Discovery of novel anxiolytic agents--the trials and tribulations of pre-clinical models of anxiety.

Anxiety disorders are the most common class of mental disorders present in the general population with an estimated lifetime prevalence of any anxiety disorder being approximately 15%, while the 12-month prevalence is more than 10%. They are classified into simple phobias, social phobias, obsessive-compulsive disorder (OCD) and panic attacks. Anxiety disorders are more prevalent in females than males and respond to pharmacological and non-pharmacological (behavioral) treatments. Anxiety disorders are complex with genetic and environmental factors interacting to produce the final psychopathology. There are many tests used to detect behaviors that indicate heightened anxiety in rodents however there are few pathological models of anxiety in rodents. Most compound testing is performed on naive, non-pathologically anxious, male animals which is a potential limitation to current strategies since these animals do not reflect the anxious patient. This article briefly describes some of the most common anxiety tests used in rodent research and concludes with a short perspective on areas the field could concentrate on to improve the understanding and successful translation of novel targets into new therapies in the clinic.

Initial experience with neuroendoscopic surgery in West Africa

Introduction: Neuroendoscopic surgery is commonly utilized for the management of intracranial cystic lesions; hydrocephalus; tumor resections and biopsies and for all types of microsurgical procedures that can involve endoscopic assistance. Patients and Methods This study presents a retrospective evaluation of the clinical results of the first twenty consecutive patients who underwent neuroendoscopic procedures. The following parameters were examined; demographics; clinical; radiological; operative and outcome data. Patient follow up averaged 17months (R 3-38months).Results: Twenty (15M; 5F) patients with a mean age of 34 years (R 10 months-74years) underwent a total of 23 neuroendoscopic procedures. Eighty five percent of the patients had a preop diagnosis of supratentorial tumor; 53of these were extraventricular tumors (EVT). Forty eight percent of the neuroendoscopic procedures were at an extraventricular site. Eighty eight percent of the patients with IVT presented with non-communicating hydrocephalus (NCHC); [chi sq; p0.05]; of these 57presented with total blindness. Two with IVT and NCHC underwent total neuroendoscopic tumor excision with complete resolution of hydrocephalus; another two required external ventricular drainage (EVD) followed by ventriculo-peritoneal shunting; three patients underwent subtotal resection followed by neuroendoscopic third ventriculostomy (NETV). There was one patient with congenital aqueductal stenosis and another with NCHC from a posterior fossa tumor; these patients underwent aqueductoplasty and NETV respectively. One patient underwent evacuation of a large hypertensive putaminal hematoma. The complications noted from the series were as follows : one patient died; morbidity rate of 8.7. No blood transfusions were given or required. Conclusion: The initial experience with neuroendoscopic surgery in West Africa consists of the safe performance of IVT and EVT resections ; NETV and aqueductoplasty for the management of hydrocephalus ; and evacuation of intraaxial hematoma

Reduction by gabapentin of K+-evoked release of [3H]-glutamate from the caudal trigeminal nucleus of the streptozotocin-treated rat.

Recently, we showed that gabapentin can inhibit a facilitatory effect of substance P (SP) on K(+)-evoked glutamate release in rat trigeminal slices (Maneuf et al., 2001), and we have now examined the effect of gabapentin on glutamate release in the trigeminal slice from the streptozotocin (STZ)-treated rat. 1. At 4 weeks following STZ treatment (50 mg kg(-1) i.p.), blood glucose was increased in the majority of cases, compared to the control level. All the treated animals showed a significant degree (P<0.001) of tactile allodynia (assessed using von Frey filaments) that did not appear to correlate with blood glucose levels. 2. In this study, we demonstrated that, after STZ treatment, 30 microM gabapentin reduced K(+)-evoked release of [(3)H]-glutamate in either normal (11 mM) or high (30 mM) glucose conditions by 24 and 22%, respectively. In the normal rat, gabapentin (up to 100 microM) is ordinarily unable to affect release of glutamate from the trigeminal slice. 3. The uptake of glutamate in Sp5C punches from streptozotocin-treated rats was reduced under normal glucose conditions (41.7% of control), whereas high glucose restored uptake to normal (84.7% of control). 4. The addition of 1 microm substance P potentiated the evoked release of glutamate in both normal (40% increase) and high glucose (28%), and this was blocked by gabapentin (30 microM) in both conditions. It is interesting to speculate that this ability of gabapentin to reduce the release of glutamate in the trigeminal nucleus after streptozotocin treatment may be of relevance to the antihyperalgesic-allodynic actions of the drug.

Expression of the E-cadherin-catenin cell adhesion complex in primary squamous cell carcinomas of the head and neck and their nodal metastases.

Reductions in cell-cell adhesion and stromal and vascular invasion are essential steps in the progression from localized malignancy to metastatic disease. In this study, changes in the expression of the components of the E-cadherin-catenin cell adhesion complex have been investigated using immunohistochemical techniques in primary tumours and nodal metastases from 36 patients with squamous cell carcinoma of the head and neck. For 14 patients the corresponding primary and nodal metastases samples were available. None of the 51 samples showed normal E-cadherin expression when compared with either the adjacent normal squamous epithelium or with normal colonic epithelium that was used as positive control material. In 88% of primary tumours fewer than 50% of cells exhibited normal membranous E-cadherin expression. Loss of membranous E-cadherin expression was more extensive in poorly differentiated carcinomas while, in individual carcinomas, membranous E-cadherin expression was stronger in those parts of the neoplasm that expressed the differentiation marker involucrin. Expression of beta-catenin generally paralleled that of E-cadherin, but in 12 cases there was strong membranous beta-catenin expression in samples that exhibited predominantly cytoplasmic E-cadherin labelling. Expression of alpha-catenin was generally weak and did not correlate with the expression of either beta-catenin or E-cadherin. Marked intratumoral heterogeneity for protein expression was evident for all antibodies, and the abnormal expression of the catenins is a novel finding. E-cadherin is expressed more intensely in cells with greater squamous differentiation, but there was no correlation between the decreased expression of any of the adhesion molecules of the E-cadherin complex tested and local recurrence, metastasis or survival. The loss of expression of components of the E-cadherin complex is a common abnormality in squamous carcinomas and, while it may be permissive for metastasis, it does not appear to be the only determinant of this process.