Proposed model for alterations in the histaminergic transmission system underlying bipolar disorder. Factors as stress, inflammation, increased levels of reactive oxygen species (ROS), and sleep alterations are known to induce and or worsen BD episodes, and are risk factors for developing the disorder. In our proposed model, these factors can induce a molecular environment that can increase intracellular Ca2+ levels and depolarize the plasmatic membrane in histaminergic neurons. In turn, these processes could affect the H3 histaminergic auto receptor affecting the autoregulation of Histaminergic neurons, reducing Na+/K+ ATPase activity and inducing mitochondrial damage. This damage leads to intracellular Ca+ increase and membrane depolarization that inhibits the H3 receptor, leading to an increased HA release. Additionally, saturated fatty acids promote mast cells degranulation and consequently histamine release, while polyunsaturated fatty acids (PUFAs) inhibit it. Released histamine by both means, acting on it targets will induce increased motor activity, arousal, and motivated behaviors, characteristic from a manic phenotype. On the contrary, all these behaviors will be reduced in depression in parallel with reduced histamine levels.