RESUMO
The catecholamine neuromodulators dopamine and norepinephrine are implicated in motor function, motivation, and cognition. Although roles for striatal dopamine in these aspects of behavior are well established, the specific roles for cortical catecholamines in regulating striatal dopamine dynamics and behavior are less clear. We recently showed that elevating cortical dopamine but not norepinephrine suppresses hyperactivity in dopamine transporter knockout (DAT-KO) mice, which have elevated striatal dopamine levels. In contrast, norepinephrine transporter knockout (NET-KO) mice have a phenotype distinct from DAT-KO mice, as they show elevated extracellular cortical catecholamines but reduced baseline striatal dopamine levels. Here we evaluated the consequences of altered catecholamine levels in NET-KO mice on cognitive flexibility and striatal dopamine dynamics. In a probabilistic reversal learning task, NET-KO mice showed enhanced reversal learning, which was consistent with larger phasic dopamine transients (dLight) in the dorsomedial striatum (DMS) during reward delivery and reward omission, compared to WT controls. Selective depletion of dorsal medial prefrontal cortex (mPFC) norepinephrine in WT mice did not alter performance on the reversal learning task but reduced nestlet shredding. Surprisingly, NET-KO mice did not show altered breakpoints in a progressive ratio task, suggesting intact food motivation. Collectively, these studies show novel roles of cortical catecholamines in the regulation of tonic and phasic striatal dopamine dynamics and cognitive flexibility, updating our current views on dopamine regulation and informing future therapeutic strategies to counter multiple psychiatric disorders.
RESUMO
BACKGROUND: Tumor necrosis factor (TNF)-alpha inhibitors and other biologic response modifiers (BRMs) are frequently used to treat a variety of inflammatory diseases. Use of these agents may increase risk of serious infections, malignancies, and other complications such as worsening symptoms of heart failure or demyelinating disease. Because of these risks, a baseline assessment and routine monitoring have been recommended, but standardized guidelines for monitoring have yet to be established. OBJECTIVE: To measure the compliance with the recommended safety monitoring in the Clinical Care Guidelines for BRMs at the University of Illinois Hospitals and Health Sciences System (UI Health). METHODS: The Clinical Care Guidelines for BRMs was developed by a committee of pharmacists, nurses, and physicians based on an assessment of published literature and medication labeling. The guidelines included recommendations for safety monitoring prior to BRM therapy, such as the tuberculosis (TB) test, Hepatitis B surface Antigen (HBsAg) test, liver function test (LFT), complete blood count (CBC), up-to-date vaccinations, risk assessment for cancer, pregnancy testing, monitoring for contraindications with concomitant medications, concomitant disease state risk assessment, and patient education. The guidelines were introduced to UI Health in February 2012 by a systemwide email and by in-services given by the health system's Specialty Pharmacy Service. In-services were given in the clinics known to generate large numbers of BRM orders (e.g., gastroenterology and rheumatology) and at the outpatient center for infused therapies. The purpose of the in-services was to introduce providers to the guidelines and encourage their compliance. To ensure that guideline requirements were met when BRMs were ordered, a process was established to identify BRM orders, assess the orders for compliance with 4 of the safety monitoring tests from the guidelines (TB, HBsAg, LFT, and CBC), and make interventions. When necessary, Specialty Pharmacy Services coordinated with the pharmacists and other providers in the clinic to order lab tests and ensure they were completed prior to the start of therapy. Feedback was provided during the study to proactively improve compliance with the guidelines. After completion of the study, a report containing outpatient prescription orders for BRMs (abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, and tocilizumab) from August 2011 through July 2012 was generated from the electronic medical record. Retrospective analyses of completion of safety monitoring were conducted for patients administered BRM treatment. Completion rates were compared before and after implementation of guidelines in February 2012. Completion was considered to have occurred when all 4 safety monitoring tests had been conducted -TB (unless known to be positive from a previous test), HBsAg, LFT, and CBC. Completion data from August 2011 through January 2012 were before the guidelines were implemented, and data from February 2012 through July 2012 were after the guidelines. Chi square analyses were performed on completion frequencies in the patients before and after the guidelines were implemented. RESULTS: Of the 320 unique patient BRM orders evaluated in this study, 195 (61%) were generated in the Rheumatology clinic, 99 (31%) in the Gastroenterology clinic, 21 (6.5%) in the Dermatology clinic, and 5 (1.5%) in the Transplant clinic. Before the guidelines were implemented, 54 ( 31%) of 173 patient orders complied with the safety monitoring by having all 4 clinical tests performed at the appropriate time points. After guideline implementation, 88 (60%) of 147 patient orders were compliant and had all 4 clinical tests conducted, which represents a statistically significant improvement in the rate of compliance (Pearson chi square = 26.43, degrees of freedom (df) = 1, P less than 0.0001). This significant improvement in compliance rates after guideline implementation was observed in both the new patient group and the patients with continuing prescription orders/treatment changes. There was also an improvement in patients whose prescriptions were dispensed by UI Health and to a lesser degree those whose prescriptions were dispensed by an outside pharmacy. When the new patient group was analyzed separately (n = 92), 50 patients were treated before the guidelines were implemented, and 42 patients were treated after the guidelines were implemented. Compliance rates with safety monitoring in these 2 groups were 52% pre-implementation and 83% post-implementation, which represented a statistically significant improvement in compliance (Pearson chi square = 10.03, df=1, P = 0.0015). Similar results were observed in the second patient subgroup with continuing prescription orders/treatment change (n = 228). A total of 123 patients were treated before the guidelines were implemented, and 105 were treated after the guidelines were implemented. Compliance rates were 23% pre-implementation compared with 50% post-implementation, which represented a statistically significant improvement in compliance (Pearson chi square = 18.99, df = 1, P less than 0.0001). CONCLUSION: Given the widespread and long-term use of BRMs, safety monitoring and management should be an important part of a comprehensive medication management program for their use. A coordinated effort may have a significant impact on compliance with safety monitoring guidelines.
