Changes in hippocampal histamine receptors across the hibernation cycle in ground squirrels

Hibernation is a physiological state characterized by a dramatic reduction in various functions, such as body temperature, heart rate, and metabolism. The hippocampus is thought to be important for regulation of the hibernation bout because it remains electrophysiologically active throughout this extremely depressed state. The question arises as to what neuronal influences act within the hippocampus during hibernation to sustain its activity. We hypothesized that histaminergic input might be an important contributor. Brain histamine is involved in functions relevant to hibernation, such as the regulation of diurnal rhythms, body temperature, and energy metabolism. Furthermore, we have previously shown that the histaminergic system appears to be activated during the hibernating state. In this study, we used receptor binding autoradiography, in situ hybridization, and GTP-gamma-S binding autoradiography to study changes in histamine receptors across the hibernation bout. We were able to demonstrate an increase in histamine H1 and H2 receptors in the hippocampus during hibernation, whereas the mRNA expression and receptor density of the inhibitory H3 receptor decreased. Histamine H3 receptors were shown to exhibit both histamine-activated and constitutive GTP-gamma-S-binding activity in the ground squirrel hippocampus, both of which decreased during hibernation, indicating a decrease in H3 receptor G-protein activation. Taken together, our results indicate that histamine may be involved in maintaining hibernation by sustaining hippocampal activity, possibly through H1 and H2 receptor activity and decreased inhibition by H3 receptors. The involvement of brain histamine, which is generally thought of as an arousal molecule, in maintaining a depressed state of the brain suggests a more general role for the amine in controlling arousal state.