Publicação
Adenosine A2A Receptors and Stress-induced alterations in the rat ventral striatum
| Resumo: | Chronic stress is a major risk factor for the implementation of depression, a mental disorder that affects nearly 121 million people worldwide and is known to be associated with increased risk of suicide. The neurobiology underlying this pathology is not fully understood and available treatments for depression appear to be ineffective in a subset of patients, thus making this illness a public health burden. However, certain aspects of depression seem to result from maladaptive stress-induced modifications in specific brain regions and neural circuits. Synaptic dysfunction is a key aspect of depression and is a well-known consequence of chronic stress, as well as an imbalance between glutamatergic and GABAergic neurotransmission. The ventral striatum is one of the regions affected in depression. Decreased functioning in this brain area has been evidenced in depression patients and also correlated with some symptoms of this disease. To study mechanisms involved in depression is possible to use animal models such as social defeat stress and restraint stress. Distinct features observed in depressive syndrome, such as anhedonia, anxiety and social avoidance can be successfully replicated in laboratory animals. Adenosine is a purine nucleoside present in all cells which in noxious brain conditions, like stress, is increased and activates adenosine A2A receptors. Activation of these receptors allows controlling neuronal excitability and thus neurotransmitter release and the action of some receptors. Consumption of caffeine, a non-selective A2A receptors antagonist, is inversely correlated with the risk of depression and suicide, and manipulation of A2A receptors, either by blockade or depletion, has proven to modify several behavioral responses relevant for mood function in humans. Furthermore, the adenosinergic system is able to modulate dopaminergic, glutamatergic, serotoninergic and corticotrophin systems, known to be altered in depression. Since there is not much information about A2A receptors in the ventral striatum, we aimed to explore a possible role for these receptors and also stress-induced alterations in the ventral striatum. Aims of this study were: (i) to validate the social defeat stress model; (ii) investigate the predominant localization of A2A receptors in the ventral striatum; (iii) evaluate if A2A receptors density is altered upon stress; (iv) explore if there are alterations in A2A receptors upon stress in glutamatergic, GABAergic and dopaminergic nerve terminals, (v) as well as if restraint stress induced changes in synaptic markers such as synaptosomal-associated protein 25 (SNAP-25), syntaxin, synaptophysin and postsynaptic density protein 95 (PSD-95); and finally, (vi) evaluate if stress altered the balance between glutamatergic/GABAergic nerve terminals, assessed by their vesicular transporters. Social defeat stress is a model that allows mimicking some of the symptoms of depression such as anhedonia, social avoidance, anxiety and depressive like-behaviors, in mice. In order for us to validate the use of this model, we performed a series of behavioral tests that informed us about the model’s reproducibility. Social defeat stress induced social avoidance in mice but failed to reproduce other key features of depression. Since we could not validate the model (i), this aim was left behind and alterations in the ventral striatum were then explored using restraint stress animal samples. In the present work we used synaptosomes, structures that comprise both pre- and postsynaptic nerve terminal components, isolated from our region of interest - the ventral striatum, of animals subjected to restraint stress and also nonstressed animals, in order to assess alterations at the synaptic level. Results obtained show (ii) a predominant synaptic localization of ventral striatum A2A receptors, (iii) which were downregulated upon stress exposure. Additionally, (iv) A2A receptors are present in glutamatergic, GABAergic and dopaminergic nerve terminals in the ventral striatum and stress does not appear to induce any alterations in their localization. Regarding alterations in synaptic markers we observed an increased PSD-95 density after restraint stress, whereas levels of SNAP-25, synaptophysin and syntaxin remained unaltered. At last, (v) the number of glutamatergic and GABAergic nerve terminals and vGluT1 density remained unchanged upon exposure to restraint stress. Altogether, the data obtained in this work will help to gain further knowledge about the role that A2A receptors in ventral striatum may play in the pathology of depression. |
|---|---|
| Autores principais: | Amaral, Inês Margarida Dias Cabaço |
| Assunto: | Depressão, stresse Recetores A2A de adenosina Estriado ventral |
| Ano: | 2015 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso embargado |
| Instituição associada: | Universidade de Coimbra |
| Idioma: | inglês |
| Origem: | Estudo Geral - Universidade de Coimbra |
| Resumo: | Chronic stress is a major risk factor for the implementation of depression, a mental disorder that affects nearly 121 million people worldwide and is known to be associated with increased risk of suicide. The neurobiology underlying this pathology is not fully understood and available treatments for depression appear to be ineffective in a subset of patients, thus making this illness a public health burden. However, certain aspects of depression seem to result from maladaptive stress-induced modifications in specific brain regions and neural circuits. Synaptic dysfunction is a key aspect of depression and is a well-known consequence of chronic stress, as well as an imbalance between glutamatergic and GABAergic neurotransmission. The ventral striatum is one of the regions affected in depression. Decreased functioning in this brain area has been evidenced in depression patients and also correlated with some symptoms of this disease. To study mechanisms involved in depression is possible to use animal models such as social defeat stress and restraint stress. Distinct features observed in depressive syndrome, such as anhedonia, anxiety and social avoidance can be successfully replicated in laboratory animals. Adenosine is a purine nucleoside present in all cells which in noxious brain conditions, like stress, is increased and activates adenosine A2A receptors. Activation of these receptors allows controlling neuronal excitability and thus neurotransmitter release and the action of some receptors. Consumption of caffeine, a non-selective A2A receptors antagonist, is inversely correlated with the risk of depression and suicide, and manipulation of A2A receptors, either by blockade or depletion, has proven to modify several behavioral responses relevant for mood function in humans. Furthermore, the adenosinergic system is able to modulate dopaminergic, glutamatergic, serotoninergic and corticotrophin systems, known to be altered in depression. Since there is not much information about A2A receptors in the ventral striatum, we aimed to explore a possible role for these receptors and also stress-induced alterations in the ventral striatum. Aims of this study were: (i) to validate the social defeat stress model; (ii) investigate the predominant localization of A2A receptors in the ventral striatum; (iii) evaluate if A2A receptors density is altered upon stress; (iv) explore if there are alterations in A2A receptors upon stress in glutamatergic, GABAergic and dopaminergic nerve terminals, (v) as well as if restraint stress induced changes in synaptic markers such as synaptosomal-associated protein 25 (SNAP-25), syntaxin, synaptophysin and postsynaptic density protein 95 (PSD-95); and finally, (vi) evaluate if stress altered the balance between glutamatergic/GABAergic nerve terminals, assessed by their vesicular transporters. Social defeat stress is a model that allows mimicking some of the symptoms of depression such as anhedonia, social avoidance, anxiety and depressive like-behaviors, in mice. In order for us to validate the use of this model, we performed a series of behavioral tests that informed us about the model’s reproducibility. Social defeat stress induced social avoidance in mice but failed to reproduce other key features of depression. Since we could not validate the model (i), this aim was left behind and alterations in the ventral striatum were then explored using restraint stress animal samples. In the present work we used synaptosomes, structures that comprise both pre- and postsynaptic nerve terminal components, isolated from our region of interest - the ventral striatum, of animals subjected to restraint stress and also nonstressed animals, in order to assess alterations at the synaptic level. Results obtained show (ii) a predominant synaptic localization of ventral striatum A2A receptors, (iii) which were downregulated upon stress exposure. Additionally, (iv) A2A receptors are present in glutamatergic, GABAergic and dopaminergic nerve terminals in the ventral striatum and stress does not appear to induce any alterations in their localization. Regarding alterations in synaptic markers we observed an increased PSD-95 density after restraint stress, whereas levels of SNAP-25, synaptophysin and syntaxin remained unaltered. At last, (v) the number of glutamatergic and GABAergic nerve terminals and vGluT1 density remained unchanged upon exposure to restraint stress. Altogether, the data obtained in this work will help to gain further knowledge about the role that A2A receptors in ventral striatum may play in the pathology of depression. |
|---|