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Residual Next-Day Effects of Alprazolam on Psychomotor Performance and Simulated Driving in Healthy Normal Adults
No full textThe prevalence of drugged driving has increased in the United States. Some drugged driving may be unintentional as prescription medications used as sleeping aids, like zolpidem, cause impairment after the predicted duration of therapeutic action has elapsed. The aim of this study was to determine if nighttime administration of alprazolam, a drug commonly prescribed off-label as a sleeping aid, impacts driving performance the following day. Participants were healthy adults (n = 15) who completed a double-blind, double-dummy, within-subjects inpatient study examining the effects of nighttime administration of alprazolam (0.5, 1, and 2 mg), zolpidem (10 mg), and placebo on driving performance the following day. Alprazolam (1 mg; morning) and zolpidem (nighttime) both served as positive control conditions. Driving simulator measures, cognitive and psychomotor tasks, and questionnaires querying drug effects were collected the afternoon before drug administration and for 5.5 hr the next day and analyzed using symmetry and mixed-model approaches. Morning alprazolam signicantly impaired driving performance. Driving impairment was observed up to 12.5 hr after nighttime alprazolam 2 mg and for 8.5 hr after nighttime zolpidem 10 mg. Participant reports on driving ability indicated that they were not aware of their level of impairment. These results suggest that alprazolam used before bed may pose a yet unrecognized public safety risk in the form of next-day drugged driving
INVESTIGATING THE ROLE OF DYNAMIC SIGNALING OF NRG3-ERBB4 IN THE PREFRONTAL CORTEX IN MEDIATING NICOTINE WITHDRAWAL PHENOTYPES
No full textWhile several pharmacotherapies are currently available for nicotine use disorder (NUD), smoking cessation success rates remain below 10% each year. The molecular mechanisms underlying failed quit attempts continue to represent a critical gap in our knowledge. However, recent advances in understanding the genetic contributions to nicotine dependence offer a promising avenue for developing more effective cessation therapies. Prior research has identified genetic variation in Neuregulin 3 (Nrg3) and its cognate receptor ErbB4 as potential contributors to affective nicotine withdrawal (WD) phenotypes and cessation outcomes. Therefore, this dissertation aims to systematically investigate the region-specific, functional role of the Neuregulin Signaling Pathway (NSP) during nicotine exposure and WD.
The prefrontal cortex (PFC), a critical brain region for emotional regulation, cognitive function, and decision-making, is particularly vulnerable to the effects of nicotine exposure and WD. Given its relevance to NUD and comorbid psychiatric conditions such as schizophrenia, this work focuses on PFC-specific ErbB4 function. Additional exploratory studies evaluated the potential of repurposing aripiprazole, an atypical antipsychotic shown to modulate the NSP and reduce smoking in patients with schizophrenia, as a candidate treatment for WD symptoms. Experiments in Chapters 2 and 3 assess the effects of NSP manipulation by using an ErbB4-flox mouse model or aripiprazole administration in mice exposed to chronic nicotine followed by 24-hour spontaneous WD. Behavioral assays for anxiety-like phenotypes were paired with transcriptomic analyses of medial PFC (mPFC) and orbitofrontal cortex (OFC) tissue, using RT-qPCR, RNAscope, and bulk RNA sequencing to characterize the expression of NSP components and related synaptic signaling pathways.
Chapter 2 demonstrates that mPFC-specific knockdown (KD) of ErbB4 alters nicotine WD-related behaviors in a sex-specific manner. In the acoustic startle response (ASR) task, ErbB4 KD resulted in a prominent reduction of startle response in WD males, while in the open field (OF) test, only females showed reduced thigmotaxis during WD. OF fecal output mirrored ASR patterns, suggesting distinct effects of ErbB4 on emotional reactivity and anxiety-like behavior across sexes. Molecular analyses revealed that ErbB4 KD attenuated WD-induced Nrg3 upregulation. This finding is complemented by reductions in glutamatergic N-methyl-D-aspartate receptor (NMDAR) subunits 2A and 2B, as well as reciprocal subregion-specific transcriptional changes. Chapter 3 explores aripiprazole as a potential WD therapeutic, as administration reduces anxiety-like behaviors during WD, with corresponding sex-, subregion- and treatment-specific changes in prefrontal expression of genes related to the NSP, glutamatergic signaling, and serotonin receptors.
In summary, chronic nicotine exposure dysregulates region-specific NSP and glutamatergic gene expression in the PFC, exacerbating anxiety-like symptoms during WD. ErbB4 signaling in the mPFC is necessary for the presentation of these behavioral deficits. Aripiprazole alleviates WD-related anxiety-like behavior in mice through sex-dependent transcriptional modulation of neuroplasticity-related pathways. Overall, these findings employ a multidisciplinary approach to highlight the role of Nrg3-ErbB4 signaling in the molecular and behavioral effects of nicotine WD and provide a mechanistic framework for developing personalized treatments that target affective disruption to improve smoking cessation outcomes
Balancing Broad Disclosure and Candid Consideration: Third-Party Consultants and Intra-Agency Exemptions under the Freedom of Information Act
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The WNBA\u27s 2020 Collective Bargaining Agreement: A Slam Dunk for Working Women and Mothers
No full textWage Enslavement: How the Tax System Holds back Historically Disadvantaged Groups of Americans
Get PDFRedistricting in the Political Thicket: The Ghosts of \u3ci\u3eColegrove v. Green\u3c/i\u3e
No full textPatterns of Tillering and Tiller Bud Development of Some Temperate Herbage Grasses Under Different Light Intensities
Get PDFThe tiller and tiller bud development in young seedlings of orchardgrass (Dactylis glomerata L.), tall fescue (Festuca arundinacea Schreb.), timothy (Phleum pratense L.) and reed canarygrass (Phalaris arundinacea L.)were studied anatomically. Regular appearance of successive leaves on main shoot and emerged primary tillers were observed in grasses grown under both normal (30,000 lux) and reduced (6,000 lux) light intensities. The leaves expanding simultaneously on different shoots developed analogously. These growth habits in tillering and leaf production were well supported by Katayama\u27s concept on tillering systems in cereals such as rice plant, wheat and barley. The visible synchronization in appearance of any corresponding leaves of main shoot and emerged tillers should be the results of their simultaneous initiation and analogous development occurring at the subapical regions. The course of tiller bud development was supposed to consist of two different morphogenetic phases, i. e., the process from the initiation of tiller bud primordium to the completion of bud structure, and the rapid elongation of first leaf of just completed tiller bud. In general, the basic structure as a tiller bud was achieved immediately after the full expansion of its subtending leaf of main shoot in every grass examined. Under normal light intensity, the bud elongation began without any intermission, and concluded with leaf emergence as a tiller. This phase was strongly disturbed when plants were transferred to a reduced light condition, and the completed tiller bud could not develop further
Advantages and Management of Grass-Legume Associations in Forage Production
No full textThe quality and forage yield of grass/legume associations is higher than in pure grass stands, with comparable nitrogen inputs. During a 180 day growing season, 10 - 15 t/ha of forage dry matter can be produced with less than 150 kg fertilizer nitrogen. Forage from mixed swards has a higher energy and protein content and a better balanced mineral composition. Both the high content of digestible organic matter and the legumes have a positive influence on the dry matter, energy and protein intake of the cows and the amount of milk these can produce therefrom. The decrease in quality with age of a crop is less when it contains legumes. The practical benefit from this is a greater flexibility in time of crop utilization. If the desired botanical composition of grass-legume association can be obtained depends mainly on the seed mixture, the planting conditions, the frequency of utilization and the nitrogen regime. Simple associations are best for leys of short duration Complex mixtures are more advantageous for long-duration meadows or pastures