Developmental methamphetamine exposure results in short- and long-term alterations in hypothalamic-pituitary-adrenal-axis-associated proteins.

ABSTRACT

Developmental exposure to methamphetamine (MA) causes long-term behavioral and cognitive deficits. One pathway through which MA might induce these deficits is by elevating glucocorticoid levels. Glucocorticoid overexposure during brain development can lead to long-term disruptions in the hypothalamic-pituitary-adrenal (HPA) axis. These disruptions affect the regulation of stress responses and may contribute to behavioral and cognitive deficits reported following developmental MA exposure. Furthermore, alterations in proteins associated with the HPA axis, including vasopressin, oxytocin, and glucocorticoid receptors (GR), are correlated with disruptions in mood and cognition. We therefore hypothesized that early MA exposure will result in short- and long-term alterations in the expression of HPA axis-associated proteins. Male mice were treated with MA (5 mg/kg daily) or saline from postnatal day (P) 11 to P20. At P20 and P90, mice were perfused and their brains processed for vasopressin, oxytocin, and GR immunoreactivity within HPA axis-associated regions. At P20, there was a significant decrease in the number of vasopressin-immunoreactive cells and the area occupied by vasopressin immunoreactivity in the paraventricular nucleus (PVN) of MA-treated mice, but no difference in oxytocin immunoreactivity in the PVN, or GR immunoreactivity in the hippocampus or PVN. In the central nucleus of the amygdala, the area occupied by GR immunoreactivity was decreased by MA. At P90, the number of vasopressin-immunoreactive cells was still decreased, but the area occupied by vasopressin immunoreactivity no longer differed from saline controls. No effects of MA were found on oxytocin or GR immunoreactivity at P90. Thus developmental MA exposure has short- and long-term effects on vasopressin immunoreactivity and short-term effects on GR immunoreactivity.