On the resilience of remote traumatic memories against exposure therapy‐mediated attenuation

How to attenuate traumatic memories has long been the focus of intensive research efforts, as traumatic memories are extremely persistent and heavily impinge on the quality of life. Despite the fact that traumatic memories are often not readily amenable to immediate intervention, surprisingly few studies have investigated treatment options for remote traumata in animal models. The few that have unanimously concluded that exposure therapy‐based approaches, the most successful behavioral intervention for the attenuation of recent forms of traumata in humans, fail to effectively reduce remote fear memories. Here, we provide an overview of these animal studies with an emphasis on why remote traumatic memories might be refractory to behavioral interventions: A lack of neuroplasticity in brain areas relevant for learning and memory emerges as a common denominator of such resilience. We then outline the findings of a recent study in mice showing that by combining exposure therapy‐like approaches with small molecule inhibitors of histone deacetylases (HDACis), even remote memories can be persistently attenuated. This pharmacological intervention reinstated neuroplasticity to levels comparable to those found upon successful attenuation of recent memories. Thus, HDACis—or any other agent capable of heightening neuroplasticity—in conjunction with exposure therapy‐based treatments might constitute a promising approach to overcome remote traumata.     

药物成瘾记忆的神经生物机制及临床干预方法

药物成瘾者戒断后的持久复吸是治疗药物成瘾的难点.成瘾者出现持续复吸的重要原因是由于成瘾记忆的长期存在.成瘾物质的长期反复使用导致前额叶-边缘多巴胺系统结构和功能的适应性改变,这种改变是成瘾记忆形成的神经基础.本文从学习记忆的角度来理解成瘾形成,介绍了成瘾记忆的初始形成阶段、习惯化阶段和成瘾行为维持阶段及其相应的神经基础.回顾了近年来成瘾记忆的临床干预方法,包括消退干预方法、增强消退干预的多情境干预方法,以及直接干预消除成瘾记忆的记忆再巩固干预方法,并总结了虚拟现实、神经调控技术在成瘾记忆干预中的应用.对记忆再巩固干预方法与虚拟现实、神经调控技术相结合干预成瘾记忆进行展望,为药物成瘾的临床干预和治疗提供了新方法、新思路.     

Lambda-carrageenan: A novel chiral selector for capillary electrophoresis

Lambda-carrageenan, a linear high molecular weight sulfated polysaccharide, has been employed as a chiral selector in capillary electrophoresis for the separation of enantiomers of weakly basic pharmaceutical compounds. The racemic compounds that were enantioresolved included propranolol, pindolol, tryptophanol, laudanosine and laudanosoline. In addition, the diastereomeric pair of cinchonine and cinchonidine were also resolved. Method conditions such as buffer pH, electrolyte concentration, column temperature, and chiral selector concentration were found to be important for improvement of enantioselectivity. © 1996 Wiley-Liss, Inc.     

Tempol-nebivolol therapy potentiates hypotensive effect increasing NO bioavailability and signaling pathway

Abstract

Nebivolol is a third generation beta blocker with endothelial nitric oxide synthase (eNOS) agonist properties. Considering the role of reactive oxygen species (ROS) in the uncoupling of eNOS, we hypothesized that the preadministration of an antioxidant as tempol, could improve the hypotensive response of nebivolol in normotensive animals increasing the nitric oxide (NO) bioavailability by a reduction of superoxide (O₂^??) basal level production in the vascular tissue.

Male Sprague Dawley rats were given tap water to drink (control group) or tempol (an antioxidant scavenger of superoxide) for 1 week. After 1 week, Nebivolol, at a dose of 3 mg/kg, was injected intravenously to the control group or to the tempol-treated group. Mean arterial pressure, heart rate, and blood pressure variability were evaluated in the control, tempol, nebivolol, and tempol nebivolol groups, as well as, the effect of different inhibitor as Nβ-nitro-l-arginine methyl ester (L-NAME, a Nitric oxide synthase blocker) or glybenclamide, a K_ATP channel inhibitor. Also, the expression of α,β soluble guanylate cyclase (sGC), phospho-eNOS, and phospho-vasodilator-stimulated phosphoprotein (P-VASP) were evaluated by Western Blot and cyclic guanosine monophosphate (cGMP) levels by an enzyme-linked immunosorbent assay (ELISA) commercial kit assay.

We showed that pretreatment with tempol in normotensive rats produces a hypotensive response after nebivolol administration through an increase in the NO bioavailability and sGC, improving the NO/cGMP/protein kinase G (PKG) pathway compared to that of the nebivolol group.

We demonstrated that tempol preadministration beneficiates the response of a third-generation beta blocker with eNOS stimulation properties, decreasing the basal uncoupling of eNOS, and improving NO bioavailability. Our results clearly open a possible new strategy therapeutic for treating hypertension.     

Retrieval and the Extinction of Memory

1. Memory is assessed by measuring retrieval which is often elicited by the solely presentation of the conditioned stimulus (CS). However, as known since Pavlov, presentation of the CS alone generates extinction.2. One-trial avoidance (IA) is a much used conditioned fear paradigm in which the CS is the safe part of a training apparatus, the unconditioned stimulus (US) is a footshock and the conditioned response (CR) is to stay in the safe area. Retrieval of the memory for the step-down version of this task is measured in the absence of the US, as latency to step-down from the safe area (i.e., a platform).3. Extinction of the IA response is installed at the moment of the first non-reinforced test session, as clearly shown by the fact that many drugs, including PKA, ERK and protein synthesis inhibitors as well as NMDA receptor antagonists, hinder extinction when infused into the hippocampus or the basolateral amygdala at the moment of the first test session but not later.4. Some, but not all the molecular systems required for extinction are also activated by retrieval, further endorsing the hypothesis that although retrieval is necessary for the generation of extinction this last process constitutes a new learning secondary to the non-reinforced expression of the original trace.