Subacute Administration Research Articles

Lack of Effect of Repeated Administration of Milnacipran, a Double Noradrenaline and Serotonin Reuptake Inhibitor, on the β-adrenoceptor-linked Adenylate Cyclase System in the Rat Cerebral Cortex

The effects of subacute administration of the double noradrenaline and serotonin uptake inhibitor antidepressant, milnacipran, and the tricyclic antidepressant, imipramine, on radioligand binding to β-adrenergic receptors and on β-adrenergic agonist-stimulated adenylate cyclase activity, in the rat cerebral cortex, have been determined. Rats were injected intraperitoneally for 21 days with milnacipran (3, 10 or 30 mg/kg/day) or imipramine (10 mg/kg/day). The treatment with milnacipran up to 30 mg/kg/day did not modify either the maximum number of [ 3H]CGP-12177 binding sites ( B max) or the equilibrium dissociation constant ( K d). On the other hand, treatment of the rats with 10 mg/kg/day imipramine induced a decrease (27%) in B max [ 3H]CGP-12177 binding sites without affecting the K d value. Furthermore, milnacipran did not affect the stimulation of cAMP production induced by either 30 μM isoprenaline, 10 μM GTPγS or 10 μM forskolin. Under similar conditions, treatment with imipramine reduced by 70% the isoprenaline-induced stimulation of cAMP production without affecting that induced by either GTPγS or forskolin. These results demonstrate that, unlike imipramine, subacute administration of milnacipran does not produce any change in β-adrenoceptor sensitivity in the rat brain cortex. Copyright © 1996 Elsevier Science Ltd.

Behavioral, neurochemical, and immunological responses to CRF administration. Is CRF a mediator of stress?

The effect of subacute intracerebroventricular (icv 0.1, 0.5, and 1.0 microgram) administration of corticotropin-releasing factor (CRF) for 5 days on behavior, neurotransmitter concentrations, and immune functions was studied in rats. The results showed that CRF administration produced a dose-dependent increase in locomotor activity in the "open field" test compared with controls; rearing scores were also significantly increased. In the elevated plus maze apparatus, rats given 1.0 microgram CRF spent considerably less time on the open arms when compared with controls. Following 0.5 and 1.0 microgram of CRF infusion, the concentrations of noradrenaline (NA), dopamine (DA) and 5-hydroxy indole acetic acid (5-HIAA) were significantly increased in the hypothalamus. There was no significant change in the concentrations of neurotransmitters in the other brain regions. CRF administration also produced a dose-dependent increase in the levels of corticosterone in the serum. The immunological results clearly showed that subacute icv CRF administration caused a reduction of lymphocyte proliferation, a decrease in the percentage of lymphocytes, and an increase in neutrophil percentage in the differential white blood cell (WBC) count, a decrease in neutrophil phagocytosis, and elevated leucocyte adhesiveness/aggregation (LAA) compared with control animals. These results suggest that icv subacute administration of CRF has anxiogenic effects, increases biogenic amine concentrations in the hypothalamus, and changes in some aspects of immune functions that may reflect the stress-inducing properties of the peptide. These effects are time and dose dependent.

Some behavioural and neurochemical aspects of subacute (±)3,4-methylenedioxymethamphetamine administration in rats

(±)3, 4-methylenedioxymethamphetamine (MDMA; “Ecstasy”), an increasingly popular recreational drug, is known to damage brain serotonin (5-hydroxytryptamine [5-HT]) neurons, whilst also having a less pronounced effect on the dopaminergic system. Treatment with MDMA results in an increased locomotor activity, elevated basal serum corticosterone concentrations, decreased exploratory activity, and changes in body temperature. The aim of this study was to examine the dose related effects of subacute administration of MDMA (5, 10, and 20 mg/kg IP twice daily for 4 days) on home cage locomotor activity, “open field” and “step-down passive avoidance” behaviours, changes due to an 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) challenge, and on plasma corticosterone and brain neurotransmitter concentrations. Total locomotor activity counts were significantly increased by both 10 and 20 mg/kg MDMA for the 4 days of drug administration. There were no significant differences seen in the “open field” or “step down passive avoidance” behaviour, in the 8-OH-DPAT induced hypothermia, or in basal serum corticosterone concentrations. MDMA caused a significant depletion of both 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the frontal cortex and amygdala and a significant elevation of dopamine and noradrenaline in the hippocampus. Apart from the increase in locomotor activity following subacute administration, the observed behaviour of the MDMA treated rats would not appear to reflect the substantial changes in brain biogenic amine neurotransmitters.

Effect of subacute xylene administration on peripheral blood

The ability of cyclosporin-A (CSA) and four of its metabolites M1, M17, M18 and M21, to inhibit antigen-stimulated release of β-hexoseaminidase from IgE-sensitized rat basophilic leukemia cells (RBL-2H3), as an in vitro correlate of anti-allergic effect, was studied. Metabolites M17, M1 and M21 were effective in inhibiting enzyme release, though less potent than the parent compound. The concentrations achieving 50% inhibition (IC50 values) were 53.3, 315.5 and 875.7ng/ml for CSA, M17 and Ml, respectively. M21 had approximately same IC50 as M1 while M18 was essentially inactive. At the highest concentration tested (1000 ng/ml) the mean maximum percentage inhibitions were 98.6, 79.5, 53.9, 48.6 and 12.2 for CSA, M17, M1, M21 and M18, respectively. The relative anti-allergic potency of the metabolites was similar to their reported relative immunosuppressive potency. Combinations of low concentrations of CSA and its metabolites were synergistic in inhibiting enzyme release whereas at higher concentrations interactions were either additive or antagonistic. Even the concentrations of the metabolites that have little or no activity when used alone also potentiated the effect of CSA. The immunosuppressor FK 506 was found to be about three times more potent than CSA in this system and the interactions between FK 506 (3, 10 and 30ng/ml) and CSA (10, 30 and 100 ng/ml) or M 17 (20, 100 and 500 ng/ml) were synergistic at all combinations. Both CSA and M17 synergized more strongly with FK 506 than they did between themselves. These results show that some metabolites of CSA, like the parent compound, possess anti-allergic effects and that at concentrations that are obtainable in transplant patients, synergistic interaction occurs between CSA and its metabolites, and this may be of some therapeutic significance.

Effects of subacute ethinylestradiol administration on cell proliferation of 5 organs, including tumorigenic target and non-target organs, in male F344 rats.

The effect of ethinylestradiol (EE), a synthetic estrogen which is tumorigenic to the mammary gland, pituitary gland, and liver, on the cell proliferation in 5 organs was investigated in male rats. Cell proliferation was estimated by bromodeoxyuridine (BrdU) immunohistochemistry after 72 hr continuous administration of BrdU through an osmotic minipump prior to sacrifice. Two experimental protocols were applied. In one, EE was administered to rats at l ppm in feed for 3, 7, 14, 28, and 91 days. The BrdU labeling indices (LI) in the pars distalis of the pituitary gland were significantly increased in the EE-treated rats compared to the control rats throughout the experimental period. The LI in the Harderian gland, a non-target organ of EE tumorigenesis, were also higher in the EE-treated rats on day 14 and thereafter. Other non-target organs, including the adrenal cortex and medulla, kidneys, and pancreas, showed variable or consistently lower LI in the EE-treated rats. In the other protocol, EE wa administered to rats at 0.1, 0.5, and 2 ppm in feed for 3, 7, and 14 days, and the serum prolactin (PRL) concentration and LI in the pars distalis were compared. EE treatment increased the serum PRL concentration, the LI in the pars distalis, and the numerical density (No. of cells/mm2) of BrdU-labeled PRL cells in a dose-dependent manner with complete parallelism among them. The increase in LI was observed within 14 days after the start of EE treatment, and the profiles of cell proliferation were unique to each organ, including tumorigenic target and non-target organs.

Risperidone prevents the development of supersensitivity, but not tolerance, to phencyclidine in rats treated with subacute phencyclidine

We investigated whether risperidone, a 5-HT2/dopamine-D2 receptor antagonist, inhibits the development of tolerance and supersensitivity to PCP and whether subacute administration of PCP with risperidone affects the [3H]MK-801 binding in rat brain, in comparison with dopamine-D2 receptor antagonist haloperidol and 5-HT2 receptor antagonist ritanserin. In rats treated with PCP (10 mg/kg, i.p.) for 14 days, PCP (10 mg/kg, i.p.)-induced hyperlocomotion, rearing and sniffing were potentiated (supersensitivity), and head-weaving, head-twitch, backpedalling and turning were diminished (tolerance). The development of supersensitivity to PCP was blocked by oral co-administration of risperidone (2.4 mg/kg, p.o.) and haloperidol (1.0 mg/kg, p.o.) for 14 days, but not ritanserin (10 mg/kg, p.o.) and risperidone (0.8 mg/kg, p.o.), while no drugs prevented the development of tolerance to PCP. Both risperidone (2.4 mg/kg, p.o.) and haloperidol (1.0 mg/kg, p.o.) also inhibited the cross-supersensitivity to methamphetamine (MAP; 2.5 mg/kg, i.p.)-induced rearing in rats treated with PCP for 14 days. The profiles of [3H]MK-801 binding in discrete brain areas did not change after subacute administration of PCP alone or in combination with risperidone, haloperidol or ritanserin for 14 days. Therefore, it is suggested that subacute administration of PCP may cause functional changes in the dopaminergic neuronal transmission under conditions where the binding of [3H]MK-801 in discrete brain areas is unchanged, and that co-administration of risperidone may block these PCP-induced changes in neuronal function.

Opioids modulate stress-induced proenkephalin gene expression in the hypothalamus of transgenic mice: a model of endogenous opioid gene regulation by exogenous opioids

Stressful stimuli strongly induce proenkephalin gene expression within the paraventricular nucleus (PVN) of the hypothalamus. A human proenkephalin-beta-galactosidase fusion gene has previously been shown to give correct phenotypic expression and appropriate stress regulation within the hypothalamus of transgenic mice; this model provides high sensitivity, cellular resolution, and ready quantification of levels of proenkephalin gene expression. Here we describe use of this transgenic model to study modulation of stress-regulated gene expression in the PVN by opiates. Acute or subacute morphine administration prior to a hypertonic saline stress produced marked superinduction of transgene expression compared with hypertonic saline stress alone. In contrast, chronic morphine administration decreased basal expression of the transgene, and inhibited stress-induced expression of the transgene. The endogenous proenkephalin mRNA was induced in parallel with the transgene as demonstrated by in situ hybridization; the immediate-early gene c-fos was also regulated in parallel with the transgene. These data suggest that acute or subacute morphine administration sensitizes proenkephalin neurons within the PVN and other regions of the hypothalamus to stress and that chronic morphine administration desensitizes this response. Because the molecular mechanisms regulating the expression of the transgene are well understood, this model provides a useful tool for investigating cellular and molecular effects of opioids on the hypothalamus.

Opioids modulate stress-induced proenkephalin gene expression in the hypothalamus of transgenic mice: A model of endogenous opioid gene regulation by exogenous opioids

Stressful stimuli strongly induce proenkephalin gene expression within the paraventricular nucleus (PVN) of the hypothalamus. A human proenkephalin-β-galactosidase fusion gene has previously been shown to give correct phenotypic expression and appropriate stress-regulation within the hypothalamus of transgenic mice; this model provides high sensitivity, cellular resolution, and ready quantification of levels of proenkephalin gene expression. Here we describe use of this transgenic model to study modulation of stress-regulated gene expression in the PVN by opiates. Acute or subacute morphine administration prior to a hypertonic saline stress produced marked superinduction of transgene expression compared with hypertonic saline stress alone. In contrast, chronic morphine administration decreased basal expression of the transgene, and inhibited stress-induced expression of the transgene. The endogenous proenkephalin mRNA was induced in parallel with the transgene as demonstrated by in situ hybridization; the immediate early gene, c-Fos was also regulated in parallel with the transgene. These data suggest that acute or subacute morphine administration sensitizes proenkephalin neurons within the PVN and other regions of the hypothalamus to stress and chronic morphine administration desensitizes this response. Because the molecular mechanisms regulating the expression of the transgene are well understood, this model provides a useful tool for investigating cellular and molecular effects of opioids on the hypothalamus.

Attenuation of the hypothalamic-pituitary-adrenal response to chronic “binge” pattern cocaine administration corresponds to decreased CRH mRNA in rat hypothalamus

The effects of subacute or chronic “binge” pattern administration of cocaine on the levels of corticotropin-releasing hormone (CRH) mRNA in rat hypothalamus and corticosterone concentrations in blood were studied. On day 3 of cocaine administration (15 mg/kg, i.p. at 1 hour intervals × 3 /day), no significant change in hypothalamic CRH mRNA levels was observed in injection-adapted rats. In contrast, this subacute “binge” pattern cocaine administration caused a significant elevation in plasma corticosterone concentrations ( p < 0.001 ). Following 14 days of chronic cocaine administration using the “binge” pattern, the levels of CRH mRNA in the hypothalamus were significantly reduced by 32% ( p < 0.05 ), compared with control animals. This decrease was coupled with a reduction in levels of plasma corticosterone compared to corticosterone levels in the subacute cocaine administration group ( p < 0.01 ). These results suggest that chronic “binge” pattern cocaine administration alters the hypothalamic — pituitary — adrenal response through a hypothalamic CRH-mediated mechanism.

Systemic or Local Administration of Azide Produces Striatal Lesions by an Energy Impairment-Induced Excitotoxic Mechanism

Sodium azide is an inhibitor of cytochrome oxidase which produces selective striatal lesions in both rodents and primates. In the present study we investigated the neurochemical and histologic effects of both intrastriatal and systemic administration of sodium azide, as well as the age dependence and mechanism of the lesions. Intrastriatal administration of sodium azide produced dose-dependent lesions. Neurochemical and histologic evaluation showed that markers of both spiny projection neurons (GABA, substance P) and aspiny interneurons (somatostatin, neuropeptide Y, NADPH-diaphorase) were equally affected. Subacute systemic administration of sodium azide resulted in lesions with a similar neurochemical profile; however, in contrast to intrastriatal injections there was sparing of dopaminergic striatal afferents. Prior decortication significantly attenuated lesions produced by intrastriatal administration of sodium azide, consistent with an excitotoxic process. Chronic administration of sodium azide for 1 month lead to striatal neuropathological changes. Lesions produced by intrastriatal administration of sodium azide in 1-, 4-, and 12-month-old animals showed age dependence. Both freeze-clamp measurements and chemical-shift magnetic resonance spectroscopy confirmed that sodium azide impairs oxidative phosphorylation in the striatum following either intrastriatal or systemic administration. These results show that the striatum is particularly vulnerable to oxidative stress produced by sodium azide, and that it produces striatal lesions by a secondary excitotoxic mechanism.

Stereoselective pharmacokinetics of stiripentol: an explanation for the development of tolerance to anticonvulsant effect

An earlier pharmacodynamic study of the chiral antiepileptic drug stiripentol in an intravenous pentylenetetrazol-induced seizure model in the rat showed the development of a significant degree of tolerance to the anticonvulsant and neurotoxic effects following subacute treatment with the racemic compound. A more recent study with the pure enantiomers of stiripentol indicated that the (+)-enantiomer is 2.4 times more potent than the (−)-enantiomer, based on a comparison of brain EC 50 values for the anticonvulsant effect. Moreover, (−)-stiripentol has a much longer elimination half-life than (+)-stiripentol. We have re-analyzed the brain and blood samples from the first pharmacodynamic study using a newly developed chiral HPLC assay to investigate whether the tolerance phenomenon with racemic stiripentol was due to a shift in the enantiomeric composition of stiripentol in brain tissue during repetitive administration of racemic drug. A large increase, as much as 5–6-fold, in the (−)/(+) ratio in brain concentration of stiripentol was observed after subacute administration, as compared with that after a single dose of the racemic drug. The enrichment in the less potent enantiomers during repetitive drug administration explains the previous observation of an apparent development of tolerance when the pharmacologic effects were related to total [(−) + (+)] brain concentrations of stiripentol as measured by a non-stereoselective assay. The results of this study highlight the importance of Stereoselective pharmacokinetics in investigating the pharmacodynamics of the racemic mixture of a chiral anticonvulsant.

Toxicologic evaluation of acute and subacute oral administration of Cucurbita maxima seed extracts to rats and swine

The extract prepared from dried seeds of Cucurbita maxima was administered to rats and pigs. Following a single dose or 4 weeks of daily oral administration, the extract produced no changes in serum glucose, urea, creatinine, total protein, uric acid, GOT, GPT, LDH or blood counts. Urine analysis (urea, uric acid, creatinine, total protein, Na and K), as well as histopathological investigation, showed no abnormalities. These results taken as a whole indicate that the seeds of C. maxima as used in Brazilian folk medicine are not toxic for rats and swine.

Modification of testicular cytochrome P-450 after fenitrothion administration

1. 1. The effect of fenitrothion on testicular microsomal system was analyzed and compared to the modifications induced by the drug at the hepatic level. 2. 2. Acute (165 mg/kg, 1 day) and subacute (55 mg/kg, 3 days) administration of fenitrothion caused a significant decrease on testicular cytochrome P-450 content (51 and 50% respectively) but no modification on cytochrome b 5 and NADPH cytochrome c reductase. No changes were induced by fenitrothion in testicular microsomal system after chronic treatment (5.5 mg/ml, 30 days). 3. 3. Results obtained in the liver were very similar to those observed in testis even though the percentage of cytochrome P-450 inhibition obtained after acute and subacute drug administration (45 and 43%) was smaller. 4. 4. In addition, changes in testosterone blood concentrations were also analyzed. A significant reduction of hormone plasma levels were detected at 165 and 55 mg/kg doses of fenitrothion (98% in both cases). Fenitrothion was not able to modify the levels of testosterone in the blood after chronic administration.

Effect of subacute toluene administration on the enkephalinergic neuromodulatory system in rats and protective action of ganglioside treatments.

Gangliosides perform protective functions in the central nervous system. This paper describes a study of the effect of ganglioside administration on toluene neurotoxicity. Rat brain met-enkephalin immunostaining in the central amygdaloid nuclei showed changes in rats treated simultaneously with gangliosides and toluene with respect to rats treated with toluene alone. It is suggested that gangliosides prevent toluene neurotoxicity at this level, leading to hypothetical neurobehavioral changes.

Nicotine effects on the regulation of amyloid precursor protein splicing, neurotrophin and glucose transporter RNA levels in aged rats

It has been reported that an inverse relationship exists between nicotine intake and the incidence of Alzheimer's Disease (AD). Although nicotine has been reported to induce c-fos, in the present study it was shown that this induction does not alter the accumulation of a number of transcripts associated with AD. Altered splicing patterns of Amyloid Precursor Protein (APP) and changes in neurotrophin and glucose transporter expression have been implicated in AD and behavioral deficits in rats. The effects of subacute administration of nicotine (12 mg/ml at 2.3 μl/hr for 14 days) on the abundance levels of APP, glucose transporter(GLUT) and neurotrophin transcripts were determined by rtPCR in the hippocampus, cortex, and striatum of aged (22–24 months) male Wistar rats. No significant differences between saline and nicotine infused rats were detected for APP abundance levels or ratio of the various isoforms. However, both groups had a higher level of APP transcripts containing the Kunitz Protease Inhibitor (KPI) domain in the hippocampus than in either the cortex or striatum. The mean percentages of APP 695 for the two groups were 75% in the hippocampus and 82 and 81% in the cortex and striatum, respectively (P<0.01). No changes in the abundance of GLUT1, GLUT3, nerve growth factor (NGF) or brain derived neurotrophic factor (BDNF) transcripts were detected. However, since both APP and GLUT1 are thought to be regulated post-transcriptionally, the present results do not rule out a change at the protein level. Further work will be required to determine whether nicotine can influence the expression of these proteins which affect neuronal function.

Effects of subacute administration of methamphetamine and nicotine on locomotor activity in transgenic mice expressing the human tyrosine hydroxylase gene.

We produced transgenic (Tg) mice carrying the human tyrosine hydroxylase (TH) gene. To investigate differences in the dopaminergic (DAergic) neuronal activity between the Tg and nTg mice, we examined changes in the locomotor activity induced by methamphetamine (MAP) and nicotine (NIC), which enhances DA release and induces TH enzyme activation, respectively. Surprisingly, however, the intensity of MAP (2.5 mg/kg, once a day for 14 days)-induced hyperlocomotion in the nTg mice was greater than that in the Tg mice, and, furthermore, the Tg mice were less sensitive to subacute administration of NIC (0.5 mg/kg, once a day for 14 days) than the nTg mice. These results suggest that DAergic neuronal function is suppressed in Tg mice to compensate for the overexpression of TH.

Brain met-enkephalin immunostaining after subacute and subchronic exposure to benzene.

Benzene is used in a wide variety of domestic and occupational activities, and due to its lipophilic nature, it accumulates in lipid-rich tissues like the brain. In this sense, neurotoxic action has long been associated with organic solvent exposure and it has been shown that benzene, injected in a single dose or during a prolongued administration, modifies the content of dopamine, noradrenaline, serotonin and its main metabolite 5-hydroxy indolacetic acid, in several brain regions of the rat, then revealing a stimulating action on brain monoamine synthesis and turnover. However, information concerning neurotoxic action of benzene exposure in vivo on peptidergic neuromodulatory systems is still lacking. Nevertheless, it has been recently described that subacute benzene exposure in rats generates regional changes in brain aminopeptidase activity. These proteolytic enzymes have been widely associated with metabolic control of neuropeptides and it has been suggested that they could play a role in benzene neurotoxic mechanism by hypothetically changing regional neuropeptide levels. This being the case, we focused on analyzing met-enkephalin immunostaining in different brain regions of the rat after subacute and subchronic administration of benzene. 12 refs., 3 figs.

Assessment of the influence of subacute phenobarbitone administration on multi-tissue cell proliferation in the rat using bromodeoxyuridine immunocytochemistry.

The effects of daily administration of phenobarbitone on the mitotic rates of several tissues were investigated by bromodeoxyuridine (BrdU) immunocytochemistry. Phenobarbitone (80 mg/kg per day) was dosed to AP Wistar male rats for up to 7 days and BrdU (10 mg/ml) was given by infusion at a rate of 10 microliters/h via subcutaneously implanted osmotic minipumps for 2 days prior to necropsy on days 1, 2, 3, 5 and 7. BrdU-labelled nuclei were visualised by peroxidase-antiperoxidase immunocytochemistry and counts of the numbers of labelled cells (labelling index, LI%) made from at least 1000 cells per tissue section(s). The LIs of several tissues (testis, adrenal cortex and medulla, kidney distal convoluted tubule and exocrine pancreas) showed no statistical difference by comparison with controls. Several tissues exhibited characteristic responses to phenobarbitone administration. Pituitary and endocrine pancreas LIs were decreased while those of thyroid, liver and kidney proximal convoluted tubule were increased. The pattern of LI increase was unique to each tissue with liver (median and lateral lobes) increased two-fold on day 3 and returning to control levels thereafter while kidney proximal tubule LI rose gradually with time and remained elevated on day 7. Thyroid LI on day 1 was almost double that of day 0 control and increased steadily thereafter. These data illustrate the varied responses of different tissues to phenobarbitone exposure, namely, depression and stimulation of mitosis. The causation of these functional changes is discussed in relation to direct and indirect effects on functional parameters, especially enzyme induction, alterations in hormonal and growth factor status and receptor regulation.

Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid

An impairment of energy metabolism may underlie slow excitotoxic neuronal death in neurodegenerative diseases. We therefore examined the effects of intrastriatal, subacute systemic, or chronic systemic administration of the mitochondrial toxin 3-nitropropionic acid (3-NP) in rats. Following intrastriatal injection 3-NP produced dose-dependent striatal lesions. Neurochemical and histologic evaluation showed that markers of both spiny projection neurons (GABA, substance P, calbindin) and aspiny interneurons (somatostatin, neuropeptide Y, NADPH-diaphorase) were equally affected. Subacute systemic administration of 3-NP produced age-dependent bilateral striatal lesions with a similar neurochemical profile. However, in contrast to the intrastriatal injections, striatal dopaminergic afferent projections were spared. Both freeze-clamp measurements and chemical shift magnetic resonance spectroscopy showed that 3-NP impairs energy metabolism in the striatum in vivo. Microdialysis showed no increase in extracellular glutamate concentrations after systemic administration of 3-NP. The lesions produced by intrastriatal injection or systemic administration of 3-NP were blocked by prior decortication. However, the NMDA antagonist MK-801 did not block the effects of intrastriatal 3-NP, consistent with a non-NMDA excitotoxic mechanism. In contrast to subacute systemic administration of 3-NP, chronic (1 month) administration produced lesions confined to the striatum in which there was relative sparing of NADPH-diaphorase interneurons, consistent with an NMDA excitotoxic process. Chronic administration showed growth-related proliferative changes in dendrites of spiny neurons similar to changes in Huntington's disease (HD). These results are consistent with in vitro studies showing that mild metabolic compromise can selectively activate NMDA receptors while more severe compromise activates both NMDA and non-NMDA receptors. Chronic administration of 3-NP over 1 month produces selective striatal lesions that replicate many of the characteristic histologic and neurochemical features of HD.

Effects of a subacute treatment in rats by a fresh cola extract on EEG and pharmacokinetics

The compared effects of an acute and subacute treatment by fresh cola extract and caffeine on the caffeine pharmacokinetics and on cortical activities by spectral analysis of the electroencephalogram (EEG) are studied in rats. After acute cola administration, we observed an increase in half-life elimination of caffeine and a stabilization of its plasma/erythrocyte ratio. Chronic administration revealed differences in cola-caffeine penetration in erythrocytes and a reduction of the area under the curve (AUC) and plasma/erythrocyte ratio. We also noted a significant difference in the binding of the caffeine on plasma proteins after subacute administration of cola seed extract. Cola seed treatment induces an increase in the cortical activity with a widening of the dominant frequency spectrum 7-to 10-Hz band of EEG, whereas caffeine alone induces a shift of the dominant frequency band toward higher frequencies. The observed delay to obtain the greatest EEG effect related to the caffeine contained in cola seeds can be partially explained by the pharmacokinetic data.