Publicação
New insights on the interplay between psychopharmacology and neuroplasticity in psychiatric disorders
| Resumo: | It is now clear that various forms of structural plasticity, including the generation of new neurons and glial cells, may modify pathophysiological processes in neuropsychiatric disorders, namely in depression. In fact, several studies have shown decreased hippocampal neurogenesis in depressed patients, while treatment with different antidepressant drugs in animal models increases neurogenesis in this region, allowing the recovery from emotional and cognitive changes. However, these effects have not been described for all the available classes of antidepressant drugs. Furthermore, the neuroplastic effects of antidepressants in other neurogenic regions such as the hypothalamus have yet to be determined. Despite the importance of these drugs in the recovery from depression, a significant proportion of depressed patients reveal incomplete remission and develop treatment-resistant forms of the disorder. The use of atypical antipsychotics in these cases has been widely used in the clinical setting. However, the neuroplastic effects of these drugs in depression and schizophrenia are still largely unknown. Taking this into consideration we aimed to explore new perspectives on the interplay between psychopharmacology and neuroplasticity in these psychiatric disorders. To explore the neuroplastic effects of the antidepressant Pirlindole, a MAO-A (monoamine oxidase, type A) inhibitor, we used the unpredictable chronic mild stress (uCMS) animal model of depression. Our results indicate that Pirlindole is able to reverse the behavioural effects of stress exposure, potentiating hippocampal adult neurogenesis and rescuing the stress-induced dendritic atrophy of granule neurons in the dentate gyrus of the hippocampus. These results further reinforce the notion that the modulation of monoaminergic neurotransmission is involved in the neuroplastic effects of currently available antidepressant drugs. To dissect the potential actions of antidepressants in adult neurogenesis in the hypothalamus we treated animals exposed to uCMS with two different classes of antidepressants: fluoxetine (a selective serotonin reuptake inhibitor) and imipramine (a tricyclic antidepressant). Our results demonstrate that chronic stress and antidepressant treatment can modulate hypothalamic neurogenesis. Moreover, we proved that different classes of antidepressants, with an opposite action on appetite and body weight gain, differentially modulate hypothalamic neurogenesis. This data indicates that in addition to the neuroplastic effects on the hippocampus, stress and antidepressant drugs also modulate hypothalamic adult neurogenesis.Furthermore, we explored the role of neuroplasticity in the therapeutic actions of atypical antipsychotics in depression. To achieve this, we treated animals exposed to uCMS with a classical (haloperidol) and an atypical (clozapine) antipsychotic. Our data demonstrates that the atypical antipsychotic clozapine improved measures of depressive-like behavior while haloperidol had no beneficial effect, aggravating learned helplessness in the forced swimming test and behavior flexibility in a cognitive task. Importantly, an upregulation of adult neurogenesis and neuronal survival was observed in animals treated with clozapine while haloperidol promoted a downregulation of these processes. These results demonstrate that the atypical antipsychotic is able to reverse the behavioral effects of chronic stress by improving adult neurogenesis, cell survival and neuronal reorganization. Finally, to understand the impact of different classes of antipsychotics in the negative and cognitive symptoms of schizophrenia, we used a neurodevelopmental model of schizophrenia. Animals expose prenatally to the cytostatic agent methylazoxymethanol (MAM) presented specific cognitive deficits and social impairments. The classical antipsychotic haloperidol presented no beneficial effects in these behavioral dimensions. The atypical antipsychotic clozapine and risperidone revealed a positive effect on both dimensions while aripiprazole presented a significant effect in the social measure. Adult gliogenesis is affected in animals exposed to MAM, being modulated by the atypical antipsychotics used. Neurogenesis is not altered in MAM animals, with haloperidol negatively affecting this phenomenon. In this work, we proved that classical and atypical antipsychotics differentially modulate hippocampal cell genesis possibly contributing to different behavioural actions in hippocampal dependent functions. Together, these findings contribute to expand our knowledge on the role of psychopharmacological agents (including antidepressants and antipsychotics) on the modulation of different neuroplastic events, including cell genesis and neuronal remodelling. In the future, this knowledge may help to pave the way for new therapeutic interventions both in depression and schizophrenia. |
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| Autores principais: | Morais, Mónica Susana Dias |
| Assunto: | depression schizophrenia neuroplasticity neurogenesis gliogenesis depressão esquizofrenia neuroplasticidade neurogénese gliogénese |
| Ano: | 2017 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | It is now clear that various forms of structural plasticity, including the generation of new neurons and glial cells, may modify pathophysiological processes in neuropsychiatric disorders, namely in depression. In fact, several studies have shown decreased hippocampal neurogenesis in depressed patients, while treatment with different antidepressant drugs in animal models increases neurogenesis in this region, allowing the recovery from emotional and cognitive changes. However, these effects have not been described for all the available classes of antidepressant drugs. Furthermore, the neuroplastic effects of antidepressants in other neurogenic regions such as the hypothalamus have yet to be determined. Despite the importance of these drugs in the recovery from depression, a significant proportion of depressed patients reveal incomplete remission and develop treatment-resistant forms of the disorder. The use of atypical antipsychotics in these cases has been widely used in the clinical setting. However, the neuroplastic effects of these drugs in depression and schizophrenia are still largely unknown. Taking this into consideration we aimed to explore new perspectives on the interplay between psychopharmacology and neuroplasticity in these psychiatric disorders. To explore the neuroplastic effects of the antidepressant Pirlindole, a MAO-A (monoamine oxidase, type A) inhibitor, we used the unpredictable chronic mild stress (uCMS) animal model of depression. Our results indicate that Pirlindole is able to reverse the behavioural effects of stress exposure, potentiating hippocampal adult neurogenesis and rescuing the stress-induced dendritic atrophy of granule neurons in the dentate gyrus of the hippocampus. These results further reinforce the notion that the modulation of monoaminergic neurotransmission is involved in the neuroplastic effects of currently available antidepressant drugs. To dissect the potential actions of antidepressants in adult neurogenesis in the hypothalamus we treated animals exposed to uCMS with two different classes of antidepressants: fluoxetine (a selective serotonin reuptake inhibitor) and imipramine (a tricyclic antidepressant). Our results demonstrate that chronic stress and antidepressant treatment can modulate hypothalamic neurogenesis. Moreover, we proved that different classes of antidepressants, with an opposite action on appetite and body weight gain, differentially modulate hypothalamic neurogenesis. This data indicates that in addition to the neuroplastic effects on the hippocampus, stress and antidepressant drugs also modulate hypothalamic adult neurogenesis.Furthermore, we explored the role of neuroplasticity in the therapeutic actions of atypical antipsychotics in depression. To achieve this, we treated animals exposed to uCMS with a classical (haloperidol) and an atypical (clozapine) antipsychotic. Our data demonstrates that the atypical antipsychotic clozapine improved measures of depressive-like behavior while haloperidol had no beneficial effect, aggravating learned helplessness in the forced swimming test and behavior flexibility in a cognitive task. Importantly, an upregulation of adult neurogenesis and neuronal survival was observed in animals treated with clozapine while haloperidol promoted a downregulation of these processes. These results demonstrate that the atypical antipsychotic is able to reverse the behavioral effects of chronic stress by improving adult neurogenesis, cell survival and neuronal reorganization. Finally, to understand the impact of different classes of antipsychotics in the negative and cognitive symptoms of schizophrenia, we used a neurodevelopmental model of schizophrenia. Animals expose prenatally to the cytostatic agent methylazoxymethanol (MAM) presented specific cognitive deficits and social impairments. The classical antipsychotic haloperidol presented no beneficial effects in these behavioral dimensions. The atypical antipsychotic clozapine and risperidone revealed a positive effect on both dimensions while aripiprazole presented a significant effect in the social measure. Adult gliogenesis is affected in animals exposed to MAM, being modulated by the atypical antipsychotics used. Neurogenesis is not altered in MAM animals, with haloperidol negatively affecting this phenomenon. In this work, we proved that classical and atypical antipsychotics differentially modulate hippocampal cell genesis possibly contributing to different behavioural actions in hippocampal dependent functions. Together, these findings contribute to expand our knowledge on the role of psychopharmacological agents (including antidepressants and antipsychotics) on the modulation of different neuroplastic events, including cell genesis and neuronal remodelling. In the future, this knowledge may help to pave the way for new therapeutic interventions both in depression and schizophrenia. |
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