Effekte akuter systemischer und intra-cerebraler Injektion von Serotonin- 2A/C-Rezeptor-Liganden in Tiermodellen für impulsives Verhalten

Abstract

Impulsivity or diminished inhibitory control of behavior is an essential feature of neuropsychiatric diseases. In order to examine the role of 5-HT2 receptors in the modulation of impulse control within a regulatory network, comprising the orbitofrontal cortex (OFC) and the basolateral nucleus of the amygdala (BLA), the present experiments investigated effects of serotonin (5-HT)-2 receptor ligands on the performance of rats in the 5-choice serial reaction time task (5-CSRTT). The results indicate that simultaneous bilateral infusion of the 5-HT2A/C receptor agonist DOI [(Ã ±)-1-(2.5-Dimethoxy-4-iodophenyl)-2-aminopropan hydrochlorid] (5mg/0.3ml) into the OFC and the BLA significantly increased impulsive responding in the 5-CSRTT. Our data suggest that both the OFC and the BLA are implicated in the mediation of DOI-induced impulsivity seen after 5-CSRTT performance. Furthermore, these data confirm that cortico-limbic 5-HT2A/C receptors are a major component in the OFC-BLA-network, necessary for impulse control and response selection in mammals.A further important aspect of impulsive behaviour is the inability to tolerate delays in reward. In animals the ability to wait for food reward is proposed as an operational measure of impulsive-related behaviour. This work additionally characterized the effects of the 5-HT2A/C receptor ligands DOI [(Ã ±)-1-(2.5-Dimethoxy-4-iodophenyl)-2-aminopropan hydrochlorid] and ketanserin on impulsive behavior measured in a delay-based decision-making task. Male Wistar rats were trained in a T-maze to choose between a small immediate reward and a large but 10-sec-delayed reward. After stable baseline perfromance effects of acute systemic administration of 5-HT2A/C receptor ligands on waiting capacity were analyzed. Systemic administration of DOI (0.1, 0.3 and 0.5mg/kg) impaired waiting capacity in rats in a dose-dependent manner while ketanserin had no effect. When combined with ketanserin, DOI did not impair waiting capacity. The data suggest that DOI-induced impairment of the ability to tolerate delay in reward in a T-maze is probably regulated by 5-HT2A receptors. Furthermore, this work extends the existing findings of 5-HT2 receptor involvement in different tasks of delay aversion in rodents.Taken together, the present work revealed that 5-HT2A/C-receptors are crucially involved in mediating impulsivity in both, impulsive action and impulsive decision-making or delay aversion. However, the fact that the functional status of the mesocortico-limbic DA-system is partially mediated by the 5-HT-system suggests that DA may play a regulatory role in impulsivity as well. Regarding to the involvement of neural substrates in impulsivity, it was shown that the OFC, the BLA, and presumably the network these structures form, are inter alia responsible for mediating impulsive behavior through activation and/or inhibition of 5-HT2A/C-receptors. Overall, this work sheds more light on the neuropharmacological interactions as well as on the neural correlates involved in impulsive behavior in rodents, and extends the existing findings on this topic of research.