Effects Of Endogenous Histamine And Its Receptors On Turning Behavior In 6-hydroxydopamine-lesioned Rats

Parkinson's disease (PD) is a chronic neurodegenerative disease of nervous system, which is mainly characterized by a progressive loss of dopaminergic (DAergic) neurons in the substantia nigra and depletion of dopamine in the striatum. The etiology and the underlying mechanism of PD remain unclear. The disturbance of neurotransmission mediated by several neurotransmitters might contribute to the progressive degeneration of DAergic neurons. The role of histamine in the pathogenesis and pathophysiology of PD has recently attracted considerable attention. Some studies from clinical or post-mortem PD patients have reported that brain histamine concentration in PD patients was significantly higher than that in normal subjects, which suggested that histaminergic system could be involved in the pathologic processes of PD. In addition, histamine H₃ receptors were also found to be related to the regulation of the neural circuit of basal ganglia. However, little is known about the role of histamine H₁ and H₂ receptors in basal ganglia. In this study, we investigated the role of histamine and its receptors in turning behavior in 6-hydroxydopamine (6-OHDA)-lesioned rats by treatment with histamine precursor, inhibitor of histamine synthetase and other agents. Moreover, we also observed whether the histaminergic neurons in tuberomammillary nucleu (TMN) ofhypothalamus degenerate in PD rats.Objective: To investigate the effects of endogenous histamine and its receptors on turning behavior and whether the histaminergic neurons degenerate in PD rats. Methods: Rats were unilaterally infused with 6-OHDA into both substantia nigra pars campacta (SNc) and medial forebrain bundle (MFB). On the 7th and 14th day, histamine precursor, inhibitor of histamine synthetase and other agents were administrated 30 or 60 minutes before apomorphine injection. Apomorphine (apo, 0.5 mg/kg, s.c.) were injected to induce contralateral turning behavior and the full turns per minute (at least 30 min test) were recorded for each rat. hi addition, the immunoreactivity of DAergic neurons in SNc and histaminergic neurons in TMN were evaluated by tyrosine hydroxylase (TH) and histidine decarboxylase (HDC) immunohistochemistry, respectively. Results: On the 7th and 14th day after 6-OHDA lesion, in comparison to model group, histidine (500 mg/kg, i.p.), a histamine precursor, increased the number of turns per min of apo-induced contralateral turning behavior in PD rats (d 7, P>0.05;d 14, P<0.05). On the contrary, a-fluoromethylhistidine (a-FMH, 25 u.g, i.c.v.), an irreversible inhibitor of histidine decarboxylase (HDC), significantly decreased the number of turns per min (d 7, P<0.05;d 14, P<0.05). Additionally, Hi receptor antagonist pyrilamine (10 and 50 ng, i.c.v.) and H2 receptor antagonist cimetidine(10 and 50 u.g, i.c.v.) also significantly reduced the number of turns in a dose-dependent mannar (PO.05) on day 7 and 14 after lesion. Similarly, H3 receptor agonist immepip (10 u.g, i.c.v.) and antagonist clobenpropit (10 and 25 ug, i.c.v.) decreased the number of turns (immepip: d 7 , P>0.05, d 14, Z><0.05;clobenpropit: d 7, PO.05, d 14, PX).05). Furthermore, in comparison to controls, the immunoreactivity of TH-positive neurons in SNc was markedly decreased on the lesioned side of PD rats and that of histaminergic neurons in TMN of hypothalamus was not changed. Conclusion: Endogeneous histamine may modify the neural circuit of basal ganglia via its Hi > H2and H3 auto- and hetero-receptors, and the central histaminergic neurons are preserved in PD.