Metabotropic glutamate receptors as therapeutic targets for cognitive disorders.

Since more than one decade, metabotropic glutamate receptors have been under investigation as targets for various CNS disorders such as anxiety, pain, depression, schizpohrenia, Alzheimer's disease and Parkinson's disease. It has been shown that some mGluRs play a crucial role in cognitive processes such as learning and memory, which was initially, demonstrated using knockout mice for each receptor subtype. Later, selective pharmacological tools were developed allowing more specific examinations of the involvement of mGluR1-8 in various forms of learning and memory. Ligands for group I and II mGluRs have been proposed as promising candidates for the treatment of cognitive disorders such as schizophrenia, Fragile X syndrome, Alzheimer's and Parkinson's disease and post traumatic stress disorder, of which some have made it to clinical testing. The present paper reviews relevant data on the role of mGluRs in learning and cognition processes focusing on their utility as targets for cognition enhancement in several CNS diseases.

On the interactions between antimuscarinic atropine and NMDA receptor antagonists in anticholinesterase-treated mice.

Both organophosphate (OP) and carbamate pesticides may produce seizures and death commonly attributed to the inhibition of acetylcholinesterase (AChE) and subsequent excess of acetylcholine (ACh). The anticonvulsant and neuroprotective properties of N-methyl-D-aspartate (NMDA) receptor antagonists in animals encouraged us to investigate their effects on the toxic and convulsant properties of OP and carbamate pesticides. Adult Swiss mice were systemically injected with the OP pesticide, chlorfenvinphos (CVP), or the carbamate pesticide, methomyl (MET). Both CVP and MET induced dose-dependent seizure activity and death in mice. Pretreatment with the muscarinic antagonist, atropine (ATR), at a dose of 1.8 mg/kg did not prevent seizures but decreased the lethal effects of CVP and MET. Pretreatment with the NMDA antagonists, dizocilpine (MK-801) at a dose of 1 mg/kg or 3-((R,S)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) at a dose of 10 mg/kg, influenced neither MET-induced seizures nor CVP- or MET-induced death. However, both MK-801 and CPP blocked CVP-induced seizures. Concurrent administration of ATR and the NMDA antagonists prevented seizures produced by CVP, but not those produced by MET. Nevertheless, both MK801 and CPP coadministered with ATR markedly enhanced its antilethal effects in CVP- and MET-intoxicated mice. The antidotes had no influence upon brain AChE activities in mice treated with saline or CVP or MET. It seems that combined treatment with ATR and NMDA receptor antagonists might be of clinical relevance.