The modulation of
histamine neuron activity by various non-competitive
NMDA-receptor antagonists was evaluated by changes in
tele-methylhistamine (t-MeHA) levels and
histidine decarboxylase (hdc)
mRNA expression induced in rodent brain. The
NMDA open-channel blockers
phencyclidine (PCP) and
MK-801 enhanced t-MeHA levels in mouse brain by 50-60%.
Ifenprodil, which interacts with
polyamine sites of NR2B-containing
NMDA receptors, had no effect. PCP also increased hdc
mRNA expression in the rat tuberomammillary nucleus. The enhancement of t-MeHA levels elicited by
MK-801 (ED50 of approximately 0.1 mg/kg) was observed in the hypothalamus, cerebral cortex, striatum and hippocampus. Control t-MeHA levels and the t-MeHA response to
MK-801 were not different in male and female mice. Double immunostaining for HDC and
NMDA receptor subunits showed that
histamine neurons of the rat tuberomammillary nucleus express
NMDA receptor subunit 1 (NR1) with
NMDA receptor subunit 2A (NR2A) and
NMDA receptor 2B subunit (NR2B). In addition, immunoreactivity for the neuronal
glutamate transporter EAAC1 was observed near most histaminergic perikarya. Hence, these findings support the existence of
histamine/
glutamate functional interactions in the brain. The increase in
histamine neuron activity induced by
NMDA receptor antagonists further suggests a role of
histamine neurons in
psychotic disorders. In addition, the decrease in MK-801-induced hyperlocomotion observed in mice after administration of
ciproxifan further strengthens the potential interest of H3-receptor antagonist/inverse agonists for the symptomatic treatment of
schizophrenia.