| Grant number: | 16/04620-1 |
| Support type: | Regular Research Grants |
| Duration: | September 01, 2016 - November 30, 2018 |
| Field of knowledge: | Biological Sciences - Pharmacology |
| Principal Investigator: | Marcus Lira Brandão |
| Grantee: | Marcus Lira Brandão |
| Home Institution: | Instituto de Neurociências e Comportamento (INEC). Ribeirão Preto , SP, Brazil |
| Assoc. researchers: | Amanda Ribeiro de Oliveira ; Helene Aparecida Fachim ; Karina Di Sicco Genaro ; Milene Cristina de Carvalho |
Abstract
It is well established that the neural substrates of fear and anxiety are part of an encephalic aversion system (EAS) comprising the amygdala, medial hypothalamus and periaqueductal gray matter. Other structures such as inferior and superior colliculi have also been proposed as components of this system as well as the prefrontal cortex and nucleus accumbens. A sensorimotor gating in these structures processes the aversive information that ascends to the SEA in order to filter those that are important for the organization and elaboration of aversive states serving as triggers for the defense reaction associated to fear, stress and anxiety. The challenge in this project will be to establish an integrative approach (ethopharmacological, electrophysiological and neurochemical) that will enable us to characterize the different aversive stimulus-defensive behavior processes that underlies the consequences of stress to the organism. Increasing amount of evidence from animal studies has suggested modulatory roles for g-aminobutyric acid (GABA), serotonin, opioid peptides, excitatory amino acids, canabinnoids and nitric oxide in the EAS. Recently, the interest for dopamine (DA) mediation of the defense reaction has grown considerably, in particular for the DA mediation of conditioned fear, which has been associated with anxiety. In this respect, it has been found that increased DA metabolism in the mesolimbic system is correlated with conditioned fear and reduction of the DA activity in the basolateral amygdala courses with a reduction in the conditioned fear expression. Although the precise neural circuitry of DA transmission involved in aversive states remains unclear, pharmacological and neurochemical studies appear to implicate the prefrontal cortex, nucleus accumbens and amygdala DA terminals in the response to conditioned aversive stimuli. However, investigations of DA mediation of the defense reaction associated to fear/panic have been scarce. Taking this evidence into account in this project a thorough ethopharmacological (through activation or inhibition of dopaminergic receptors), electrophysiological and neurochemical analysis (use of microdyalisis to measure extracellular concentration of DA and its metabolites) of the DA transmission of the neural substrates of the EAS and in prosencephalic structures, such as prefrontal cortex and nucleus accumbens during conditioned and unconditioned fear will be conducted. Given the prospect of an important mediation of the EAS by neurokinins based on consistent evidence obtained in this and other laboratories this project will also investigate the involvement of NK1 receptors of these structures in the processing of aversive information and the generation of defense reaction in the EAS. The comprehension of the electrophysiological, neurochemical and behavioral responses to threatening experiences could give a better insight into the mechanisms involved in the onset of anxiety- related disorders, and might indicate potential targets for psychotherapeutic drugs development. The obtained results will be discussed in the light of clinical implications concerning the understanding of the neural mediation of anxiety and panic disorder with obvious reflection on the pharmacotherapy of these mental disorders. (AU)