LP-211, a selective 5-HT7 receptor agonist, increases novelty-preference and promotes risk-prone behavior in rats

Gambling disorder is associated to an increased impulsivity, a high level of novelty-seeking and a dysregulation of the forebrain neurotransmission systems. However, the neurobiological mechanisms of this addictive disorder are not fully understood and no valid pharmacological approach has yet been approved. The present study aimed to investigate the effect of 5-HT7 receptor (5-HT₇ R) stimulation with a brain penetrant and selective agonist, LP-211 (0.25 and 0.50 mg kg^-1 i.p.) during post-experience consolidation, (i) acutely in a novelty-preference test (Exp. 1) or (ii) sub-chronically in the Probabilistic-Delivery Task (rPDT, commonly used to measure individual differences in risk proneness of rats; Exp. 2). Results of Exp. 1 showed that 5-HT₇ R activation improves consolidation of chamber-shape memory in the novelty-preference test, leading to significant novelty-induced hyperactivity and recognition, in conditions where controls displayed a null-preference. These results suggest that 5-HT₇ Rs may be involved in the consolidation of information inherent to spatial environments, facilitating the recognition of novelty. Furthermore, in the operant rPDT (Exp. 2), 5-HT₇ R activation shifts the choice towards a larger yet unlikely reward and turns the propensity of rats towards risk-prone behavior. Thus, 5-HT₇ Rs stimulation apparently strengthens the consideration of future, bigger rewards, also enhancing the seeking of it by operant pokes. These effects may well be explained by LP-211 actions on hippocampal versus prefrontal cortex-mediated regulations, leading to improved (though suboptimal) strategy formation. However, further experiments are necessary to determine more in depth the serotonergic pathways involved.