A High Throughput Screen Identifies Chemical Modulators of the Laminin-Induced Clustering of Dystroglycan and Aquaporin-4 in Primary Astrocytes

Background: Aquaporin-4 (AQP4) constitutes the principal water channel in the brain and is clusteredat the perivascular astrocyte endfeet. This specific distribution of AQP4 plays a major role in maintaining water homeostasis in the brain. A growing body of evidence points to a role ofthe dystroglycan complex and its interaction with perivascular laminin in the clusteringof AQP4 atperivascular astrocyte endfeet. Indeed, mice lacking components of this complex or in which laminindystroglycan interaction is disrupted show a delayed onset of brain edema due to a redistribution of AQP4 away from astrocyte endfeet. It is therefore important to identify inhibitory drugs of laminin-dependent AQP4 clustering which may prevent or reduce brain edema. Methodolgy/Principal Findings: In the present study we used primary rat astrocyte cultures toscreen a library of.3,500 chemicals and identified 6 drugs that inhibit the laminin-induced clustering of dystroglycan and AQP4. Detailed analysis of the inhibitory drug, chloranil, revealed that its inhibition of the clustering is due to the metalloproteinase-2-mediated ß-dystroglycan shedding and subsequent loss of laminin interaction with dystroglycan. Furthermore, chemical variants of chloranil induced a similar effect on ß-dystroglycan and this was prevented by the antioxidant N-acetylcysteine. Conclusion/Significance: These findings reveal the mechanism of action of chloranil in preventing the laminin-induced clustering of dystroglycan and AQP4 and validate the use of high-throughput screening as a tool to identify drugs tha

Nicotinic receptors

Regulation of normal or abnormal behaviour is critically controlled by the central serotonergic systems. Recent evidence has suggested that serotonin (5-HT) neurotransmission dysfunction contributes to a variety of pathological conditions, including depression, anxiety, schizophrenia and Parkinson’s disorders. There is also a great amount of evidence indicating that 5-HT signalling may affect the reinforcing properties of drugs of abuse by the interaction and modulation of dopamine (DA) function. This chapter is focused on one of the more addictive drugs, nicotine. It is widely recognised that the effects of nicotine are strongly associated with the stimulatory action it exhibits on mesolimbic DAergic function. We outline the role of 5-HT and its plethora of receptors, focusing on 5-HT2 subtypes with relation to their involvement in the neurobiology of nicotine addiction. We also explore the novel pharmacological approaches using 5-HT agents for the treatment of nicotine dependence. Compelling evidence shows that 5-HT2C receptor agonists may be possible therapeutic targets for smoking cessation, although further investigation is required.peer-reviewe

Disconnection of the Entorhinal Cortex and Dorsomedial Striatum Impairs the Sensitivity to Instrumental Contingency Degradation

The capacity to detect changes in the causal efficacy of actions is mediated by a number of brain areas, including the entorhinal cortex (EC) and the posterior part of the dorsomedial striatum (pDMS). In this study we examined whether interactions between the EC and pDMS are required to detect changes in the instrumental contingency. Rats that received EC–pDMS disconnection lesions, that is, unilateral cell body lesions of the EC and contralateral dopamine depletions of the pDMS, were trained to press two levers, with one delivering food pellets and the other a sucrose solution. Thereafter, we tested whether rats were sensitive (1) to a selective devaluation of the value of one of two outcomes using a specific satiety procedure, and (2) to a selective degradation of one of two contingencies controlling instrumental choice behavior. Our results reveal that rats with EC–pDMS disconnection lesions were sensitive to outcome devaluation. However, unlike rats with sham lesions or unilateral EC and pDMS lesions, rats with EC–pDMS disconnection lesions showed a reduced sensitivity to contingency degradation. These findings suggest that EC and pDMS may be part of a neural system that supports the detection of changes in the causal relationship between an action and its consequences