Modulation of hippocampal theta oscillation by histamine H3 receptors

Preclinical findings demonstrate procognitive actions of histamine 3 (H3) receptor antagonists/inverse agonists. Since a prominent role of neuronal network oscillations of the hippocampus, such as theta band oscillation, has been recognized in numerous cognitive functions, in the present study, the potential involvement of H3 receptors in modulation of hippocampal theta activity has been investigated using various recording paradigms. Systemic administration of the selective H3 receptor antagonists/inverse agonists, thioperamide and ciproxifan (0.1 mg/kg to 1 mg/kg i.v.), dose dependently increased hippocampal theta power, similarly to methylphenidate (0.1-1 mg/kg i.v.), in chloral hydrate anesthetized rats. When hippocampal theta oscillation was elicited by electrical brainstem (nucleus pontis oralis) stimulation, ciproxifan (1 mg/kg i.v.) augmented the power of stimulation-induced theta. In contrast, systemic administration of methylphenidate (1 mg/kg i.v.) did not modify elicited theta. To analyze the role of H3 receptors on stage- and behavior-dependent hippocampal theta activity, polysomnographic recordings were carried out together with field potential recordings at the hippocampal fissure in freely moving rats for 8 h during the light phase of the circadian cycle. Systemic administration of ciproxifan (3.0 mg/kg, i.p.) promoted wakefulness with a concomitant reduction in cortical delta power and augmented novelty-induced hippocampal theta activity. These findings provide evidence that H3 receptors play an important role in regulation of hippocampal theta oscillation, representing one of the probable mechanisms involved in histamine-induced modulation of higher brain functions, such as attention and learning.