A carregar...
Publicação
Interaction between adenosine A2A receptors and cannabinoid CB1 receptors at the hippocampus : consequences for memory and plasticity
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 8.47 MB | Adobe PDF |
Orientador(es)
Resumo(s)
Adenosine is an ubiquitous neuromodulator of the central nervous system (CNS) and through receptors of the A2A subtype (A2ARs) can influence both synaptic plasticity and neuronal death. Likewise, endocannabinoids are important neuromodulators that act at the CNS, being involved in several physiological processes. Activation of the cannabinoid receptor 1 (CB1Rs) is responsible for mediating the physiological actions of endocannabinoids and the psychoactive effects of Δ9-THC. Neuromodulators of the central nervous system show the ability to modify the activity of N-methyl-D-aspartate receptors (NMDARs), known to play a key role in both synaptic plasticity and neurodegeneration. Considering the prejudicial effects upon memory associated with cannabinoid consumption and that NMDARs can induce neurodegeneration and excitotoxicity, this work was designed to understand if adenosine A2AR activity could be pharmacologically manipulated to protect neurons and synapses from insults coming from cannabinoid exposure and NMDARs hyperfunction. The results show that an adenosine A2AR agonist could selectively increase synaptic NMDAR activity, known to be related with neuroprotection. Also, it is whereby demonstrated that the activation of CB1Rs is associated with long term potentiation (LTP) impairments and disruptions in recognition memory. Simultaneous administration of an A2ARs antagonist was able to partially restore LTP and to fully cancel impairments in recognition memory. Also, it was found that chronic cannabinoid exposure modified brain metabolic activity, resulting in patterns of abnormal functional connectivity within the limbic system. These results point to dysfunctionalities in a multiplitude of brain regions involved in recognition memory. This work highlights the ability of adenosine A2ARs to act as metamodulators of synaptic transmission in the CNS. The fact that these receptors are able of increasing and decreasing, respectively, the positive outcomes of synaptic NMDAR activity and the negative consequences of CB1Rs upon recognition memory, show the potential of A2AR as therapeutic targets to tackle neuronal imbalances in psychiatric and neurologic diseases.
Descrição
Tese de doutoramento, Ciências Biomédicas (Neurociências), Universidade de Lisboa, Faculdade de Medicina, 2018
Palavras-chave
Adenosina Receptor A2A de adenosina Canabinóides Receptores de N-Metil-D-Aspartato Memória Plasticidade neuronal Teses de doutoramento - 2018