Histaminergic activity in a rodent model of Parkinson's disease.

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 noradrenergic lesion alters histaminergic activity in adult rats.

To determine whether noradrenergic nerves might have a modulatory role on the sensitivity or reactivity of histaminergic receptor systems in brain, behavioral effects of the respective histamine H1, H2 and H3 antagonists S(+)chlorpheniramine, cimetidine and thioperimide in control adult rats were compared to the effects in adult rats that had been lesioned as neonates with the noradrenergic neurotoxin DSP-4. On the 1st and 3rd days after birth rat pups were treated with either saline or DSP-4 (50 mg/kg sc), then returned to their home cages with the dam. At 8 weeks when rats were tested, S(+)chlorpheniramine (10 mg/kg ip) was found to increase locomotor activity in intact and DSP-4 lesioned rats, while cimetidine (5 mg/kg, ip) and thioperimide (5 mg/kg, ip) increased activity several-fold solely in the DSP-4 group. Exploratory activity, nociceptive activity, and irritability were little altered by the histamine antagonists, although oral activity was increased by thioperimide in intact and lesioned rats, and by cimetidine or S(+)chlorpheniramine in DSP-4 rats. High performance liquid chromatography with electrochemical detection was used to determine that DSP-4 produced a 90% reduction in frontal cortex, hippocampus and hypothalamus, with a 90% elevation of NE in cerebellum--reflecting reactive sprouting of noradrenergic fibers consequent to lesion of noradrenergic tracts projecting to proximal brain regions. These findings indicate that perinatal noradrenergic fiber lesioning in rat brain is associated with an altered behavioral spectrum by histamine H1, H2 and H3 receptor antagonists, thereby implicating histaminergic systems as modulators of noradrenergic systems in brain.

Nitric oxide modulates the amphetamine effect on [3H]glucose uptake in the brain of rats prenatally exposed to lead.

Glucose is the main source of energy for the central nervous system (CNS). In this study, we examined the effects of the psychostimulant amphetamine (AMPH) and the neuronal mediator nitric oxide (NO) on [3H]glucose uptake in the brain of adult rats that had been prenatally exposed to lead. Lead [Pb(CH3COO)2 . 3H2O; 250 ppm] was added to the drinking water of pregnant Wistar rats for the duration of pregnancy. On the day of parturition, lead was discontinued as an additive in the drinking water. Offspring remained ith dams for 21 days. The control group consisted of rats that consumed water without lead. In adulthood, male offspring from both groups (lead-exposed and control) were pretreated with 7-nitroindazole (nNOS blocking agent) (10.0 mg/kg ip) or saline (1.0 ml/kg ip), 30 min before AMPH (1.0 mg/kg ip). After another 30 min, and 15 min before termination, all rats were injected with 6-[3H]-D-glucose (500 muCi/kg ip). Brain specimens were taken (striatum, frontal cortex, hippocampus, and thalamus with hypothalamus, and pons with medulla oblongata) for determination of radioactivity in a liquid scintillation counter. We found that lead did not alter [3H]glucose uptake in brain regions studied (with exception of frontal cortex) but that AMPH increased [3H]glucose uptake in the striatum, frontal cortex and hippocampus, and that the AMPH effect was lessened in the hippocampus of lead-exposed rats. Moreover, the AMPH effect on [3H]glucose uptake in the frontal cortex, hippocampus, thalamus with hypothalamus and pons of control rats was potentiated by 7-NI pretreatment. Similar effect was observed in lead-intoxicated rats (striatum, frontal cortex and hippocampus). These results indicate that NO modulates AMPH-induced [3H]glucose uptake in the brain of rats prenatally exposed to lead.