Perinatal Manganese Exposure and Hydroxyl Radical Formation in Rat Brain

The present study was designed to investigate the role of pre- and postnatal manganese (Mn) exposure on hydroxyl radical (HO•) formation in the brains of dopamine (DA) partially denervated rats (Parkinsonian rats). Wistar rats were given tap water containing 10,000 ppm manganese chloride during the duration of pregnancy and until the time of weaning. Control rat dams consumed tap water without added Mn. Three days after birth, rats of both groups were treated with 6-hydroxydopamine at one of three doses (15, 30, or 67 µg, intraventricular on each side), or saline vehicle. We found that Mn content in the brain, kidney, liver, and bone was significantly elevated in dams exposed to Mn during pregnancy. In neonates, the major organs that accumulated Mn were the femoral bone and liver. However, Mn was not elevated in tissues in adulthood. To determine the possible effect on generation of the reactive species, HO• in Mn-induced neurotoxicity, we analyzed the contents of 2.3- and 2.5-dihydroxybenzoic acid (spin trap products of salicylate; HO• being an index of in vivo HO• generation), as well as antioxidant enzyme activities of superoxide dismutase (SOD) isoenzymes and glutathione S-transferase (GST). 6-OHDA-depletion of DA produced enhanced HO• formation in the brain tissue of newborn and adulthood rats that had been exposed to Mn, and the latter effect did not depend on the extent of DA denervation. Additionally, the extraneuronal, microdialysate, content of HO• in neostriatum was likewise elevated in 6-OHDA-lesioned rats. Interestingly, there was no difference in extraneuronal HO• formation in the neostriatum of Mn-exposed versus control rats. In summary, findings in this study indicate that Mn crosses the placenta but in contrast to other heavy metals, Mn is not deposited long term in tissues. Also, damage to the dopaminergic system acts as a “trigger mechanism,” initiating a cascade of adverse events leading to a protracted increase in HO• generation, and the effects of Mn and 6-OHDA are compounded. Moreover, HO• generation parallels the suppression of SOD isoenzymes and GST in the brains of rats lesioned with 6-OHDA and/or intoxicated with Mn—the most prominent impairments being in frontal cortex, striatum, and brain stem. In conclusion, ontogenetic Mn exposure, resulting in reactive oxygen species, HO• formation, represents a risk factor for dopaminergic neurotoxicity and development of neurodegenerative disorders

Nitric Oxide (NO) and Central Dopamine (DA) D\u3csub\u3e3\u3c/sub\u3e Receptor Reactivity to Quinpirole in Rats

Nitric oxide (NO) has been implicated in large number of pathologies and in normal physiological function of the brain. The aim of this study was to recognize the effect of Nitro-L-Arginine Methyl Ester ·HCl (NAME) and L-Arginine Ethyl Ester.HCl (ARGININE) on reactivity of the central DA D3 receptor to agonist (Quinpirole) in rats. For this reason we have been used specific behavioural procedure such yawning behaviour which is mediated via central DA D3 receptors. Experiments were perform in adult male Wistar rats treated daily with quinpirole (0.05 mg/kg IP) or vehicle (0.9% NaCl) for the first 11 days from birth to obtain of the central D3 receptor supersensitivity. NAME and ARGININE in different way modified response of the central DA receptor to quinpirole estimated by means yawning behavioural procedure

Nitro-1-Arginine Attenuates SKF 38393 - Induced Oral Activity in Neonatal 6-Hydroxydopamine-Lesioned Rats

Nitric oxide (NO) in brain has been implicated in neuronal regulatory processes and in neuropathologies. Previously we showed that NO modified quinpirole-induced yawning, a behavioral measure of dopamine (DA) Da receptor activation in rats. The aim of this study was to characterize the effect of nitro-L-arginine methyl ester HC1 (NAME) and L-arginine HC1 on reactivity of rats to the DA DI receptor agonist SKF 38393 and DA DI antagonist SCH 23390 in intact and neonatal 6-hydroxydopamine (o-OHDA)-lesioned rats (134 ng of base ICV at 3rd day after birth). L-arginine HC1 (300 mg/kg IP) increased the oral activity response in 6-OHDA-lesioned rats, like SKF 38393, and induced catalepsy in intact control rats, like SCH 23390. In contrast, NAME had no effect on oral activity or catalepsy, but fully attenuated SKF 38393-induced oral activity. These findings indicate that L-arginine HC1 has no apparent effect at the DA DI receptor, but that NAME is effective in attenuating a DA DI agonist induced effect. Consequently NO may be an intracellular second messenger for supersensitized receptors associated with DA DI agonist - induced oral activity

Prenatal Ethanol Exposure Impairs Dopamine D\u3csub\u3e2\u3c/sub\u3e and Serotonin Agonist Effects in Rats

Prolonged prenatal exposure to ethanol produces long-lasting alterations in the level of endogenous brain biogenic amines in rats. To test whether there might be long-lived alterations in the reactivity to dopaminergic, serotoninergic or muscarinic agonists in rats exposed prenatally to ethanol, the following study was done. Wistar rats were given 10% (v/v) ethanol in drinking water, starting 10 days before mating and continuing to the end of pregnancy. Male offspring were tested at 3 months for characteristic behavioral effects (oral activity) known to be induced by agonists acting at central dopamine D2 (quinpirole), serotonin 5-HT2C (m-chlorophenylpiperazine, m-CPP) and muscarine (pilocarpine) receptors. Dose-effect curves demonstrated that oral activity responses to quinpirole HCl (0.05-0.40 mg/kg i.p.) and m-CPP 2HCl (0.3-6.0 mg/kg i.p.) were greatly reduced (P \u3c .001) in rats that were exposed to ethanol in utero. Responses to pilocarpine HCl (0.1-3.0 mg/kg) remained unaltered. The findings indicate that prenatal ethanol exposure alters behavioral responses to D2 and 5-HT2C agonists in male rats tested three months after birth. We propose that prenatal ethanol diminishes reactivity of receptors for dopamine D2 and serotonin 5-HT2C receptors

Sensitivity of Central Dopamine Receptors in Rats, to Quinpirole and SKF-38393, Administered at Their Early Stages of Ontogenicity, Evaluated by Learning and Memorizing a Conditioned Avoidance Reflex

Male and Female newborn rats were primed with either quinpirole 0.05 mg/kg IP or SKF-38393 0.1 mg/kg IP on days 1-11, 12-22 and 23-33 of their lives. When the rats reached the age of 13 weeks, they were placed on metal rods in an activity avoidance chamber, and light and electric current of 30V/0.8 mA were used on them as conditioning stimuli. Avoidance of the electric shock was considered a positive conditioned reaction. Training and memorizing the conditioned avoidance reflex consisted of a series of ten trials, 60 seconds apart, once a week for ten weeks. The mean number of positive responses after quinpirole was more profound in all priming intervals tested, as compared to SKF-38393, and was higher as the priming started later in life. Significantly higher scores were obtained by the female rats primed with quinpirole, as compared to the male rats primed with the same drug. These differences were much weaker with SKF-38393. These findings confirm that the central D2 receptor system is involved in learn ing and memorizing of Conditioned Avoidance Reflex much more than the D1 receptors do, and that female rats are more sensitive and retentive to this reflex

7-OH-DPAT, Unlike Quinpirole, Does Not Prime a Yawning Response in Rats

Repeated treatment in ontogeny with the dopamine (DA) D2/D3 receptor agonist quinpirole is associated with enhanced quinpirole-induced yawning and other behaviors such as vacuous chewing, vertical jumping, and antinociception. To determine if the reputedly DA D3 agonist (±)-2-(dipropylamino)-7-hydroxy-1,2,3,4-tetrahydronaphthalene (7-OH-DPAT) would prime for yawning in a manner analogous to that for quinpirole, rats were treated for the first 11 days after birth with an equimolar dose of either quinpirole or 7-OH-DPAT (195.4 nmol/kg/day) and tested for agonist-induced yawning in adulthood. While enhanced quinpirole-induced and 7-OH-DPAT-induced yawning was observed in quinpirole-primed rats, acute treatments with quinpirole and 7-OH-DPAT did not produce an enhanced yawing response in 7-OH-DPAT-\u27primed\u27 rats. Our findings indicate that 7-OH-DPAT, unlike quinpirole, does not prime for quinpirole- or 7-OH-DPAT-induced yawning in rats

Induction of Grooming Behavior in Male Rats by M-Chlorphenylpiperazine, a Central 5-Hydroxytryptamine Receptor Agonist

Grooming behavior in rats has so far been known to be induced mainly by dopamine agonists type D1. In order to explore the involvement of serotonine (5-HT) and its receptors in such a behavior, rats were exposed to two phases of treatment: to the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), injected intraventricularly three days after birth, and to the serotonin partial agonist m-chlorophenylpiperazine (mCPP), administered in two dose levels, two months later. Grooming behavior was monitored immediately before and after the higher dose of mCPP, while brain levels of 5-HT and its major metabolite 5-HIAA were assayed one week after mCPP administration. It is documented that while a low dose of mCPP in the non-lesioned rats increased the grooming-time by 5.7-fold, the higher mCPP dose in the non-lesioned non-primed rats increased grooming behavior by 3.6-fold. The 5,7-DHT lesions caused a 6.7-fold increase in the non-primed rats, and a 4.2-fold increase in the primed ones. These increases were noticeable only in male rats. When a higher dose of mCPP followed its lower dose in the 5,7-DHT-lesioned rats, a 3.6-fold decrease was recorded only in the female rats. A 88% and 94% drop in 5-HT and 5-HIAA levels in the brain neostriatum of the 5,7-DHT-lesioned rats was noticed in both sexes, one week after mCPP administration. These findings are the first to demonstrate that the 5-HT2 partial agonist mCPP is capable of modifying grooming behavior, and that 5,7,-DHT brain lesions increase basal grooming time, suggesting that 5-HT neurons and receptors are involved in grooming behavior in rats

Serotoninergics Attenuate Hyperlocomotor Activity in Rats. Potential New Therapeutic Strategy for Hyperactivity

Hyperactivity is thought to be associated with an alteration of dopamine (DA) neurochemistry in brain. This conventional view became solidified on the basis of observed hyperactivity in DA-lesioned animals and effectiveness of the dopaminomimetics such as amphetamine (AMP) in abating hyperactivity in humans and in animal models of hyperactivity. However, because AMPreleases serotonin (5-HT) as well as DA, we investigated the potential role of 5-HT in an animal model of hyperactivity. We found that a greater intensity of hyperactivity was produced in rats when both DA and 5-HT neurons were damaged at appropriate times in ontogeny. Therefore, previously we proposed this as an animal model of attention deficit hyperactivity disorder (ADHD) - induced by destruction of dopaminergic neurons with 6-hydroxydopamine (6-OHDA (neonatally) and serotoninergic neurons with 5,7-dihydroxytryptamine (5,7-DHT) (in adulthood). In this model effects similar to that of AMP(attenuation of hyperlocomotion) were produced by m-chlorophenylpiperazine (m-CPP) but not by 1-phenylbiguanide (1-PG), respective 5-HT2 and 5-HT3 agonists. The effect of m-CPP was shown to be replicated by desipramine, and was largely attenuated by the 5-HT2 antagonist mianserin. These findings implicate 5-HT neurochemistry as potentially important therapeutic targets for treating human hyperactivity and possibly childhood ADHD

Modulation of Central Dopamine Receptor Reactivity in the Rat, by Nitric Oxide Donors and Inhibitor: Behavioral Studies

Nitric acid has been implicated in a variety of physiological functions of the mammalian brain, and in a large number of its pathologies. Recently we have demonstrated that a nitric oxide donor (L-arginine) and a nitric-oxide-synthase-inhibitor (nitro-L-arginine-methyl-ester) modified the response of central al dopamine D 1 and D 3 receptors to some of their agonists. In the present study we demonstrate the modulatory effect of L-arginine, nitro-L-arginine-methyl-ester and molsidomine (another nitric oxide donor) on the reactivity of the central dopamine receptors to specific agonists and antagonists. The agonists tested were SKF-38393, 7-OH-DPAT and quinpirole, and the antagonists - SCH-23390 and haloperidol. They were evaluated in the rat by the following behavioral methods: locomotor activity, locomotor coordination, rearings and cataleptogenic activity (D 2 modulation); grooming time (D 1 activation); yawning (D 3 activation) and ethanol- and phenobarbital-sleeping-time parameters after SKF-38393 or quinpirole pretreatment. Our results suggest that nitro-L-arginine-methyl-ester is effective in modulating the reactivity of the central dopamine receptors D 2, D 1 and D 3, to their agonists and antagonists, and that it is much more effective than L-arginine in regulating the righting reflex after ethanol and phenobarbital, in both female and male mature rats