Histaminergic Activity in a Rodent Model of Parkinson’s Disease

Abstract

Rats lesioned shortly after birth with 6-OHDA have been proposed to be a near-ideal model of severe Parkinson's disease, because of non-lethality of the procedure, near-total destruction of nigrostriatal dopaminergic fibers, and near-total dopamine (DA) denervation of striatum. There are scarce data that in Parkinson's disease, activity of the central histaminergic system is increased. Therefore, the aim of this study was to determine histamine content in the brain and the effect of histamine receptor antagonists on behavior of adult rats. At 3 days after birth, Wistar rats were pretreated with desipramine (20.0 mg/kg ip) 1 h before bilateral icv administration of the catecholaminergic neurotoxin 6-OHDA (67 microg base, on each side) or saline-ascorbic acid (0.1%) vehicle (control). At 8 weeks levels of DA and its metabolites L: -3,4-dihydroxyphenylalanine (DOPAC) and homovanillic acid (HVA) were estimated in the striatum and frontal cortex by HPCL/ED technique. In the hypothalamus, hippocampus, frontal cortex, and medulla oblongata, the level of histamine was analyzed by immunoenzymatic method. Behavioral observations (locomotion, exploratory-, oral-, and stereotyped-activity) were additionally made on control and 6-OHDA neonatally lesioned rats. Effects of DA receptor agonists (SKF 38393, apomorphine) and histamine receptor antagonists (e.g., S(+)chlorpheniramine, H(1); cimetidine, H(2); thioperamide, H(3) agonist) were determined. We confirmed that 6-OHDA significantly reduced contents of DA and its metabolites in the brain in adulthood. Histamine content was significantly increased in the hypothalamus, hipocampus, and medulla oblongata. Moreover, in 6-OHDA-lesioned rats behavioral response was altered mainly by thioperamide (H(3) antagonist). These findings indicate that histamine and the central histaminergic system are altered in the brain of rats lesioned to model Parkinson's disease, and that histaminergic neurons exert a modulating role in Parkinsonian 6-OHDA-lesioned rats.

Ontogenetic Serotoninergic Lesioning Alters Histaminergic Activity in Rats in Adulthood

“…This stands in contrast to observed 5-HT fiber hyperinnervation in forebrain of rats lesioned as neonates with 6-OHDA (Nowak et al 2009). Histamine receptor antagonists, mainly thioperamide (H 3 antagonist), intensified locomotor activity, and oral activity induced by SKF 38393 (D 1 receptor agonist); and altered stereotypy intensity induced by apomorphine (D 1 /D 2 receptor agonist).…”

“…In previous studies with the selective noradrenergic neurotoxin DSP-4 (Ross 1976) and the catecholaminergic neurotoxin 6-OHDA (Kostrzewa and Jacobowitz 1974) on the dopaminergic system in a rodent model of Parkinson's disease , we found that histamine content and histaminergic activity are altered (Nowak et al 2009). Both 5-HT and histamine appear to have a modulatory role in Parkinson's disease, as elevation of these amines in brain can attenuate motor disability (Nowak et al 2009). …”

“…It is notable that in rats lesioned as neonates with 6-OHDA (rodent model of Parkinson's disease) there was an increase in histamine content in brain, and thioperamide improved motor coordination after DA agonist treatments (SKF 38393, apomorphine) (Nowak et al 2009). The present results indicate that an intact serotoninergic innervation in brain is requisite for histamine H 3 receptor modulation of the dopaminergic system.…”

“…Cell bodies of histaminergic neurons are located mainly in the tuberoma numillary nucleus of the poster hypothalamus, and these neurons innervate nearly all regions of mammalian brain and modulate many physiological functions (Panula et al 1990;Schwartz et al 1991;Wada et al 1991). Previously, we found that the selective dopaminergic neurotoxin 6-OHDA increased histaminergic activity in rat brain (Nowak et al 2009). In those animals histamine content was significantly increased in brain, while behavioral responses to the histamine H 3 receptor antagonist thioperamide were diminished.…”

Thioperamide, an H3 Receptor Antagonist Prevents [3H]Glucose Uptake in Brain of Adult Rats Lesioned as Neonates with 5,7-Dihydroxytryptamine

“…In those animals an increase of serotoninergic and histaminergic activity was observed in brain (Kostrzewa et al, 1992;Brus et al, 1994;Nowak et al, 2008Nowak et al, , 2009a. Additionally, we found that thioperamide, a central histamine H 3 receptor antagonist, diminished behavioral hyperactivity in rats lesioned with 6-OHDA as neonates (Nowak et al, 2008(Nowak et al, , 2009b. Therefore, the aim of this study was to examine the effect of perinatal destruction of the serotonin system in brain (i.e., 5,7-DHT treatment) on [ 3 H]glucose uptake in the brain of these rats, when adult, and effects of thioperamide.…”