Chronic Administration Of Scopolamine Research Articles

Chronic Administration of Scopolamine Increased GSK3βP9, Beta Secretase, Amyloid Beta, and Oxidative Stress in the Hippocampus of Wistar Rats.

The increase of amyloid beta (Aβ) release and hyperphosphorylation of Tau protein represents the main events related to Alzheimer's disease (AD). Furthermore, the sporadic type represents the most common form of AD. Therefore, the establishment of a non-transgenic animal model that resembles the characteristics of the disease is of particular importance. Scopolamine has been linked to increases in both Aβ production and oxidative stress in rat and mice brains. Thus, the purpose of the present work was to identify changes in biomarkers that are related to AD after chronic administration of scopolamine (2mg/kg i.p., during 6 and 12weeks) to male Wistar rats. The results showed increased Aβ deposition at rat hippocampus which could be due to an increase of β-site amyloid-β-protein precursor cleaving enzyme 1 (BACE1) expression and activity. These findings could be related to the increase of glycogen synthase kinase 3 phosphorylated (GSK3βP9) expression. Finally, the establishment of a state of oxidative stress in groups treated with scopolamine was demonstrated by an increase in free radical content and MDA levels. The present study facilitates our understanding of the changes that occur in biomolecules related to AD in Wistar rats after the chronic administration of scopolamine.

Neuroprotective Effects of Apocynin and Galantamine During the Chronic Administration of Scopolamine in an Alzheimer's Disease Model.

Alzheimer's disease (AD) is one of the most complicated neurodegenerative diseases, and several hypotheses have been associated with its development and progression, such as those involving glucose hypometabolism, the cholinergic system, calcium imbalance, inflammation, oxidative imbalance, microtubule instability, and the amyloid cascade, several of which are related to oxidative stress (free radical generation), which contributes to neuronal death. Therefore, several efforts have been made to establish a sporadic AD model that takes into account these hypotheses. One model that replicates the increase in amyloid beta (Aβ) and oxidative stress in vivo is the scopolamine model. In the present work, the chronic administration (6 weeks) of scopolamine was used to analyze the neuroprotective effects of apocynin and galantamine. The results showed that scopolamine induced cognitive impairment, which was evaluated 24 h after the final dose was administered. In addition, after scopolamine administration, the Aβ and superoxide anion levels were increased, and NADPH oxidase 2 (NOX2), nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear factor kappa B (NFkB) genes were overexpressed. These effects were not observed when either apocynin or galantamine was administered during the last 3 weeks of scopolamine treatment, and although the results from both molecules were related to lower Aβ production and, consequently, lower superoxide anion production, they were likely realized through different pathways. That is, both apocynin and galantamine diminished NADPH oxidase expression, but their effects on transcription factor expression differed. Moreover, experiments in silico showed that galantamine did not interact with the active site of beta secretase, whereas diapocynin, an apocynin metabolite, interacted with the beta-site APP-cleaving enzyme (BACE1) at the catalytic site.

Play behavior in rats pretreated with scopolamine: Increased play solicitation by the non-injected partner

Play behavior was assessed in juvenile rat pups following chronic administration of scopolamine (0.5 or 1.0 mg/kg, i.p.) to one partner in each dyad of rats. Scopolamine administration significantly reduced the number of pins and mean pin duration of both playmates in pairs where only one rat was injected with scopolamine (irrespective of dose). However, dorsal contacts were significantly increased in rats exposed to a play partner that had been injected with scopolamine, indicating an increase in play solicitation when the partner was rendered non-responsive with this drug. These effects were stable and consistent over the course of 15 days of repeated testing in the presence of scopolamine. In other words, normal animals did not extinguish play solicitation even after prolonged periods of non-reciprocity. Upon cessation of drug treatment, play behavior returned largely to normal in both animals. Overall locomotor activity levels were significantly reduced in pairs where one rat had been injected with scopolamine. Together, these data suggest that the effects of repeated scopolamine are acute in nature, and that disruption of normal play behavior following chronic scopolamine treatment does not produce long-term impairments in social play behavior beyond acute action of the drug.

The action of scopolamine on retrieval and memory storage in rats evaluated in the staircase maze

Rats were trained to run on staircase stopping on the 3rd, 6th, 9th, and 12th steps (correct responses). Stopping on any other step was considered an error. The acute administration of scopolamine (1.5 mg/kg) 20 min before the trial caused a reduction of the correct responses. An interruption of the daily training for 20 days caused, in the controls, a 24% reduction of correct responses. A chronic administration of scopolamine, at doses over 10 mg/kg in the first 15 days of the no-training period, nullified the behavioral deterioration observed in the controls. The interpretation of these results is that scopolamine damages the retrieval process and blocks the spontaneous decay of memory, as was observed in the controls after 20 days of interruption of the daily training.

D 2 dopaminergic regulation of striatal preproenkephalin mRNA levels is mediated at least in part through cholinergic interneurons

The effect of administration of the muscarinic antagonist scopolamine on the increase in striatal preproenkephalin (PPE) mRNA following a 6-hydroxydopamine (6-OHDA) lesion or chronic D 2 dopamine (DA) antagonist treatment was examined by dot-blot hybridization. Administration of scopolamine dose-dependently attenuated the 6-OHDA lesion-induced increase in striatal PPE mRNA. Administration of the D 2 DA antagonist eticlopride to naive rats increased striatal PPE mRNA in a dose- and time-dependent fashion. Chronic coadministration of scopolamine attenuated the eticlopride-induced increase in striatal PPE mRNA. Chronic administration of scopolamine alone did not alter striatal PPE mRNA levels. In contrast, chronic administration of eticlopride, scopolamine or the two combined decreased striatal preprotachykinin (PPT) mRNA to the same extent, suggesting that there was no direct interaction between D 2 dopaminergic and cholinergic mechanisms in the regulation of striatal PPT mRNA. These data indicate that DA differentially regulates striatal PPE and PPT mRNA and suggest that dopaminergic regulation of striatal PPE mRNA is mediated in part through D 2 DA effects on striatal cholinergic neurons.

Changes in Sensitivity of Rat Front Cortex Neurons to Acetylcholine (ACh) after α-Amino-3-Hydroxy-4-Isoxozole Propionic Acid (AMPA) Lesions of Nucleus Basalis Magnocellularis and After Embryonic Basal Forebrain Transplants

The effects of unilateral S-AMPA lesions of nucleus basalis magnocellularis (nbm) and of subsequent ipsilateral embryonic basal forebrain transplants on the sensitivity of pyramidal cells in the frontal cortex to iontophorized acetylcholine (ACh) and carbachol were studied in anaesthetized rats. Each drug was applied with an ejection current of 30 nA for 20 s and the average response of 3 applications (separated by 1 min recovery periods) was obtained. Neurons were considered to be sensitive when their firing rate increased or decreased (Wilcoxon, P<0.05), either during or within 20 s of drug application. Neuronal firing rates were significantly reduced in the frontal cortex 8-10 weeks postlesion, when acetylcholinesterase (AChE)positive fibre staining was almost completely absent, but the percentage of ACh-sensitive neurons increased (68/82 neurons from 7 rats compared with 72/144 neurons from 12 control rats, P<0.0001); the duration of ACh’s action also significantly increased. Comparison with controls showed that this enhanced sensitivity to ACh after lesion could be explained solely by an increase in the proportion of neurons excited by ACh (Table 1). The modulatory effects of ACh were also studied on responses of cortical neurons evoked by afferent electrical stimulation (single square wave pulses, 5 ms duration, 1-3 mA, were delivered at intervals of not less than 10 s and 10 stimulations used for each procedure). ACh modulation of neuronal responses evoked by sensory stimulation was not significantly changed after the lesion. Sensitivity to carbachol and glutamate was unchanged after lesion. In normal rats, acute administration of an AChE-inhibitor, di-isopropyl fluorophosphate (DFP) significantly increased the frontal cortex neurons’ responsiveness to ACh from 50% in the control group to 87.4% in the DFP treated group (P<0.0001). DFP also decreased the latency and increased the duration of ACh action without changing the frontal cortex firing rate. The sensitivity of frontal cortex to carbachol and glutamate was not changed after DFP. Chronic administration of scopolamine (10 mg/kg s.c. in 0.9% NaC1 daily for 16 days) significantly increased the sensitivity of frontal cortex neurons to both ACh and carbachol. It also significantly increased the neuronal firing rate, prolonged the duration of ACh and carbachol action and decreased the latency of action of both drugs. In contrast, chronic administration of oxotremorine (0.5 mg/kg s.c. in 0.9% NaC1 twice daily for 11 days and 10 mg/kg in sesame oil for 9 days) significantly decreased the frontal cortex neurons’ sensitivity to both ACh and carbachol. It also significantly decreased the neuronal firing rate, decreased the duration and increased the latency of ACh and carbachol action. Cholinergic-rich transplants to the frontal cortex normalised neuronal sensitivity to ACh and its duration of action but did not restore the firing rate. Non-cholinergic transplants or cholinergie-rich transplants to the somatosensory cortex were ineffective. Histological examination showed a sprouting of ChAT and AChE from the transplant into the neocortex of

Effect of Chronic Administration of Scopolamine on Thyrotropin-Releasing Hormone (TRH)-mediated Wet-Dog Shakes and TRH Receptors as Measured by Quantitative Autoradiography

Effect of Chronic Administration of Scopolamine on Thyrotropin-Releasing Hormone (TRH)-mediated Wet-Dog Shakes and TRH Receptors as Measured by Quantitative Autoradiography

Effect of Chronic Administration of Scopolamine on Thyrotropin-Releasing Hormone (TRH)-mediated Wet-Dog Shakes and TRH Receptors as Measured by Quantitative Autoradiography

Effect of Chronic Administration of Scopolamine on Thyrotropin-Releasing Hormone (TRH)-mediated Wet-Dog Shakes and TRH Receptors as Measured by Quantitative Autoradiography

Cholinergic-dopaminergic interactions and the mechanisms of action of antidepressants

A series of experiments was performed to evaluate the mechanism(s) by which chronic administration of desipramine (DMI) facilitates the locomotor stimulant action of d-amphetamine, a response thought to be dependent on the mesolimbic dopaminergic system. Prior lesions of central noradrenergic or serotonergic neurons, induced by neonatal treatment with 6-hydroxydopamine (6-OHDA) or intraventricular injections of 5,7-dihydroxytryptamine (5,7-DHT) respectively, failed to block DMI-induced facilitation of amphetamine hypermotility. Chronic administration of DMI did not significantly influence specific [ 3H]spiperone binding in the striatum or the nucleus accumbens. In other experiments it was found that chronic administration of some (amitryptyline, imipramine, mianserin, iprindole) but not all (zimelidine, nomifensine, fluoxetine) antidepressants enhanced the locomotor response to d-amphetamine. The weak anticholinergic effects of the latter compounds suggest that the positive results obtained with the former drugs may be related to their anticholinergic properties. This hypothesis is consistent with the observation that chronic administration of scopolamine also increased the locomotor response to d-amphetamine. The results suggest that the facilitation by chronic DMI of amphetamine-induced locomotor activity is not mediated by primary actions of this tricyclic antidepressant on central noradrenergic or serotonergic systems. In addition, the results argue against an effect of DMI on dopamine receptors as measured by [ 3H]spiperone binding. Instead, the facilitation of the amphetamine response by some of these antidepressant compounds may be related to their anticholinergic effects. The results are viewed as being consistent with a dopaminergic-cholinergic hypothesis of affective illness and suggest that the anticholinergic properties of some antidepressant compounds may contribute to their therapeutic effects.