Effect of prenatal lead exposure on nigrostriatal neurotransmission and hydroxyl radical formation in rat neostriatum: dopaminergic-nitrergic interaction.

The present study was designed to explore the role of ontogenetic lead (Pb(2+)) exposure on a putative dopaminergic-nitrergic interaction in the nigrostriatal pathway. Pregnant Wistar rats were given tap water containing 250-ppm lead acetate, for the duration of pregnancy, with regular tap water (without Pb(2+)) being substituted at birth. Control rats were derived from dams that consumed tap water throughout pregnancy, and had no exposure to Pb(2+) afterwards. At 12 weeks after birth in vivo microdialysis of the neostriatum was employed to demonstrate that maternal Pb(2+) exposure was without effect on the baseline dopamine (DA) microdialysate concentration as well as amphetamine (AMPH, 1.0mg/kg i.p.)-evoked release of striatal DA. Also, prenatal Pb(2+) exposure did not enhance AMPH- and 7-nitroindazole (neuronal nitric oxide synthase inhibitor) (7-NI, 20mg/kg i.p.)-induced hydroxyl radical (HO) formation in the striatum, as indicated by analysis of the salicylate spin-trap product 2,5-dihydroxybenzoic acid. However, in rats exposed prenatally to Pb(2+), the facilitatory effect of 7-NI on DA exocytosis was attenuated. On the basis of the current study we conclude that maternal Pb(2+) exposure distorts the dopaminergic-nitrergic interaction in the nigrostriatal pathway, but without involvement of reactive oxygen species (ROS).

Cortical dopaminergic neurotransmission in rats intoxicated with lead during pregnancy. Nitric oxide and hydroxyl radicals formation involvement.

It is well established that low level Pb-exposure is associated with a wide range of cognitive and neurobehavioral dysfunctions in children. In fact, Pb-induced damage occurs preferentially in the prefrontal cerebral cortex, hippocampus and cerebellum - the anatomical sites which are crucial in modulating emotional response, memory and learning. Previously it was also shown that nitric oxide (NO) signaling pathway as well as glutamatergic neurotransmission are both involved in brain development, neurotoxicity and neurodegeneration processes whereas Pb(2+) interfere with both. For this reason we investigated the effect of ontogenetic Pb(2+) exposure on dopaminergic neurotransmission in the medial prefrontal cortex (mPFC) of rats after amphetamine (AMPH) and/or 7-nitroindazole (7-NI) administration. Furthermore, the possible role of oxidative stress in Pb(2+)-induced neurotoxicity in prenatally Pb(2+)-treated rats was explored in the content of hydroxyl radical (HO) species in mPFC after AMPH and/or 7-NI injection, assessed by HPLC analysis of 2.3-dihydroxybenzoic acid (2.3-DHBA) - spin trap product of salicylate. As shown, the results of this study suggest that Pb(2+) exposure during intrauterine life did not substantially affect cortical dopaminergic neurotransmission in adult offspring rats evaluated by means of microdialysis of mPFC and the content of the cortical HO. It is likely that striatum, nucleus accumbens or other dopamine rich brain areas are more intricately associated with Pb(2+) precipitated behavioral, dopamine - dependent impairments observed in mammalians.

Histamine H3 receptor agonist- and antagonist-evoked vacuous chewing movements in 6-OHDA-lesioned rats occurs in an absence of change in microdialysate dopamine levels.

In rats lesioned neonatally with 6-hydroxydopamine (6-OHDA), repeated treatment with SKF 38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol), a dopamine D(1)/D(5) receptor agonist, produces robust stereotyped and locomotor activities. The gradual induction of dopamine D(1) receptor supersensitivity is known as a priming phenomenon, and this process is thought to underlie not only the appearance of vacuous chewing movements in humans with tardive dyskinesia, but also the onset of motor dyskinesias in L-dihydroxyphenylalanine (L-DOPA)-treated Parkinson's disease patients. The object of the present study was to determine the possible influence of the histaminergic system on dopamine D(1) agonist-induced activities. We found that neither imetit (5.0 mg/kg i.p.), a histamine H(3) receptor agonist, nor thioperamide (5.0 mg/kg i.p.), a histamine H(3) receptor antagonist/inverse agonist, altered the numbers of vacuous chewing movements in non-primed-lesioned rats. However, in dopamine D(1) agonist-primed rats, thioperamide alone produced a vacuous chewing movements response (i.e., P < 0.05 vs SKF 38393, 1.0 mg/kg i.p.), but did not modify the SKF 38393 effect. Notably, both imetit and thioperamide-induced catalepsy in both non-primed and primed 6-OHDA-lesioned rats, comparable in magnitude to the effect of the dopamine D(1)/D(5) receptor antagonist SCH 23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.5 mg/kg i.p.). Furthermore, in primed animals both imetit and thioperamide intensified SCH 23390-evoked catalepsy. In vivo microdialysis established that neither imetit nor thioperamide altered extraneuronal levels of dopamine and its metabolites in the striatum of 6-OHDA-lesioned rats. On the basis of the present study, we believe that histaminergic systems may augment dyskinesias induced by dopamine receptor agonists, independent of direct actions on dopaminergic neurons.

Trimetazidine increases [3H]glucose uptake in rat brain.

Trimetazidine, a clinically effective antianginal agent with no negative inotropic or vascular properties, acts by optimizing cardiac energy metabolism through inhibition of free fatty acid oxidation, shifting substrate utilization from fatty acids to glucose. Up to now there has been no study associating trimetazidine's effect on metabolic processes with glucose utilization in the mammalian brain. The objective of the present study was to determine if trimetazidine altered [(3)H]glucose uptake in rat brain. Adult male Wistar rats were administered trimetazidine (Metazydyna, Polfa) either as a single dose (10.0 mg/kg po) or for 14 consecutive days (5.0 mg/kg po per day) or vehicle saline (2.0 ml/kg po). Sixty minutes after the single dose or 14th dose of trimetazidine, and 15 min before experiment termination and brain dissection, 6-[(3)H]D-glucose (500 Ci/kg ip; Amersham) was administered. Using liquid scintillation counting, trimetazidine, either in a single or multiple dose regimen, was found to increase [(3)H]glucose uptake (DPM/100 mg of wet tissue) in all dissected regions of the brain (i.e., striatum, hippocampus, frontal cortex, thalamus with hypothalamus, pons with medulla oblongata, and cerebellum). Therefore, central effects need to be taken into consideration as possibly adding to known beneficial cardiac effects of trimetazidine.

[Molecular mechanisms of levodopa action in animal models of Parkinson's disease]. / Molekularne mechanizmy dzialania lewodopy w zwierzecych modelach choroby Parkinsona.

Parkinson's disease is a progressive neurodegenerative movement disorder, affecting mainly the elderly. One of the most important hallmarks of Parkinson's disease is the loss of neuronal cell bodies containing neuromelanin in the substantia nigra zona compacta, and subsequently, loss of dopamine terminals in basal ganglia nuclei of the brain. The discovery by Hornykiewicz and co-workers that levodopa could successfully treat Parkinson's disease in humans was one of the most important events of medicine in the 20th century. Since loss of nigrostriatal dopaminergic function is the basic underlying pathophysiology of this disease, drugs that enhance dopaminergic function in the striatum, including the exogenous precursor levodopa, remain the most effective symptomatic agents in the treatment of Parkinson's disease. However, there are some areas of controversy about levodopa-evoked motor complications (dyskinesias, on-off phenomena) as well as neuroprotective or neurotoxic activity of this drug, etc. In this article the authors try to clarify the molecular mechanisms involved in levodopa action, such as volume transmission - a crucial process for successful levodopa therapy, evidence that serotoninergic neurons may accumulate levodopa and convert it into dopamine as well as some aspects of neuroprotective action of levodopa.

Maternal lead exposure produces long-term enhancement of dopaminergic reactivity in rat offspring.

To determine the effect of prenatal lead exposure on brain monoaminergic systems, pregnant rats were given tap water containing 250 ppm lead acetate, for the duration of pregnancy, while tap water without lead (Pb(2+)) was substituted at birth. Control rats were derived from dams that consumed tap water during pregnancy, and had no exposure to lead afterwards. At 12 weeks after birth, Pb(2+) content of brain cortex was increased 3- to 4-fold (P < 0.05). At this time the endogenous striatal levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid were 19% lower in Pb(2+) exposed rats (P < 0.05), while there was no change in the striatal level of dopamine (DA), noradrenaline, 3,4-dihydroxyphenylglycol, serotonin (5-HT) and 5-hydroxyindoleacetic acid (HPLC/ED). Also there was no change in these monoamines and metabolites in the prefrontal cortex of Pb(2+) exposed rats. However, turnover of 5-HT in prefrontal cortex, as indicated by 5-hydroxytryptophan accumulation 30 min after acute treatment with the decarboxylase inhibitor NSD-1015 (100 mg/kg IP), was lower in the Pb(2+) exposed rats. In the striatum AMPH-induced (1 mg/kg IP) turnover of DA, evidenced as L-DOPA accumulation after NSD-1015, was increased to a lesser extent in the Pb(2+) exposed rats (P < 0.05). The nitric oxide synthase inhibitor 7-nitroindazole (10 mg/kg IP) attenuated the latter effect, indicating that neuronal NO mediates this AMPH effect, at least in part. Moreover, DA D(2) receptor sensitivity developed in Pb(2+) exposed rats, as evidenced by enhanced quinpirole-induced yawning activity and enhanced quinpirole-induced locomotor activity (each, P < 0.05). These findings indicate that ontogenetic exposure to lead can have consequences on monoaminergic neuronal function at an adult stage of life, generally promoting accentuated behavioral effects of direct and indirect monoaminergic agonists, and related to increased dopamine turnover in basal ganglia.