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The effects of selective blockade of group I metabotropic glutamate receptor subtype 1 (mGluR1) on neuronal cell survival and post-traumatic recovery was examined using rat in vitroand in vivotrauma models. The selective mGluR1 antagonists (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), and (S)-(+)-α-amino-4-carboxy-2-methylbezeneacetic acid (LY367385) provided significant neuroprotection in rat cortical neuronal cultures subjected to mechanical injury, in both pretreatment or posttreatment paradigms. Administration of the antagonists also attenuated glutamate-induced neuronal cell death in the cultures. Coapplication of these antagonists with the N-methyl-d-aspartate (NMDA) receptor antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) had additive neuroprotective effects in glutamate injured cultures. Intracerebroventricular administration of AIDA to rats markedly improved recovery from motor dysfunction after lateral fluid percussion induced traumatic brain injury (TBI). Treatment with mGluR1 antagonists also significantly reduced lesion volumes in rats after TBI, as evaluated by MRI. It appears that these compounds mediate their neuroprotective effect through an mGluR1 antagonist action, as demonstrated by inhibition of agonist induced phosphoinositide hydrolysis in our in vitrosystem. Moreover, AIDA, CPCCOEt, and LY367385, at concentrations shown to be neuroprotective, had no significant effects on the steady state NMDA evoked whole cell current. Taken together, these data suggest that modulation of mGluR1 activity may have substantial therapeutic potential in brain injury.

AbstractWith each high profile case of sexual assault perpetrated against a child there generally follows a media driven reaction narrowly focusing on stranger danger or paedophile activity The difficulty is that this can present the false impression that therein lies the greatest danger to our children.The situation with which parentdcarers, and professionals, are faced with in dealing with cases of child sexual abuse is much more complex for a variety of reasons. These include the fact that such abuse is mostly perpetrated by a member of the family or a close friend of the family or child; there are many cases of crossgenerational and sibling abuse; there is often fragmentation of families following disclosure; the immense challenge to strongly held beliefs regarding familv, society and religious values; and thaf a child's coping strategies often involves blocking out the abuse, disassociation and extreme forms of self-harm.Much good literature exists on the phenomenon of child sexual abuse. However, there is a lack of written material on models of therapeutic intervention, and to engage in this area of work in the absence of a well thought-out framework for intervention would be highly irresponsible and dangerous. The purpose of this paper is to discuss the issue of intervention and in setting out a framework for intervention, the premise is followed that the child is not abused in isolation, but within a family and community context. For this reason theoretical considerations relating to victim impact, family functioning, social learning and developmental stages will be viewed as underpinning practice.

The metabotropic glutamate receptors (mGluRs) are a family of G‐protein linked receptors that can be divided into three groups (group I, II and III). A number of studies have implicated group I mGluR activation in acute neuronal injury, but until recently it was not possible to pharmacologically differentiate the roles of the two individual subunits (mGluR1 and mGluR5) in this group.We investigated the role of mGluR5 in acute NMDA and glutamate mediated neurodegeneration in cultured rat cortical cells using the mGluR5 antagonists MPEP and SIB‐1893, and found that they provide significant protection at concentrations of 20 or 200 μM.These compounds act as effective mGluR5 antagonists in our cell culture system, as indicated by the ability of SIB‐1893 to prevent phosphoinositol hydrolysis induced by the specific mGluR5 agonist, (RS)‐2‐chloro‐5‐hydroxyphenylglycine (CHPG).However, they also significantly reduce NMDA evoked current recorded from whole cells voltage clamped at −60 mV, and significantly decrease the duration of opening of NMDA channels recorded in the outside out patch configuration.This suggests that although MPEP and SIB‐1893 are effective mGluR5 antagonists, they also act as noncompetitive NMDA receptor antagonists. Therefore, the neuroprotective effects of these compounds are most likely mediated through their NMDA receptor antagonist action, and caution should be exercised when drawing conclusions about the roles of mGluR5 based on their use.

1 The metabotropic glutamate receptors (mGluRs) are a family of G-protein linked receptors that can be divided into three groups (group I, II and III). A number of studies have implicated group I mGluR activation in acute neuronal injury, but until recently it was not possible to pharmacologically differentiate the roles of the two individual subunits (mGluR1 and mGluR5) in this group. 2 We investigated the role of mGluR5 in acute NMDA and glutamate mediated neurodegeneration in cultured rat cortical cells using the mGluR5 antagonists MPEP and SIB-1893, and found that they provide significant protection at concentrations of 20 or 200 μM. 3 These compounds act as effective mGluR5 antagonists in our cell culture system, as indicated by the ability of SIB-1893 to prevent phosphoinositol hydrolysis induced by the specific mGluR5 agonist, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG). 4 However, they also significantly reduce NMDA evoked current recorded from whole cells voltage clamped at −60 mV, and significantly decrease the duration of opening of NMDA channels recorded in the outside out patch configuration. 5 This suggests that although MPEP and SIB-1893 are effective mGluR5 antagonists, they also act as noncompetitive NMDA receptor antagonists. Therefore, the neuroprotective effects of these compounds are most likely mediated through their NMDA receptor antagonist action, and caution should be exercised when drawing conclusions about the roles of mGluR5 based on their use. British Journal of Pharmacology (2000) 131, 1429 – 1437

Coogan, Andrew N., Deirdre M. O'Leary, and John J. O'Connor.P42/44 MAP kinase inhibitor PD98059 attenuates multiple forms of synaptic plasticity in rat dentate gyrus in vitro. J. Neurophysiol.81: 103–110, 1999. The effects of the specific p42/44 mitogen-activated protein (MAP) kinase cascade inhibitor, PD98059, were investigated on three types of long-term potentiation (LTP) in the medial perforant path of the rat dentate gyrus in vitro: LTP induced by 1) high-frequency stimulation (HFS-LTP), 2) application for 10 min of the K+channel blocker, tetraethylammonium chloride (TEA-LTP), and 3) application of the metabotropic glutamate receptor (mGluR) agonist (S)-dihydrophenylglycine (S-DHPG) for 2 min (DHPG-LTP). Bath perfusion of PD98059 (50 μM) for 1 h inhibited HFS-LTP (111 ± 5%, mean ± SE, at 90 min posttetanus in test slices compared with 144 ± 5% in control slices; n= 6–7). Concentrations of 10 and 20 μM PD98059 had no effect on HFS-LTP (n= 6). PD98059 (50 μM) had no effect on the isolated N-methyl-d-aspartate excitatory postsynaptic potential (NMDA-EPSP) or on the maintenance phase of HFS-LTP. PD98059 (50 μM) did not affect paired-pulse depression (PPD; interstimulus intervals of 10 and 100 ms) of synaptic transmission as is typically observed in the medial perforant path of the dentate gyrus. Bath application of (S)-DHPG (40 μM) for 2 min gave rise to a potentiation of the EPSPs slope (148 ± 4% at 1 h post-DHPG wash out; n= 5). Pretreatment of slices with PD98059 (50 μM) inhibited the DHPG-LTP (98 ± 3% at 1 h post-DHPG wash out; n= 5). The TEA-LTP (125 ± 4% at 1 h post-TEA wash out; n= 6) was found to be both d-2-amino-5-phosphonopentanoic acid (d-AP5; 100 μM) and nifedipine (20 μM) independent. However, the T type voltage-dependent calcium-channel blocker, NiCl2(50 μM), completely inhibited the observed potentiation. The mGluR receptor antagonist α-methyl-4-carboxy-phenyl glycine (MCPG; 100 μM) and PD98059 (50 μM) caused a complete block of the TEA-LTP. These data show for the first time an involvement of the p42/44 MAP kinase in the induction and expression of both an NMDA-dependent and two forms of NMDA-independent LTP in the dentate gyrus.

Several letters to the editor are presented in response to articles in previous issues including about solar panels in the number 49 issue, plan for an open fireplace in the number 48 issue, and "Going Local," by David Fleming in the number 48 issue.