Participation of glutamate and nitric oxide on the pathophysiology of neuropsychiatry disorders

Abstract

Glutamate is well recognized as the main excitatory neurotransmitter on mammalian central nervous system. Its receptors are classified in ionotropic and metabotropic. Whereas 8 subtypes of the former have already bee recognized ionotropic glutamate receptors are usually divided in NMDA, AMPA and Kainic subtypes. Glutamate activation of NMDA receptors leads to calcium influx, activation of nitric oxide synthase (NOS) and formation of nitric oxide (NO). In the last decade our group has proposed the participation of glutamate/NO mediated neurotransmission in several neuropsychiatric disorders and brain functions. The main objective of the present project is to continue the investigation of a possible glutamate/NO role on anxiety, affective, motor and psychotic disorders. We also want to test new possible therapeutic approaches to these disorders based on pharmacological interventions on glutamate/NO mediated neurotransmission. Six main groups of projects are proposed. The first four groups are related to pre-clinical studies on animal models (e.g. elevated plus maze, learned helplessness, predator exposure, electrical and/or chemical stimulation of aversive areas, pre-pulse inhibition, catalepsy, motor lesions) and/or studies of the molecular changes induced by such models or by glutamate/NO related drugs. The last two groups of studies involve clinical research on volunteers and/or patients exposed to models of anxiety (public speaking) or psychosis (ketamine administration) and non-invasive evaluation methods (magnetic resonance imaging, spectroscopy and salivary cortisol evaluation). Considering our previous studies and results from the literature suggesting an interaction between glutamatergic and endocannabinoid systems on psychosis, we will also evaluate a possible antipsychotic effect of cannabidiol, a component of Cannabis sativa. (AU)