. For econometric advice, many thanks to Jin Hahn and Moshe Buchinsky. I am also appreciative for the help of fellow students in the History and Applied proseminars at UCLA. Particular thanks also go to the city and BID employees who were kind, patient and helpful with my repeated questions. Finally, I am very grateful for help from UCLA's statistical computing consultants, who provide elegant solutions to tricky problems.
Purpose: To compare the binding and agonistic activity of Acthar V R Gel and synthetic melanocortin receptor (MCR) agonists and examine how the activity of select agonists affects the in vivo production of corticosterone. Materials and Methods: In vitro binding was determined using concentration-dependent displacement of the ligand [ 125 I]Nle 4 , D-Phe 7-a-melanocyte-stimulating hormone (a-MSH) on cells expressing MC1R, MC3R, MC4R, or MC5R. Functional activity was determined using a time-resolved fluorescence cyclic adenosine monophosphate (cAMP) assay in cells expressing MC1R, MC2R, MC3R, MC4R, or MC5R. In vivo corticosterone analyses were performed by measuring plasma corticosterone levels in Sprague Dawley rats. Results: Acthar Gel and synthetic MCR agonists exhibited the highest binding at MC1R, lowest binding at MC5R, and moderate binding at MC3R and MC4R. Acthar Gel stimulated the production of cAMP in all 5 MCR-expressing cell lines, with MC2R displaying the lowest level of full agonist activity, 3-, 6.6-, and 10-fold lower than MC1R, MC3R, and MC4R, respectively. Acthar Gel was a partial agonist at MC5R. The synthetic MCR agonists induced full activity at all 5 MCRs, with the exception of a-MSH having no activity at MC2R. Acthar Gel treatment had less of an impact on in vivo production of corticosterone compared with synthetic ACTH 1-24 depot. Conclusions: Acthar Gel bound to and activated each MCR tested in this study, with partial agonist activity at MC5R and the lowest level of full agonist activity at MC2R, which distinguished it from synthetic MCR agonists. The minimal activity of Acthar Gel at MC2R corresponded to lower endogenous corticosteroid production.
Rationale-Although selective 5-HT reuptake inhibitors (SSRIs) can reduce anxiety after chronic treatment, acute SSRI administration is associated with an increase in anxiety consistent with an acute increase in 5-HT neurotransmission. Exercise is anxiolytic in humans, and wheel running prevents anxiety-like behavioral consequences of uncontrollable stress in rats, but the effects of exercise on acute fluoxetine-induced anxiety-like behaviors are unknown.Objectives-The current studies tested the hypothesis that acute administration of the SSRI fluoxetine would produce behaviors in rats resembling those produced by uncontrollable stress and that these behaviors would be blocked by prior wheel running.Results-Adult, male Fisher 344 rats administered moderate (10 mg/kg) or high (20 mg/kg) doses of fluoxetine demonstrated exaggerated shock-elicited freezing and an interference with shuttle box escape compared to rats given either saline or low-dose fluoxetine (2.5 mg/kg). Fluoxetine-induced behaviors were similar to, but smaller in magnitude than, those produced by uncontrollable stress and were blocked by pretreatment with the 5-HT 2C receptor antagonist SB 242084 (1 mg/kg). Rats allowed access to running wheels for 6 weeks were protected against the anxiety-like behaviors produced by a single injection of fluoxetine (10 mg/kg).Conclusions-Behavioral effects of acute fluoxetine administration resemble those produced by uncontrollable stress. Results are consistent with the idea that exercise can produce resistance against the anxiogenic effects of acute increases in 5-HT and suggest that acute behavioral effects of antidepressants can depend on history of physical activity.
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