Rationale Problematic patterns of gambling are characterised by loss of control and persistent gambling often to recover losses. However, little is known about the mechanisms that mediate initial choices to begin gambling and then continue to gamble in the face of losing outcomes. Objectives These experiments first assessed gambling and loss-chasing performance under different win/lose probabilities in C57Bl/6 mice, and then investigated the effects of antagonism of 5-HT 2C R with SB242084, 5-HT 1A R agonism with 8-OH-DPAT and modafinil, a putative cognitive enhancer. Results As seen in humans and other species, mice demonstrated the expected patterns of behaviour as the odds for winning were altered increasing gambling and loss-chasing when winning was more likely. SB242084 decreased the likelihood to initially gamble, but had no effects on subsequent gambling choices in the face of repeated losses. In contrast, 8-OH-DPAT had no effects on choosing to gamble in the first place, but once started 8-OH-DPAT increased gambling choices in a dose-sensitive manner. Modafinil effects were different to the serotonergic drugs in both decreasing the propensity to initiate gambling and chase losses. Conclusions We present evidence for dissociable effects of systemic drug administration on different aspects of gambling behaviour. These data extend and reinforce the importance of serotonergic mechanisms in mediating discrete components of gambling behaviour. They further demonstrate the ability of modafinil to reduce gambling behaviour. Our work using a novel mouse paradigm may be of utility in modelling the complex psychological and neurobiological underpinnings of gambling problems, including the analysis of genetic and environmental factors.