Subacute Administration Research Articles

Toxicity of subacute oral administration of cypermethrin in rats with special reference to histopathological changes

Pyrethrins are obtained from the flowers of Chrysanthemum cinerarifolium. These are strong insecticides with low mammalian toxicity. The toxic effects of pyrethroid cypermethrin were studied using various biochemical parameters along with histopathological changes in a 30-day study in Wistar rats. The rats were divided into two groups. Rats of the test group were given sublethal doses of cypermethrin (14.5 mg/kg) by gavage once daily for 30 days and the control rats were given an equal volume of the vehicle. The animals were sacrificed on day 0, 10, 20 and 30 of the study. The results showed that cypermethrin caused a significant increase in the levels of serum aspartate transaminase, alanine transaminase, lactate dehydrogenase and plasma creatinine. It significantly lowered the levels of total proteins. The histopathological studies on various organs like liver, lungs, kidneys and heart were carried out. The changes in various biochemical parameters correlated well with the histopathological changes in various organs. In conclusion, the results of this study demonstrate that subacute oral administration of cypermethrin, even in low doses such as 1/10 LD50 for 30 days induces toxic effects on different vital organs. Key words: Chrysanthemum cinerariifolium, pyrethrins, subacute toxicity

Anti-hyperglycaemic activity of IND 01 and its interaction with glyburide and pioglitazone in alloxan induced diabetic mice

The antihyperglycaemic activity of IND 01 and its interaction with glyburide and pioglitazone on serum glucose, body weight and oral glucose tolerance test (OGTT) was determined in alloxan-induced diabetic mice. IND 01 (100 mg/kg), glyburide (10 mg/kg), pioglitzone (10 mg/kg) and their concomitant administration were administered orally in alloxan (80 mg/kg, i.v.) induced diabetic mice. The study design consisted of estimation of serum glucose after acute, subacute and glucose load administration. Administration of IND 01 (100 mg/kg) alone significantly (p<0.001) reduced serum glucose level at 6 h after administration. The antihyperglycaemic effect of glyburide and their concomitant administration of IND 01 with glyburide were similar, that is, onset was 2 h; peak effect was 6 h but the effect waned at 24 h. The onset of concomitant administration of IND 01 with pioglitazone was 4 h; peak effect was at 6 h but the effect waned at 24 h. In the subacute study, reduction in serum glucose was observed on 28th day after withdrawal for 7 days. The effects of concomitant administration were more pronounced than single drug treatment. In mice treated with either IND 01 (100 mg/kg), glyburide, pioglitazone alone or their combination, the body weight was not reduced in contrast to that in the control group. In the oral glucose tolerance test (OGTT), increased glucose utilization was observed in animals after concomitant administration of IND 01 (100 mg/kg) and glyburide (10 mg/kg) as well as IND 01 (100 mg/kg) and pioglitazone (10 mg/kg). The concomitant administration of IND 01 with glyburide as well as pioglitzone produced synergistic antihyperglycaemic effect than either drug alone.

Effect of Subacute Exposure ofWrightia tinctoriaBark Extract on Hematological, Biochemical and Antioxidant Enzyme Parameters of Rat

Wrightia tinctoria (Roxb.) R.Br. extensively used in the Indian system of medicine, is a small deciduous tree of the family Apocynaceae The plant is very useful as stomachic, antidysenteric, carminative, astringent, aphrodisiac and diuretic, used in the treatment of abdominal pain, skin diseases and bilious affections. This plant is reported to have fungicidal, antinociceptive, wound healing, immunomodulatory and antiulcer activity. The major phytoconstituents are triacontanol, tryptanthrin, (â-amyrin, ursolic acid, oleanolic acid, (â-sitosterol, cycloartenone, cycloeucalenol, (â-sitosterol, lupeol, wrightial, 14a-methylzymosterol desmosterol and clerosterol. A number of poly herbal formulations containing W. tinctoria is available in market for psoriasis, diarrhoea and dysentery, dandruff and for rejuvenation of joint function. The present study was undertaken to investigate the effect of sub-acute administration of W. tinctoria bark extract on some haematological, biochemical, histological and antioxidant enzyme status of rat liver and kidney following 21 and 45 days treatment. The animals were observed for gross physiological and behavioural responses, food and water intake and body weight changes. Free radical scavenging activity and histopathology was done on liver and kidney samples. W. tinctoria showed significant hemopoiesis with increase in body weight signifying anabolic effect. It significantly reduced serum SGOT level and increased glucose levels. W. tinctoria caused increased SOD activity of liver along with catalase of both liver and kidney and decreased liver peroxidase (P W. tinctoria upto 1000 mg/kg daily dose is safe and has potential to be consumed for long time in management of various diseases.

GABA A receptors in nucleus accumbens shell mediate the hyperphagia and weight gain following haloperidol treatment in rats

Aims Weight gain is a common outcome of antipsychotics therapy in schizophrenic patients. However, the underlying neuronal mechanisms are unclear. The present study was undertaken to investigate the role of GABA A receptors within the framework of nucleus accumbens shell (AcbSh) in haloperidol-induced hyperphagia and body weight gain in sated rats. Main methods In acute studies, GABA A receptor agonists muscimol, diazepam or antagonist bicuculline were administered by AcbSh route, alone or in combination with haloperidol (intraperitoneal/ip). Immediately after these treatments, preweighed food was offered to the animals at commencement of dark phase. Cumulative food intake was measured at 2 and 6 h post-injection time-points. Furthermore, effects of subacute haloperidol treatment, alone or in combination with muscimol, diazepam or bicuculline, on food intake and body weight were investigated. Key findings While acute treatment with haloperidol, muscimol or diazepam dose dependently stimulated the food intake, bicuculline suppressed the same. Prior administration of muscimol (20 ng/rat, intra-AcbSh) and diazepam (5 µg/rat, intra-AcbSh) significantly potentiated, whereas bicuculline (40 ng/rat, intra-AcbSh) negated the hyperphagic effect of acute haloperidol (0.005 or 0.01 mg/kg/rat, ip). Subacute administration of haloperidol (0.01 mg/kg/rat/day, ip) for 15 days produced increase in food intake and body weight. Although, concomitant administration of muscimol (20 ng/rat/day, intra-AcbSh) or diazepam (5 μg/rat/day, intra-AcbSh) markedly enhanced, bicuculline (40 ng/rat/day, intra-AcbSh) prevented the subacute haloperidol-induced hyperphagia and weight gain. Significance The results of present study suggest that increased food intake and body weight following haloperidol treatment in rats, may be mediated via AcbSh GABA A receptors.

Neurokinin-1 receptor antagonists modulate brain noradrenaline and serotonin interactions

Substance P (neurokinin-1; NK1) receptor antagonists represent a putative new class of antidepressant/anxiolytic drugs. Using in vivo electrophysiological paradigms in rats, this study examined the effects of acute, sub-acute and long-term administration of these drugs on the firing of rat noradrenaline and serotonin (5-HT) neurons. In the locus coeruleus, neither a 2-day treatment with the tachykinin NK1 receptor antagonists [(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl) methyl]-1-azabicyclo[2.2.2]octan-3-amine (CP-96,345, 10 mg/kg/day, i.p.), CP-99,994 (10 mg/kg/day, i.p.), nor a 14-day of treatment with (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994, 10 mg/kg/day, s.c.) significantly modified the firing rate of noradrenaline neurons. However, all these treatments attenuated the inhibitory action of the α 2-adrenoceptor agonist clonidine on noradrenaline neuronal firing. While acute administration of the tachykinin NK1 receptor antagonist CP-96,345 (10 mg/kg, i.p.) attenuated the responsiveness of dorsal raphe 5-HT 1A autoreceptors, lesioning noradrenaline neurons with the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) prevented the enhancing action of a 2-day treatment with CP-96,345 on 5-HT neuronal firing, suggesting that tachykinin NK1 receptor antagonists influence 5-HT system via noradrenaline neurons independently of their firing rate.

Neurobehavioral and genotoxic parameters of duloxetine in mice using the inhibitory avoidance task and comet assay as experimental models

Duloxetine is a potent inhibitor of serotonin and noradrenaline reuptake, with weak effects on dopamine reuptake, used in the treatment of major depression. It has been recognized that some antidepressants can affect memory in humans, but there is not study that report the duloxetine effect on memory using the inhibitory avoidance. The aim of this work was to investigate the effect of duloxetine on short- and long-term memory (STM and LTM) in the inhibitory avoidance task in mice. Duloxetine (10 and 20 mg/kg; i.p.) administered before or after the inhibitory avoidance training was not able to produce effects on STM e LTM ( p > 0.05). The group that received MK-801 (0.0625 mg/kg), an NMDA receptor antagonist, showed an impairment in STM and LTM ( p < 0.01). These effects were not reversed by duloxetine administration ( p = 0.114 and p = 0.06, respectively). Duloxetine effect on memory 5 days after i.p. administration was also investigated. After this treatment both duloxetine doses used were unable to affect STM or LTM in the inhibitory avoidance task ( p = 0.371 and p = 0.807, respectively). DNA damages were evaluated in brain tissues and blood by the comet assay, after subacute treatment (10 or 20 mg/kg by 5 days). Duloxetine did not induce genotoxic effects. However, when the cells were treated ex vivo hydrogen peroxide, a pro-oxidant effect on brain tissue from treated animals was observed with significantly higher DNA damage in comparison to untreated animals, suggesting increased susceptibility to injuries by reactive oxygen species in brain after treatment with duloxetine. Duloxetine did not produce any effect on memory after acute and subacute administration, suggesting that this antidepressant does not affect either memory acquisition or consolidation.

Effects of an oral subacute administration of benzo(a)pyrene on cerebral CYP1A1 expression and anxiety-related behaviour in adult mice

Effects of an oral subacute administration of benzo(a)pyrene on cerebral CYP1A1 expression and anxiety-related behaviour in adult mice

Long-term administration of monoamine oxidase inhibitors alters the firing rate and pattern of dopamine neurons in the ventral tegmental area

Monoamine oxidase inhibitors (MAOIs) exert their antidepressant action by increasing the function of the serotonin (5-HT), norepinephrine and dopamine (DA) systems. There is, however, limited electrophysiological data on the effects of MAOIs on DA neurons. The effects of 2-d and 21-d administration of three MAOIs were investigated (clorgyline, selective MAOI-A; deprenyl, selective MAOI-B; phenelzine, non-selective MAOI) on the firing activity of DA neurons in the ventral tegmental area using in-vivo electrophysiology in rats. Short-term clorgyline (1 mg/kg) and phenelzine (2.5 mg/kg) was devoid of effect on DA neurons, whereas prolonged administration significantly decreased their firing rate (by 30% and 20%, respectively), number of bursts (by 80% and 45%, respectively), and percentage of spikes occurring in bursts only in clorgyline-treated rats (70%). Deprenyl (0.25 mg/kg) was without effects. DA firing was restored in clorgyline-treated rats by inhibiting 5-HT synthesis using para-chlorophenylalanine (p-CPA; 300 mg/kg. d for three consecutive days). The 5-HT3 antagonist ondansetron (0.5 mg/kg) was devoid of effect in control rats, but completely reversed the alterations of DA neuronal activity in clorgyline-treated rats. An attenuation of DA neuronal activity was thus produced by prolonged blockade of MAOA activity. The absence of effect of MAOA inhibition after subacute administration suggested an indirect mechanism. This was confirmed by the observation that p-CPA antagonized the effects of clorgyline. Since ondansetron completely reversed the effects of clorgyline on DA neuronal activity, the effects of MAOA inhibition appeared to be mediated by 5-HT3 receptors.

Broad neuroprotective profile of nicotinamide in different mouse models of MPTP‐induced parkinsonism

The factors contributing to substantia nigra pars compacta (SNc) dopamine (DA) neuron death and striatal DA depletion in Parkinson's disease (PD) are still poorly understood. However, mitochondrial dysfunction, cellular energy depletion and oxidative stress appear to play important roles in the pathogenesis of PD. In view of this, the current study examined the potential of nicotinamide, a form of the B-complex vitamin niacin, to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced SNc cell loss and striatal DA depletion in two mouse MPTP models that respond differently to putative neuroprotective agents. Adult male C57Bl/6 mice received nicotinamide (125, 250 or 500 mg/kg i.p.) prior to either acute (four injections in 1 day at 2-h intervals) or sub-acute (two injections per day at 4-h intervals for 5 days) MPTP administration. Striatal DA levels, changes in numbers of tyrosine hydroxylase (TH)- and cresyl violet-stained cells in the SNc at 2 and 6 weeks following the last MPTP exposure were analyzed. Nicotinamide administration resulted in a dose-dependent sparing of striatal DA levels and SNc neurons in acute MPTP-treated animals. Only the highest dose of nicotinamide had similar effects in sub-acute MPTP-treated animals. At 6 weeks after MPTP exposure, there was some spontaneous recovery of striatal DA levels in both models: neuroprotective effects were still apparent in acute but not sub-acute MPTP-treated animals. These results show neuroprotective effects of nicotinamide in different mouse Parkinson models associated with different forms of cell death and suggest that nicotinamide may have broad neuroprotective potential in PD.

Administration of ziprasidone for 10 days increases cocaine toxicity in mice

Long-term treatment with antipsychotic medications alters the regional density of several of the neurotransmitter receptors that mediate cocaine toxicity. However, the effect of either up- or down-regulation of the neurotransmitter receptors on cocaine toxicity is unknown. In this study, we determined if subacute administration of the atypical antipsychotic ziprasidone altered the toxic effects of cocaine in mice. Ziprasidone (4 mg/kg) or placebo was administered to the first two groups of CF-1 mice for 10 days and, then on day 10, an estimated LD50 dose of cocaine (102 mg/kg) was given to these mice. In a third group, in order to produce a ziprasidone withdrawal state, we administered ziprasidone for 10 days, followed by no treatment for 2 days before cocaine administration. There was no significant difference among the three groups in overall survival: 63% in the treatment group, 60% in the withdrawal group, and 80% in the placebo group. Survival time was significantly shorter for the withdrawal group than for the control group. Our study may have been limited by lower than expected serum ziprasidone concentrations and lower than expected lethality from cocaine. However, our findings suggest that administration of an atypical antipsychotic for 10 days may increase the toxic effects of cocaine.

Sub-acute administration of benzo[ a]pyrene (B[ a]P) reduces anxiety-related behaviour in adult mice and modulates regional expression of N-methyl- d-aspartate (NMDA) receptors genes in relevant brain regions

Abnormal glutamatergic transmission caused by modulation of N-methyl- d-aspartate (NMDA) receptors was demonstrated in animal models chronically exposed to various organic micropollutants. Recent developments in neurobiology have implicated these receptors in the regulation of anxiety. In order to investigate anxiety-related effects of benzo[ a]pyrene (B[ a]P), Balb/c mice were sub-acutely exposed to B[ a]P (0.02–200 mg kg −1 day −1, 10 days, i.p.). Their performance was tested in the elevated-plus maze and the hole-board apparatus and the NMDA receptor expression genes (NR1, 2A and 2B subunits) was measured in eight brain regions. Mice treated with 20–200 mg kg −1 B[ a]P showed a disproportionate accumulation of B[ a]P and its metabolites (in particular, the toxic 7,8-diol-B[ a]P) in the blood and even more in the brain. These mice were less anxious than controls in the hole-board test and the elevated-plus maze. This observation was associated with an overexpression of the NMDA NR1 receptor gene and concomitant decreases of the NR2A and NR2B subunits expression in the hippocampus, the hypothalamus and the cerebellum. In the temporal cortex, a significant dose-related decrease of NR2A was observed whereas the other subunits remained unchanged. In conclusion, a sub-acute exposure to B[ a]P (20 and 200 mg kg −1) reduced anxiety-related behaviour in adult mice and concomitantly impaired NMDA receptor gene expression in relevant brain regions.

Neurotoxicity of MPTP to migrating neuroblasts: Studies in acute and subacute mouse models of Parkinson's disease

The acute or subacute administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been widely used in C57BL/6 mice to develop models of Parkinson's disease (PD). The loss of dopaminergic neurons is suggested to be mediated by a mechanism of nonapoptotic cell death or by apoptosis. In recent years, the notion that the neurotoxicity of MPTP is restricted to dopaminergic neurons in the substantia nigra (SN) has been challenged. Here, we provide evidence of rapid cell death in the subventricular zone (SVZ) and rostral migratory stream (RMS) in the adult C57BL/6 mouse brain in response to acute or subacute treatment with MPTP. Significant terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) of fragmented DNA was observed at 24 h (or 1 day) after the last injection in the acute model or after the first injection in the subacute model. Ultrastructural analysis confirmed that dying cells displayed an apoptotic morphology. Using a double labeling method, we demonstrated that the phenotype of the cells undergoing apoptosis is that of migrating neuroblasts. This is further supported by evidence of a subsequent loss of migrating neuroblasts. The results raise the possibility that migrating neuroblasts in the SVZ and RMS may be more vulnerable to MPTP than nigrostriatal dopaminergic neurons in the SN, and the death of migrating neuroblasts may be a primary event in the mouse model of PD. Furthermore, our data suggests that the death and subsequent loss of migrating neuroblasts in the acute or subacute model probably lead to a decreased potential for neurogenesis to some extent.

Caffeic acid phenethyl ester protects rabbit brains against permanent focal ischemia by antioxidant action: A biochemical and planimetric study

The present study was conducted to investigate whether caffeic acid phenethyl ester (CAPE), an active component of propolis extract, has a protective effect on brain injury after focal permanent cerebral ischemia, and to determine the possible antioxidant mechanisms. Cerebral infarction in adult male New Zealand rabbits was induced by microsurgical procedures producing right focal permanent middle cerebral artery occlusion (pMCAO). CAPE was administered to the treatment group after pMCAO at a dose of 10 μmol kg − 1 once a day intraperitoneally for 7 days. Neurological deficits were evaluated, using a modified six-point scale. Spectrophotometric assay was used to determine the contents of malondialdehyde (MDA), glutathione (GSH), catalase (CAT), nitric oxide (NO) and xanthine oxidase (XO). In the ipsilateral hemisphere, the infarct volume of the brain was assessed in brain slices stained with heamatoxylen and eosin. The results showed that treatment with CAPE significantly reduced the percentage of infarction in the ipsilateral hemisphere compared with the ischemia group. CAPE treatment significantly attenuated the elevation of plasma MDA, CAT and XO content ( p < 0.05), whereas it significantly increased the levels of plasma GSH and NO ( p < 0.05). Therefore, subacute CAPE administration plays a protective role in focal pMCAO due to attenuation of lipid peroxidation and its antioxidant activity. All of these findings suggest that CAPE provides neuroprotection against cerebral ischemia injury through its antioxidant action.

Effects Of Subacute Administration Of Chloroquine On The Nissl Substance Of The Inferior Colliculus Of Adult Wistar Rats

The effects of subacute administration of chloroquine commonly used for prophylaxis or treatment of malaria, rheumatoid arthritis and lupus erythematosis on the inferior colliculus (IC) of adult wistar rats was studied. The rats of both sexes (n=17), average weight of 184g were randomly assigned into treatment (n=10) and control (n=7) groups. The rats in the treatment group received 2mg/kg body weight of chloroquine phosphate dissolved in distilled water daily for fourteen days. The control rats received equal volume of distilled water daily. The rats were fed with rat pellets and given water liberally and were then sacrificed on day fifteen of the experiment. The inferior colliculus was carefully dissected out and quickly fixed in 10% formal saline for histological study. Histological findings of the nissl substance indicate that the treatment groups showed sparsely distributed neurons, which stain less intensely when compared with the control. The nissl substance in some of the neurons appeared degenerative while some hypertrophied. These findings indicate that chronic administration of chloroquine has a deleterious effect on the nissl substance of the inferior colliculus. Chloroquine may have adverse effects on auditory sensibilities by its deleterious effects on the nissl substance of the inferior colliculus of the adult wistar rats. It is recommended that further studies aimed at corroborating these observations be carried out. Keywords: Chloroquine, nissl substance, inferior colliculus and wistar rats. Annals of Biomedical Science Vol.3 (1&2) 2004: pp. 33-38

Acute and subacute toxicity of the Carapa guianensis Aublet (Meliaceae) seed oil

Carapa guianensis (Meliaceae), known as Andiroba in Brazil, has been used by Amazon Rainforest indigenous communities for treatment of coughs, convulsions, skin diseases, arthritis, rheumatism, ear infections, to heal wounds and bruises and as an insect repellent. Carapa guianensis seed oil (SO) was evaluated for its acute and subacute toxicity (30 days) by the oral route in Wistar rats. In the acute toxicity test, SO (0.625–5.0 g/kg, n = 5/sex) did not produce any hazardous symptoms or deaths. The subacute treatment with SO (0.375, 0.75 and 1.5 g/kg, n = 10/group) failed to change body weight gain, food and water consumption. Hematological analysis showed no significant differences in any of the parameters examined. However, in the biochemical parameters, there was an increase in the alanine aminotransferase (ALT) serum level (29%) in the group SO 1.5 g/kg. In addition, absolute and relative liver weights were increased at the doses of 0.75 g/kg (23.4 and 19.1%) and 1.5 g/kg (18.7 and 33.1%). In conclusion, acute and subacute administration of Carapa guianensis seed oil did not produce toxic effects in male Wistar rats. However, the increase in the ALT serum level and in both absolute and relative liver weights may indicate a possible hepatic toxicity.

Oxidative stress in rat kidneys due to 3,4‐methylenedioxymetamphetamine (ecstasy) toxicity

The mechanism of MDMA (3,4-methylenedioxymethamphetamine)-induced toxicity is believed to be, in part, due to enhanced oxidative stress. As MDMA is eliminated via the kidney, the aim of this study was to investigate whether MDMA created conditions of oxidative stress within rat kidney. Adult male Wistar rats were divided into three groups, control treatment (water), acute MDMA administration (single oral dose: 5, 10, 20 or 40 mg/kg body weight) and subacute MDMA administration (5, 10, or 20 mg/kg body weight per day during 14 days). Animals were sacrificed 8 h after the single oral MDMA administration in the acute MDMA administration group and after the last MDMA administration in the subacute MDMA administration group. Rectal temperature measurements, oxidative stress status parameters and histological examinations were performed. In all MDMA-administered rats, rectal temperature markedly increased peaking approximately 1 h after MDMA ingestion. Superoxide dismutase activity and thiobarbituric acid reactive substances increased after MDMA administration. Histological examinations of the kidney revealed dose-dependent disruption of tissue structure in subacute MDMA-administered rats. The latter was not observed in acute MDMA-administered rats.

Phytochemical and Toxicological Studies of Aqueous Leaves Extracts of Erythrophleum africanum

The leaves of Erythrophleum africanum is known in the arid land of tropical Africa to posses toxicological properties. Phytochemical, acute and sub-acute evaluation of the possible toxicity risk of E. africanum aqueous leaves extracts were investigated in this study. Phytochemical constituents detected in the leaves extracts were saponins (1.16% w/v), cardiac glycosides, tannins (0.17 true tannins and 0.23% w/v pseudotannins), flavonoid glycosides, free flavonoids and alkaloids (4.34% w/v). The Lethal Dose (LD50) of the aqueous leaves extracts was greater than 3000 mg kg(-1) per os (orally) in albino rats. Sub-acute administration of the extract for 28 days resulted in significant (p<0.05) changes in some renal and liver indices at 3000 and 2000-3000 mg kg(-1) body weight, respectively. Histopathological lesions of the kidney and liver in form of moderate and marked infiltration with necrosis and perivascular lymphocytic cuff were observed. The observed lesions could be due to roles played by liver and kidneys in metabolism of xenobiotics and their elimination from the body. These investigations thus seem to indicate the toxic effects of the aqueous leaves extracts of E. africanum at 2000-3000 mg kg(-1). These could be attributed to the combined toxicity of the phytochemical constituents such as tannins, saponins, glycosides and alkaloids.

P.1.c.046 Asenapine displays high affinity and potent antagonism at an ensemble of human serotonin receptor subtypes

Substance P (neurokinin-1; NK1) receptor antagonists represent a putative new class of antidepressant/anxiolytic drugs. Using in vivo electrophysiological paradigms in rats, this study examined the effects of acute, sub-acute and long-term administration of these drugs on the firing of rat noradrenaline and serotonin (5-HT) neurons. In the locus coeruleus, neither a 2-day treatment with the tachykinin NK1 receptor antagonists [(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl) methyl]-1-azabicyclo[2.2.2]octan-3-amine (CP-96,345, 10 mg/kg/day, i.p.), CP-99,994 (10 mg/kg/day, i.p.), nor a 14-day of treatment with (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994, 10 mg/kg/day, s.c.) significantly modified the firing rate of noradrenaline neurons. However, all these treatments attenuated the inhibitory action of the α2-adrenoceptor agonist clonidine on noradrenaline neuronal firing. While acute administration of the tachykinin NK1 receptor antagonist CP-96,345 (10 mg/kg, i.p.) attenuated the responsiveness of dorsal raphe 5-HT1A autoreceptors, lesioning noradrenaline neurons with the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) prevented the enhancing action of a 2-day treatment with CP-96,345 on 5-HT neuronal firing, suggesting that tachykinin NK1 receptor antagonists influence 5-HT system via noradrenaline neurons independently of their firing rate.

The Role of 3-O-Methyldopa in the Side Effects of l-dopa

Long-term treatment of L-dopa for Parkinson's disease (PD) patients induces adverse effects, including dyskinesia, on-off and wearing-off symptoms. However, the cause of these side effects has not been established to date. In the present study, therefore, 3-O-methyldopa (3-OMD), which is a major metabolite of L-dopa, was tested to determine whether it plays a role in the aforementioned adverse effects. The effects of 3-OMD on the dopaminergic nervous system in the brain were investigated, by examining behavioral, biochemical, and cellular changes in male Sprague-Dawley rats and catecholamine-producing PC12 neuronal cells. The results revealed that the intracerebroventricular (icv) injection of 1 micromol of 3-OMD impaired locomotor activities by decreasing movement time (MT), total distance (TD), and the number of movement (NM) by 70, 74 and 61%, respectively. The biochemical analysis results showed that a single administration of 1 micromole of 3-OMD decreased the dopamine turnover rate (DOPAC/DA) by 40.0% in the rat striatum. 3-OMD inhibited dopamine transporter and uptake in rat brain striatal membranes and PC12 cells. The subacute administration of 3-OMD (5 days, icv) also significantly impaired the locomotor activities and catecholamine levels. 3-OMD induced cytotoxic effects via oxidative stress and decreased mitochondrial membrane potential in PC12 cells, indicating that 3-OMD can damage neuronal cells. Furthermore, 3-OMD potentiated L-dopa toxicity and these toxic effects induced by both 3-OMD and L-dopa were blocked by vitamin E (alpha-tocopherol) in PC12 cells, indicating that 3-OMD may increase the toxic effects of L-dopa to some extent by oxidative stress. Therefore, the present study reveals that 3-OMD accumulation from long-term L-dopa treatment may be involved in the adverse effects of L-dopa therapy. Moreover, L-dopa treatment might accelerate the progression of PD, at least in part, by 3-OMD.

Modulation of behavior and NMDA-R1 gene mRNA expression in adult female mice after sub-acute administration of benzo( a)pyrene

The behavioral performances of adult mice exposed to sub-acute doses of benzo( a)pyrene (B(a)P) were monitored in tests related to learning and memory (Y maze and Morris water maze), locomotor activity (open-field test) and motor coordination (Locotronic apparatus). At low doses (0.02 and 0.2 mg/kg), B(a)P impaired short-term learning and spatial memory performance in the Y maze and in the Morris water maze tests. Surprisingly, in the Y maze, the performances of animals exposed to the highest dose of B(a)P (200 mg/kg) were quite similar to those of control animals. Hyperactivity/hyperarousal observed in both tests at this dose and attributed to an anxiolytic-like effect of B(a)P may have blurred the learning deficit in these mice faced with a new situation. These deficits seem to be unrelated to motor impairments because B(a)P had no effect on locomotor activity and motor coordination. We demonstrated that sub-acute exposure to B(a)P in adult mice also modulates gene expression of NMDA-R1 subunit in brain areas highly involved in cognitive function like the hippocampus, suggesting a relationship between the expression of functional NMDA-R1 mRNA, impairment of short-term and spatial memory and the B(a)P exposure levels.