Publikationsdatenbank

Effects of 2-bromoterguride, a dopamine D2 receptor partial agonist, in animal models for negative symptoms and cognitive dysfunctions associated with schizophrenia (2018)

Art

Hochschulschrift

Autor

Tarland, Andrea Emilia (WE 14)

Quelle

Berlin, 2018 — x, 152 Seiten

Sprache

Englisch

Verweise

URL (Volltext): https://refubium.fu-berlin.de/handle/fub188/23717

Kontakt

Institut für Pharmakologie und Toxikologie

Koserstr. 20
14195 Berlin
+49 30 838 53221
pharmakologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

Schizophrenia is a severe psychiatric disorder, affecting about one percent of people. The treatment of schizophrenia involves alleviating the positive symptoms, negative symptoms and cognitive deficits. Overall, available antipsychotic drugs (APDs) can successfully silence the positive symptoms due to antagonistic actions on dopamine D2 receptors. Unfortunately, the APDs are associated with aversive side effects and there is still severe paucity in the treatment of negative symptoms and cognitive impairments. 2-Bromoterguride (2BT) is a dopamine D2 receptor partial agonist that shows antipsychotic-like effects in rats without inducing extrapyramidal side effects and metabolic changes. In addition to its action on D2 receptors, 2BT has affinities for several other receptor types implicated in the pathophysiology of schizophrenia, including the serotonergic and glutamatergic systems, and hence meets the prerequisites for a putative atypical APD. The objective of this PhD study, which consisted of two main projects, was to investigate the effects of 2BT on negative symptoms and cognitive deficits in drug-induced animal models. In the first project, the effect of 2BT on sensory motor gating, was measured via the prepulse inhibition of the acoustic startle response (PPI). PPI deficits in male rats were induced using either apomorphine or the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). The results showed that 2BT could block the effect of both apomorphine and PCP, indicating that 2BT has an atypical APD character in vivo. For the second experiment, a subchronic PCP (scPCP) treatment protocol was established, which caused cognitive deficits in male rats when these were tested in the Novel Object Recognition (NOR) test. Our results showed that 2BT was effective in ameliorating the scPCP treatment-induced object recognition deficit in the NOR test. In order to evaluate the effect of 2BT on negative symptoms of schizophrenia, the same scPCP treatment protocol which induced cognitive impairments in the NOR test, was used to induce social aversion in male rats. The study showed an effective disruption of social behaviours in the rats by scPCP and that 2BT successfully attenuated the social deficit. For the final study included in the first project, the impact of acute 2BT treatment on prolactin secretion was evaluated by performing a prolactin enzyme-linked immunosorbent assay. The result showed that 2BT belongs to the non-hyperprolactinemia-inducing APDs and implicates that 2BT has a profitable side-effect profile. The results from this PhD study strengthens the hypothesis of the beneficial effects elicited by dopamine D2 partial agonists like 2BT, for treatment of the complete range of symptoms in schizophrenia. Finally, the second project was dedicated to the validation of the scPCP model for social withdrawal in schizophrenia. For this purpose, an olfactory habituation/dishabituation test with both non-social and social odours was conducted to control the absence of PCP-induced anosmia in the animals used to study social interaction in the previous study. Olfactory defects would severely impact the behaviour of the rats in the social interaction test and thus, needed validation due to a serious lack of such control measures in the literature. The results, which did indicate normal olfactory function in the rats treated with scPCP hence, have important implications for the correct interpretation of the social interaction deficit of the scPCP rat model.