Project 8C: Histamine, Long Term Effects, Neonatal Methamphetamine Exposure, & Cognition (COMPLETED)

Role of histamine in the long-term effects of neonatal methamphetamine exposure on cognition

Jacob Raber, Ph.D., Principal Investigator

Human fetuses exposed to methamphetamine show poor visual recognition memory later in life. Similarly, neonatal MA treatment in rodents causes spatial learning and memory impairments in adulthood. The underlying pathogenesis is not well understood.

The hypothalamic-pituitary-adrenal (HPA) axis in neonates is hyporesponsive to stress. The SHRP is thought to lead to reduced adrenal steroids and to protect against the potentially harmful effects of high levels of these steroids.

However, some compounds disturb this hyporesponsiveness, including methamphetamine, histamine, and excitatory amino acids. Exposure to these compounds during the stress hyporesponsive period (SHRP) can lead to high levels of ACTH and corticosterone in a period where they normally are not elevated.

The HPA axis activation with glucocorticoid hypersecretion seen in neonates exposed to methamphetamine during the SHRP has been hypothesized to underlie the long-term effects of MA on cognitive deficits later in life.

Recent evidence suggests that histamine may mediate effects of methamphetamine. Our main hypothesis is that, during the SHRP in neonates, activation of the HPA axis and glucocorticoid hypersecretion by histamine mediates the detrimental long-term effects of neonatal methamphetamine exposure on cognition.

Our specific aims are:

(1) Determine whether neonatal exposure to H3 antagonists activates the HPA axis and causes deficits in hippocampus-dependent learning and memory in adulthood;

(2) Determine whether, in neonates, H3 agonists inhibit the effects of methamphetamine on HPA axis activation and deficits in hippocampus-dependent learning and memory in adulthood; and

(3) Determine whether neonatal exposure to MA or H3 antagonists reduces synaptophysin-immunoreactive presynaptic terminals and microtubule-associated protein (MAP) 2–positive neuronal dendrites in the neocortex and hippocampus in adulthood, and whether neonatal co-exposure of methamphetamine in the presence of H3 agonists prevents this neuropathology.