Cognitive interference as a possible therapeutic strategy to prevent expression of benzodiazepine withdrawal

Benzodiazepines are usually prescribed for anxiety and sleep disorders in long‐term schedules that may cause drug dependence. Discontinuation after prolonged administration may lead to withdrawal expression, being anxiety the most predominant sign. The context‐dependent associative learning process that underlies diazepam dependence can be interfered by pre‐exposure to the drug administration context, an effect known as latent inhibition. Considering this background, the primary aim of the present investigation is to develop a therapeutic strategy to prevent diazepam withdrawal in male Wistar rats by interfering with this learning process. Nitric oxide is a crucial player in learning and memory, hippocampal synaptic transmission and in diazepam withdrawal. Then, a secondary goal is to determine how latent inhibition could alter functional plasticity and neuronal nitric oxide synthase enzyme (NOS‐1) expression within the hippocampus, by using multi‐unitary cell recordings and Western blot, respectively. Our results indicate that chronic diazepam treated animals under latent inhibition did not show anxiety, or changes in hippocampal synaptic transmission, but a significant reduction in NOS‐1 expression was observed. Accordingly, pharmacological NOS‐1 inhibition resembles behavioral and electrophysiological changes induced by latent inhibition. Contrary, diazepam treated animals under Control protocol expressed anxiety and evidenced an increased hippocampal‐plasticity, without alterations in NOS‐1 expression. In conclusion, manipulation of the contextual cues presented during diazepam administration may be considered as an effective non‐pharmacological tool to prevent the withdrawal syndrome. This behavioral strategy may influence hippocampal synaptic transmission, probably by alterations in nitric oxide signaling pathways in this structure.     

Repeated cocaine exposure decreases dopamine D2‐like receptor modulation of Ca2+ homeostasis in rat nucleus accumbens neurons

The nucleus accumbens (NAc) is a limbic structure in the forebrain that plays a critical role in cognitive function and addiction. Dopamine modulates activity of medium spiny neurons (MSNs) in the NAc. Both dopamine D₁‐like and D₂‐like receptors (including D1R or D_1,5R and D2R or D_2,3,4R, respectively) are thought to play critical roles in cocaine addiction. Our previous studies demonstrated that repeated cocaine exposure (which alters dopamine transmission) decreases excitability of NAc MSNs in cocaine‐sensitized, withdrawn rats. This decrease is characterized by a reduction in voltage‐sensitive Na⁺ currents and high voltage‐activated Ca²⁺ currents, along with increased voltage‐gated K⁺ currents. These changes are associated with enhanced activity in the D1R/cAMP/PKA/protein phosphatase 1 pathway and diminished calcineurin function. Although D1R‐mediated signaling is enhanced by repeated cocaine exposure, little is known whether and how the D2R is implicated in the cocaine‐induced NAc dysfunction. Here, we performed a combined electrophysiological, biochemical, and neuroimaging study that reveals the cocaine‐induced dysregulation of Ca²⁺ homeostasis with involvement of D2R. Our novel findings reveal that D2R stimulation reduced Ca²⁺ influx preferentially via the L‐type Ca²⁺ channels and evoked intracellular Ca²⁺ release, likely via inhibiting the cAMP/PKA cascade, in the NAc MSNs of drug‐free rats. However, repeated cocaine exposure abolished the D₂R effects on modulating Ca²⁺ homeostasis with enhanced PKA activity and led to a decrease in whole‐cell Ca²⁺ influx. These adaptations, which persisted for 21 days during cocaine abstinence, may contribute to the mechanism of cocaine withdrawal. Synapse, 2011. © 2010 Wiley‐Liss, Inc.     

Withdrawal time in excellent or very poor bowel preparation qualities

AIM: To evaluate association(s) between withdrawal time and polyp detection in various bowel preparation qualities. METHODS: Retrospective cohort analysis of screening colonoscopies performed between January 2005 and June 2011 for patients with average risk of colorectal cancer. Exclusion criteria included patients with a personal history of adenomatous polyps or colon cancer, prior colonic resection, significant family history of colorectal cancer, screening colonoscopy after other abnormal screening tests such as flexible sigmoidoscopy or barium enema, and screening colonoscopies during in-patient care. All procedures were performed or directly supervised by gastroenterologists. Main measurements were number of colonic segments with polyps and total number of colonic polyps.RESULTS: Multivariate analysis of 8331 colonosco-pies showed longer withdrawal time was associated with more colonic segments with polyps in good(adjusted OR = 1.16; 95%CI: 1.13-1.19), fair(OR = 1.13; 95%CI: 1.10-1.17), and poor(OR = 1.18; 95%CI: 1.11-1.26) bowel preparation qualities. A higher number of total polyps was associated with longer withdrawal time in good(OR = 1.15; 95%CI: 1.13-1.18), fair(OR = 1.13; 95%CI: 1.10-1.16), and poor(OR = 1.20; 95%CI: 1.13-1.29) bowel preparation qualities. Longer withdrawal time was not associated with more colonic segments with polyps or greater number of colonic polyps in bowel preparations with excellent(OR = 1.07, 95%CI: 0.99-1.26; OR = 1.11, 95%CI: 0.99-1.24, respectively) and very poor(OR = 1.02, 95%CI: 0.99-1.12; OR = 1.05, 95%CI: 0.99-1.10, respectively) qualities.CONCLUSION: Longer withdrawal time is not associated with higher polyp number detected in colonoscopies with excellent or very poor bowel preparation quality.