Changes in mood which are not correlated to apparent exogenous events are part of normal behavior. In bipolar disorder, fluctuations of manic- and depressive behavior, which are often not associated with obvious external events, are essential characteristics of its clinical manifestation. Despite the importance for normal and pathological behavior, the mechanisms underlying endogenous fluctuations in mood are virtually unknown. A major obstacle preventing progress of our understanding of this behavior has been the lack of appropriate animal models. Previously, we demonstrated that the transcription factor Otx2, which has been suggested as a susceptibility gene for bipolar disorder orchestrates the development of monoaminergic neurons. Here we use mouse mutants overexpressing Otx2, to study endogenous fluctuations in manicand depressive-like behavior. We found that Otx2 mutants show in their home cage, extended periods of hyperactivity spontaneously alternating with periods of reduced activity. Repeated measurements in the open field demonstrated for Otx2 mutants increased intra-individual fluctuations in locomotor activity, habituation and different risk-taking behavioural parameters. In the sugar preference test, which was used as a measure for hedonic-like behavior Otx2 mutants showed increased intra-individual changes in sweet preference. Olanzapine, lithium and carbamazepine, which are used for the treatment of bipolar disorder reversed behavioural alterations of Otx2 mutants. We conclude that Otx2 is critical to maintain intra-individual behavioural stability. In addition we suggest that a dysfunction of Otx2 is involved in intraindividual behavioural fluctuations found in bipolar disorder by altering normal monoaminergic neurotransmission.