1 The goal of this study was to characterize the agonist pharmacology of human 5-HT 2A , 5-HT 2B and 5-HT 2C (VSV) receptors expressed in CHO-K1 (Chinese hamster ovary) cells. 2 We used a¯uorometric imaging plate reader (FLIPR) which allows rapid detection of rises in intracellular calcium levels upon the addition of agonists. 5 Many agonists tested had partial agonist actions when compared to 5-HT, and a wide range of relative e cacies were exhibited, which was cell line dependent. For example, mCPP had a relative e cacy of 65% at 5-HT 2C receptors but 525% at either 5-HT 2A or 5-HT 2B receptors. 6 Interpretation of literature values of functional assays using di erent cell lines, di erent receptor expression levels and di erent receptor isoforms, is complex. Species di erences and the previous use of antagonist radioligands to characterize agonist potency in binding assays emphasizes the importance of studying agonists in the same experiment using the same assay conditions and parental cell lines.

Fenobam [N-(3-chlorophenyl)-NЈ-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] is an atypical anxiolytic agent with unknown molecular target that has previously been demonstrated both in rodents and human to exert anxiolytic activity. Here, we report that fenobam is a selective and potent metabotropic glutamate (mGlu)5 receptor antagonist acting at an allosteric modulatory site shared with 2-methyl-6-phenylethynyl-pyridine (MPEP), the protypical selective mGlu5 receptor antagonist. Fenobam inhibited quisqualate-evoked intracellular calcium response mediated by human mGlu5 receptor with IC 50 ϭ 58 Ϯ 2 nM. It acted in a noncompetitive manner, similar to MPEP and demonstrated inverse agonist properties, blocking 66% of the mGlu5 receptor basal activity (in an over expressed cell line) with an IC 50 ϭ 84 Ϯ

Altered glutamatergic neurotransmission and neuronal metabolic dysfunction appear to be central to the pathophysiology of Parkinson's disease (PD). The substantia nigra pars compacta--the area where the primary pathological lesion is located--is particularly exposed to oxidative stress and toxic and metabolic insults. A reduced capacity to cope with metabolic demands, possibly related to impaired mitochondrial function, may render nigral highly vulnerable to the effects of glutamate, which acts as a neurotoxin in the presence of impaired cellular energy metabolism. In this way, glutamate may participate in the pathogenesis of PD. Degeneration of dopamine nigral neurons is followed by striatal dopaminergic denervation, which causes a cascade of functional modifications in the activity of basal ganglia nuclei. As an excitatory neurotransmitter, glutamate plays a pivotal role in normal basal ganglia circuitry. With nigrostriatal dopaminergic depletion, the glutamatergic projections from subthalamic nucleus to the basal ganglia output nuclei become overactive and there are regulatory changes in glutamate receptors in these regions. There is also evidence of increased glutamatergic activity in the striatum. In animal models, blockade of glutamate receptors ameliorates the motor manifestations of PD. Therefore, it appears that abnormal patterns of glutamatergic neurotransmission are important in the symptoms of PD. The involvement of the glutamatergic system in the pathogenesis and symptomatology of PD provides potential new targets for therapeutic intervention in this neurodegenerative disorder.

Metabotropic glutamate (mGlu) 5 is a G-protein-coupled metabotropic glutamate receptor that plays an important role as a modulator of synaptic plasticity, ion channel activity, and excitotoxicity. 2-Methyl-6-(phenylethynyl)-pyridine (MPEP) is a highly potent, noncompetitive, selective, and systemically active antagonist of mGlu5 receptors. It binds to a novel allosteric site that resides within the seven-transmembrane domain of mGlu5 receptors. 6.55 in TM6 helix prevents the movement of TM6 helix relative to TM3 helix, a step that is required for receptor activation, and consequently stabilizes the inactive conformation of mGlu5 receptor. In the TM6 region, we observed a striking similarity between the critical residues involved in MPEP-binding site with those of previously identified as 1-ethyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydropyrimidine-5-carbonitrile-binding pocket of mGlu1, pointing to a common mechanism of inhibition shared by both antagonists.

The defining characteristic of mammals is that females nurse and care for their young; without this, the neonate has no chance to survive. Studies on wild and domestic species show that the neonatal period is the most critical step in the lifetime of a mammal. This review compares three well-studied species (the rabbit, pig and sheep) that differ in their parental strategies and in the problems that neonates have to overcome. As a general trend, mother-young interactions vary according to the maturity of the newborn, and the size of the litter. Neonatal survival relies to a great extent on an environment that is ecologically appropriate for the developmental stage of the neonate, and on optimum interactions with the mother. Adaptive maternal care supposes that the mother provides the basic needs of the neonate: warmth (in pigs and rabbits) or shelter, food, water and immunological protection (via colostrum) and, in some instances, protection from predators and other conspecifics. A major risk facing all neonates, other than the birth process itself, is inadequate colostrum intake owing to delayed suckling or competition with siblings, which leads to starvation, hypothermia or even crushing, as has been observed in pigs.