Role of histamine in short‐ and long‐term effects of methamphetamine on the developing mouse brain

With the rise in methamphetamine use among women of childbearing age, the potential consequences of methamphetamine exposure to the developing brain for cognition in adulthood is a major concern. Histamine might mediate these methamphetamine effects. Following methamphetamine administration in neonatal mice, histamine levels in brain were elevated and the hypothalamic-pituitary-adrenal (HPA) axis was activated. Co-administration of methamphetamine with the H3 receptor agonist immepip antagonized these effects. The effects of methamphetamine on histamine levels and on HPA axis activation at P20 were more pronounced in female than male mice. These sex differences could have contributed to the increased susceptibility of female mice to the detrimental long-term cognitive effects of methamphetamine and the H3/H4 antagonist thioperamide. Following behavioral testing, mice neonatally treated with methamphetamine or thioperamide showed reduced levels of the dendritic marker microtubule-associated protein 2 in the CA3 region of the hippocampus and the enthorhinal cortex. This was not seen in mice neonatally treated with immepip and methamphetamine who did not show cognitive impairments, suggesting that these brain areas might be particularly important for the long-term effects of methamphetamine on cognitive function. These data support a role for histamine in the effects of methamphetamine on the developing brain.