (Apo-PPI; 0.5 mg/kg s.c.) were used as tests for antipsychotic activity. Delayed non-match to place (DNMTP) and five-choice serial reaction (5-CSR) tasks were used to assess short-term spatial memory and attention, respectively. Asenapine doses varied across tasks: Amp-LMA (0.01–0.3 mg/kg s.c.), Apo-PPI (0.001–0.3 mg/kg s.c.), DNMTP (0.01–0.1 mg/kg s.c.), and 5-CSR (0.003–0.3 mg/kg s.c.). Asenapine was highly potent (active at 0.03 mg/kg) in the Amp-LMA and Apo-PPI assays. DNMTP or 5-CSR performance was not improved by asenapine, olanzapine, or risperidone. All agents (P < 0.01) reduced DNMTP accuracy at short delays; post hoc analyses revealed that only 0.1 mg/kg asenapine and 0.3 mg/kg risperidone differed from vehicle. All active agents (asenapine, 0.3 mg/kg; olanzapine, 0.03–0.3 mg/kg; and risperidone, 0.01–0.1 mg/kg) significantly impaired 5-CSR accuracy (P < 0.05). Asenapine has potent antidopaminergic properties that are predictive of antipsychotic efficacy. Asenapine, like risperidone and olanzapine, did not improve cognition in normal rats. Rather, at doses greater than those required for antipsychotic activity, asenapine impaired cognitive performance due to disturbance of motor function, an effect also observed with olanzapine and risperidone

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease