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PubMed2006

Muscarinic acetylcholine receptor inhibition in transgenic Alzheimer-like Tg2576 mice by scopolamine favours the amyloidogenic route of processing of amyloid precursor protein.

The molecular mechanisms of the interrelationship between cholinergic neurotransmission, processing of amyloid precursor protein (APP) and beta-amyloid (Abeta) production in vivo are still less understood. To reveal any effect of cholinergic dysfunction on APP processing in vivo, 11-month-old transgenic Tg2576 mice with Abeta plaque pathology received intraperitoneal injections of scopolamine at a daily dosage of 2mg/kg body weight for 14 days in order to suppress cortical cholinergic transmission by chronic inhibition of muscarinic acetylcholine receptors. Scopolamine treatment of transgenic Tg2576 mice resulted in increased levels of fibrillar Abeta(1-40) and Abeta(1-42), while the soluble, SDS-extractable Abeta level remained unchanged as compared to vehicle-injected Tg2576 mice. alpha-Secretase activity determined in cortical tissue from scopolamine-treated Tg2576 mice was lower by about 30% as compared to that assayed in control mice, while beta-secretase activity and BACE1 protein expression appeared unaffected by scopolamine treatment. The amount of sAPPalpha, the product secreted by alpha-secretase-mediated APP cleavage, and the unprocessed APP were assayed in the soluble and membrane fraction, respectively, of cortical tissue preparations from treated and control mice by Western blotting. Using the anti antibody 6E10 which specifically labels human sAPPalpha and full length APP in transgenic Tg2576, an enhanced APP level was detected in the membrane fraction from treated mice as compared to controls, while in the soluble fraction scopolamine treatment did not affect the protein level of sAPPalpha. These data indicate an accumulation of APP in cortical membrane fraction in scopolamine-treated Tg2576 mice presumably due to the decreased level of alpha-secretase-mediated APP cleavage, and further suggest that chronic suppression of cortical muscarinic cholinergic transmission may alter the balance between alpha- and beta-secretory APP processing by favouring the amyloidogenic route.

Alzheimer Disease↗
PubMed2003

Hypericum perforatum extract demonstrates antioxidant properties against elevated rat brain oxidative status induced by amnestic dose of scopolamine.

This study was designed to investigate if the impairment of learning and memory induced by acute administration of scopolamine (1.4 mg/kg ip) in rats is associated with altered brain oxidative stress status. The passive avoidance paradigm was used to assess retrieval memory of rats after scopolamine treatment. Following retrieval testing, biochemical assessments of malondialdehyde (MDA), glutathione peroxidase (GSHPx), glutathione (GSH), and superoxide dismutase (SOD) levels/activities as oxidative stress indices were performed. This study also investigated the effect of acute administration of Hypericum perforatum extract (4.0, 8.0, 12.0, and 25.0 mg/kg ip), containing flavonoids with documented antioxidant activity, on brain oxidative status of nai;ve rats treated with amnestic dose of scopolamine. Results showed that administration of 1.4 mg/kg of scopolamine impaired retrieval memory of rats and that such amnesia was associated with elevated MDA and reduced GSH brain levels. In nai;ve rats, which have not been exposed to conditioned fear, scopolamine administration also increased MDA and reduced GSH levels, although with an increase in brain GSHPx activity. Pretreatment of the animals with Hypericum extract (4, 8, and 12 mg/kg) resulted in an antioxidant effect through altering brain MDA, GSHPx, and/or GSH level/activity. Since oxidative stress is implicated in the pathophysiology of dementia, the findings of this study may substantiate the value of scopolamine-induced amnesia in rats as a valid animal model to screen for drugs with potential therapeutic benefit in dementia. Exposure of animals to conditioned fear may be suggested to impair the balance between the rate of lipid peroxidation and the activation of GSHPx as a compensatory antioxidant protective mechanism. It is also concluded that low doses of Hypericum extract, demonstrating antioxidant activity, may be of value for demented patients exhibiting elevated brain oxidative status. Since depression commonly coexists with dementia, Hypericum extract as a drug with documented antidepressant action may also be a better alternative than several other antidepressant medications that have not been evaluated to test their effect on brain oxidative status during amnesia.

Amnesia↗
PubMed2005

Effects of scopolamine challenge on regional cerebral blood volume. A pharmacological model to validate the use of contrast enhanced magnetic resonance imaging to assess cerebral blood volume in a canine model of aging.

Cognitive impairment resulting from disruption of cholinergic function may occur through modulation of cerebrovascular volume (CBV). In the present study, dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) was used to examine cerebrovascular volume in young and old dogs during baseline and after administration of a cholinergic antagonist (scopolamine). In the first study, 24 animals (2-15 years of age) were given a baseline scan followed by a second scan after scopolamine administration (30 microg/kg). Gray matter rCBV was significantly higher than white matter rCBV during baseline and scopolamine administration. In the second study a subset of 7 dogs (4 young and 3 old) received scopolamine before anesthesia was induced for a second DSC-MRI scan. Consistent with the first study, gray matter rCBV was significantly higher than white matter rCBV. Scopolamine administered before anesthesia however, resulted in higher rCBV values compared to baseline in cerebral gray matter. Additionally, rCBVs were higher in young dogs at baseline in gray and white matter and marginally higher in gray matter when scopolamine was administered before anesthesia. These results indicate that in the dog, rCBV varies with brain compartment, decreases with age, and that DSC-MRI provides a measure of cerebrovascular function which may be related to age-dependent changes in cognition, brain structure, and neuropathology.

Aging↗
PubMed2005

Influence of chronic treatment with olanzapine, clozapine and scopolamine on performance of a learned 8-arm radial maze task in rats.

Cognitive deficit is a significant symptom in schizophrenic patients. Use of atypical antipsychotics has been demonstrated to improve some cognitive functions in schizophrenics, as well as in patients with dementia. However, side effects like sedation and muscarinic antagonism induced by these drugs have detracted from this improvement. We are interested in determining the behavioural effect of acute and chronic treatments with olanzapine and clozapine, two atypical antipsychotics, in a paradigm of working memory, and the influence on behavioural response of possible motor effects during test performance. Unspecific muscarinic antagonist scopolamine has been used for comparison. Male Wistar rats were trained on the 8-arm radial maze up to an accuracy level in choice of 80%. Distance travelled in the maze was also measured during test performance. Acute olanzapine, clozapine and scopolamine caused significant impairment of correct performance. Rats treated with olanzapine and clozapine presented a decrease in motor activity level at the same time. After the test at acute dosage, rats were chronically treated for 14 days with olanzapine, clozapine or scopolamine and 24 h after the last dose were again tested in the 8-arm radial maze. Under this procedure, chronic treatment with olanzapine, clozapine and scopolamine did not impair correct task performance and did not modify distance travelled. We concluded that the sedative effect masked a possible effect on working memory after acute administration of olanzapine and clozapine, whereas chronic treatment with olanzapine, clozapine and scopolamine did not adversely affect working memory performance. In the case of scopolamine, it suggests that chronic muscarinic antagonism does not induce memory impairment and for atypical antipsychotics, it suggests that chronic treatment induced a tolerance to acute motor effects of these drugs.

Animals↗
PubMed1998

The modulation by neurosteroids of the scopolamine-induced learning impairment in mice involves an interaction with sigma1 (sigma1) receptors.

Neurosteroids have been reported to modulate learning and memory processes in aged animals and in pharmacological models of amnesia. We report here the effects of dehydroepiandrosterone sulfate (DHEAS), pregnenolone sulfate (PREGS), and progesterone (PROG) on the learning impairment induced in mice by the muscarinic acetylcholine receptor antagonist, scopolamine. Spatial working memory was examined using the spontaneous alternation behavior in a Y-maze and long-term memory using place learning in a rectangular water-maze adapted for mice. Both DHEAS and PREGS (5-20 mg/kg, s.c.) prevented dose-dependently and significantly the scopolamine (2 mg/kg, s.c.)-induced alternation deficits. PROG (2-20 mg/kg, s.c.) failed to affect the scopolamine-induced deficits, but blocked, at 20 mg/kg, the beneficial effects induced by DHEAS or PREGS. In the water-maze, DHEAS (20 mg/kg) attenuated significantly the scopolamine-induced deficits, as observed during the acquisition sessions or the retention test. PROG (2, 20 mg/kg) did not affect the control or scopolamine-treated group performances, but blocked the ameliorating effect of DHEAS. Furthermore, in both tests, the selective sigma1 (sigma1) receptor antagonist NE-100 (1 mg/kg, i.p.) failed to affect the behaviors showed by the control or scopolamine-treated groups, but it blocked the ameliorating effects induced by DHEAS or PREGS. These results confirm the modulating role of neurosteroids in learning and memory processes and demonstrate that their modulation of the cholinergic systems involves an interaction with sigma1 receptors.

Animals↗
PubMed2000

Effects of scopolamine in comparison with apomorphine and phencyclidine on prepulse inhibition in rats.

The potential involvement of the muscarinic cholinergic system in the underlying mechanisms of prepulse inhibition of the acoustic startle reflex was evaluated in male Sprague-Dawley rats under conditions of varying dose, prepulse intensity, and interstimulus interval. The effects of scopolamine on prepulse inhibition were also directly compared with the effects observed using apomorphine and phencyclidine under the same test parameters. Scopolamine (0. 03-1.0 mg/kg) produced a significant dose-dependent decrease in prepulse inhibition, but had no effect on startle amplitude over the dose range tested. Apomorphine (0.03-1.0 mg/kg) and phencyclidine (0. 1-5.6 mg/kg) produced significant dose-dependent decreases in prepulse inhibition and changes in startle amplitude. The scopolamine-induced decrease in prepulse inhibition varied with prepulse intensity in that the changes produced by scopolamine became smaller in magnitude as the prepulse intensity was increased from 9 to 30 dB above background. On the other hand, apomorphine and phencyclidine decreased prepulse inhibition to approximately the same magnitude across all prepulse intensities tested. The observed decreases in prepulse inhibition produced by scopolamine, apomorphine, and phencyclidine were also dependent on interstimulus interval duration. Scopolamine produced marked decreases in prepulse inhibition at the 100- and 300-ms interstimulus interval durations, but had little or no effect on prepulse inhibition at the 30- and 1000-ms interstimulus interval durations. In contrast, apomorphine decreased prepulse inhibition across all interstimulus interval durations while phencyclidine decreased prepulse inhibition across the 30- to 300-ms interstimulus interval durations. The present findings support the hypothesis that the muscarinic cholinergic system, like the dopaminergic and glutamatergic systems, is directly involved in the mechanisms of prepulse inhibition. However, these three neurotransmitter systems appear to modulate different aspects of prepulse inhibition.

Acoustic Stimulation↗
PubMed1999

Scopolamine prevents tolerance to the effects of caffeine on rotational behavior in 6-hydroxydopamine-denervated rats.

Continuous administration of caffeine has been shown to induce tolerance to its psychostimulant effects. In this study, using unilateral 6-hydroxydopamine nigrostriatal denervated rats, we tested the hypothesis that the muscarinic receptor antagonist, scopolamine, would prevent the tolerance to caffeine-induced contralateral rotational behavior. For that purpose we administered either caffeine (40 mg/kg) plus saline or scopolamine (5, 10 and 20 mg/kg) plus saline, as well as caffeine in combination with the various doses of scopolamine for 7 consecutive days, and measured ipsilateral and contralateral rotational behavior. The results showed that acute injections of scopolamine plus saline produced similar levels of both ipsilateral and contralateral turning, while caffeine produced more contralateral than ipsilateral turning. Tolerance to caffeine-induced contralateral turning was observed as of the second administration, while scopolamine plus saline injections did not produce significant changes in rotational behavior with repeated treatment. Scopolamine co-administered with caffeine significantly attenuated the increased contralateral turning produced by acute injections of caffeine plus saline, but significantly prevented the tolerance effects with repeated administration. These findings strongly suggest that muscarinic cholinergic processes may be involved in tolerance to caffeine-induced contralateral turning. The results are interpreted in terms of the possible interactions between dopamine, adenosine and acetylcholine neurotransmitter systems within the basal ganglia circuitry involved in motor behavior.

Animals↗
PubMed2003

Scopolamine-induced convulsions in fasted mice after food intake: determination of blood glucose levels, [3H]glutamate binding kinetics and antidopaminergic drug effects.

The present study was performed to evaluate the role(s) of hypoglycemia, changes in [(3)H]glutamate binding kinetics and dopaminergic activity in the occurrence of scopolamine-induced convulsions in fasted mice after food intake. Plasma glucose levels and density (B(max)) and affinity (K(d)) of [(3)H]glutamate binding sites in whole brain synaptic membranes were determined in animals fed ad lib or fasted for 48 h and treated intraperitoneally (i.p.) with 3 mg/kg scopolamine or saline and allowed to eat for 5 min. Fasting for 48 h decreased plasma glucose levels. After refeeding, plasma glucose concentrations increased in saline treated animals, but remained unchanged in scopolamine treated animals which consumed less food. Fasting for 48 h also produced significant changes in the kinetics of [(3)H]glutamate binding. The B(max) and K(d) of the binding sites decreased in fasted animals. These changes were partially antagonized by scopolamine treatment and food intake. For the evaluation of the contribution of dopaminergic activity, another group of mice fasted for 48 h and pretreated (i.p.) with saline or dopamine antagonists, 2 mg/kg chlorpromazine or 2 or 4 mg/kg haloperidol, were treated 10 min later with either saline or 3 mg/kg scopolamine. Then 20 min later, they were allowed to eat ad lib and were observed for 30 min for the incidence and onset of clonic convulsions. Pretreatment of both 2 mg/kg chlorpromazine and 4 mg/kg haloperidol markedly suppressed the convulsions. These results indicate that the decrease in the [(3)H]glutamate binding induced by fasting, its antagonism by scopolamine treatment and food intake, and the dopaminergic hyperactivity may be possible factors contributing to the occurrence of convulsions.

Animals↗
PubMed1997

Scopolamine impairs spatial working memory in the radial maze: an analysis by error type and arm choice.

The effects of scopolamine hydrobromide on performance in uninterrupted and delayed radial maze trials were studied in the rat. In addition to defining errors as incorrect arm entries, errors were defined by incorrect nose pokes in a food trough and were summed across the number of correct choices remaining. The average time elapsed from arm entry to nose poke was also calculated as a new measure of motivation and mobility. Working memory errors increased significantly following scopolamine injection in the uninterrupted trials and occurred significantly more often before the last correct choice. Errors in nonbaited arms during the last portion of a 3-h delay task increased significantly following scopolamine injection both before and after the first portion of the task and occurred more often before the last correct choice. However, nonbaited errors occurred more readily and at lower doses when scopolamine was injected 20 min before the onset of the task than when scopolamine was injected immediately after the completion of the first portion of the task. These data indicate that scopolamine affects current working memory and specifically affects acquisition more than consolidation of working memory.

Animals↗
PubMed1997

Free recall and recognition in a network model of the hippocampus: simulating effects of scopolamine on human memory function.

Free recall and recognition are simulated in a network model of the hippocampal formation, incorporating simplified simulations of neurons, synaptic connections, and the effects of acetylcholine. Simulations focus on modeling the effects of the acetylcholine receptor blocker scopolamine on human memory. Systemic administration of scopolamine is modeled by blockade of the cellular effects of acetylcholine in the model, resulting in memory impairments replicating data from studies on human subjects. This blockade of cholinergic effects impairs the encoding of new input patterns (as measured by delayed free recall), but does not impair the delayed free recall of input patterns learned before the blockade. The impairment is selective to the free recall but not the recognition of items encoded under the influence of scopolamine. In the model, scopolamine blocks strengthening of recurrent connections in region CA3 to form attractor states for new items (encoding impaired) but allows recurrent excitation to drive the network into previously stored attractor states (retrieval spared). Neuron populations representing items (individual words) have weaker recurrent connections than neuron populations representing experimental context. When scopolamine further weakens the strength of recurrent connections it selectively prevents the subsequent reactivation of item attractor states by context input (impaired free recall) without impairing the subsequent reactivation of context attractor states by item input (spared recognition). This asymmetry in the strength of attractor states also allows simulation of the list-strength effect for free recall but not recognition. Simulation of a paired associate learning paradigm predicts that scopolamine should greatly enhance proactive interference due to retrieval of previously encoded associations during storage of new associations.

Cholinergic Antagonists↗
PubMed1997

Attenuation of the locomotor activating effects of D-amphetamine, cocaine, and scopolamine by potassium channel modulators.

1. Locomotor activating effects of D-amphetamine, cocaine, and scopolamine were determined alone and after pretreatment with K-channel modulators in mice. 2. When administered alone, D-amphetamine (1.0- 30 mg/kg) and cocaine (3.0- 56 mg/kg) produced inverted U-shaped dose-effect curves characteristic of psychomotor stimulant drugs. 3. When administered alone, scopolamine (3.0-56 mg/kg) also produced dose-dependent increases in locomotor activity but these effects plateaued with similar increases in locomotor activity induced by 10-56 mg/kg of scopolamine. 4. Pretreatment with the K-channel blockers 4-aminopyridine (0.3-1.7 mg/kg), quinine (30-100 mg/kg) or apamin (0.3-1.0 mg/kg) attenuated the locomotor increases induced by d-amphetamine, cocaine, and scopolamine. 5. Like the K-channel blockers, pretreatment with the K-channel openers cromakalim (1.0-3.0 mg/kg) and pinacidil (3.0-10 mg/kg) also attenuated the locomotor increases induced by D-amphetamine and scopolamine but did not modify the locomotor activating effects of cocaine. 6. These results demonstrate that K-channel modulation modifies the effects of D-amphetamine, cocaine, and scopolamine. 7. The results also demonstrate that K-channel openers can differentially alter the behavioral effects of cocaine and D-amphetamine.

4-Aminopyridine↗
PubMed2002

Scopolamine but not lorazepam modulates face repetition priming: a psychopharmacological fMRI study.

Repetition priming is a basic form of learning associated with decreased neuronal responses following stimulus repetition. In this experiment, we address cholinergic and GABAergic modulation of repetition priming in a face recognition paradigm. In experiment 1, we used event-related functional magnetic resonance imaging (fMRI) in combination with pharmacological challenge where participants were given placebo, lorazepam (2mg po), or scopolamine (0.4 mg IV) prior to study. Behavioral data showed intact priming for famous faces in the placebo and lorazepam group but impaired priming following scopolamine. In within-group analyses, a right fusiform region showed a fame by repetition interaction characterized by a response decrease to repetition of famous faces and a response enhancement to repetition of unfamous faces in the placebo group. In subjects treated with lorazepam, a main effect of repetition, driven by response decreases to repetition of famous faces, was seen in this right fusiform region. No significant repetition effects were found after scopolamine. In experiment 2, we further investigated behaviorally the cholinergic impairment of repetition priming. Participants were given either placebo or scopolamine (0.4 mg IV) after study. Behavioral data showed intact priming for famous faces in the placebo and scopolamine group. The results suggest that scopolamine but not lorazepam impair repetition priming for famous faces in a face recognition paradigm. These cholinergic impairments are likely to reflect interference with acquisition processes during study that may co-occur with a modulation of right fusiform decreases to repetition of famous faces.

Acetylcholine↗
PubMed1999

Scopolamine alters rhesus monkey performance on a novel neuropsychological test battery.

Rhesus monkeys (6) were trained on a test battery including cognitive tests adapted from a human neuropsychological assessment battery (CANTAB; CeNeS, Cambridge, UK) as well as a bimanual motor skill task. The complete battery included tests of memory (delayed non-match to sample, DNMS; self-ordered spatial search, SOSS), reaction time (RT), motivation (progressive ratio; PR) and fine motor coordination (bimanual). The animals were trained to asymptotic performance in all tasks and then were administered two of the four CANTAB tasks on alternate weekdays (PR/SWM; DNMS/RT) with the bimanual task being administered on each weekday. The effect of acute administration of scopolamine (3-24 microg/kg, i.m.) on performance was then determined. Although performance on DNMS was impaired there was no interaction of drug treatment with retention interval, suggesting that scopolamine does not increase the rate of forgetting in this task. Scopolamine administration produced a decrement in SOSS performance that was dependent on task difficulty as well as dose. Scopolamine also impaired motor responses, resulting in increased time required to complete the bimanual motor task and increased movement time in the RT task. Performance in the PR task was decreased in a dose-dependent fashion by scopolamine. The results suggest that scopolamine interferes with memory storage and motor responses but not memory retention/retrieval or vigilance. The findings demonstrate that the test battery is useful for distinguishing the effects of neuropharmacological manipulation on various aspects of cognitive performance in monkeys.

Analysis of Variance↗
PubMed1985

Central cholinergic involvement in working memory: effects of scopolamine on continuous nonmatching and discrimination performance in the rat.

Rats were trained to stable baselines of lever pressing on a variable intertrial interval continuous nonmatching to sample schedule (CNM) or on an analogous discrimination schedule. Scopolamine reduced accuracy of CNM performance to a similar extent over the three intertrial (retention) intervals: 2.5, 5, and 10 s, results indicating that the drug did not affect the time-dependent process of retention in working memory. When baseline levels of performance accuracy were similar in the CNM and discrimination tasks (but stimulus discriminability was greater in the CNM task), scopolamine reduced accuracy equally in the two procedures. Effects of scopolamine on accuracy of noncorrection trial CNM performance were simulated by reducing stimulus discriminability; however, scopolamine disrupted CNM correction trial performance much more than did reductions in stimulus discriminability. It is concluded that scopolamine's effects on working memory are not limited to possible effects on stimulus discrimination: Scopolamine may also affect retrieval of response rules from reference memory.

Animals↗
PubMed2003

Scopolamine impairs human recognition memory: data and modeling.

Eight subjects studied a set of complex visual images after administration of 0.4 mg scopolamine. Another 8 subjects performed the same task without drug administration. On a subsequent item recognition test, subjects rated, on a 5-point scale, their confidence that the studied pictures and an equal number of unstudied lures were actually presented. Results showed that scopolamine affected responses to studied items, but not unstudied lures, demonstrating an unambiguous effect of scopolamine on recognition memory. To describe the scopolamine-injected subjects' data, the authors constructed a new model of 2-process recognition that includes the A. P. Yonelinas (1994) model as a limiting case. The model analysis suggests that scopolamine affected both familiarity and recollection. In particular, scopolamine did not affect the frequency with which recollection took place, but rather, affected the amount of recollected information.

Adult↗
PubMed1991

No causal relationship between transdermal scopolamine and seizures: methodologic lessons for pharmacoepidemiology.

Because of case reports suggesting that use of transdermal scopolamine might be associated with the subsequent development of seizures, a retrospective cohort study was performed with computerized Medicaid claims data. Patients receiving transdermal scopolamine were compared with patients receiving diphenhydramine, meclizine, prochlorperazine, and promethazine. A four-fold increased risk of seizures after transdermal scopolamine use was observed in the claims data. However, this was not supported by the primary medical records. All patients who had seizures after using transdermal scopolamine either had seizures before receiving the drug as well or did not really suffer from seizures. The original finding appeared to be the result of the use of transdermal scopolamine for "dizziness, rule out seizures"; the ICD-9-CM coding system does not include "rule out" diagnoses. Thus these data do not confirm the existence of an association between seizures and the use of transdermal scopolamine. In addition, this study demonstrates the usefulness of pharmacoepidemiology studies in documenting drug safety and the importance of obtaining primary medical records when performing pharmacoepidemiologic studies with claims data.

Administration, Cutaneous↗
PubMed1992

In vivo muscarinic cholinergic receptor imaging in human brain with [11C]scopolamine and positron emission tomography.

Cerebral muscarinic cholinergic receptors were imaged and regionally quantified in vivo in humans with the use of [11C]scopolamine and positron emission tomography. Previous studies in experimental animals have suggested the utility of radiolabeled scopolamine for in vivo measurements, on the bases of its maintained pharmacologic specificity following systemic administration and the exclusion of labeled metabolites from the brain. The present studies describe the cerebral distribution kinetics of [11C]scopolamine in normal subjects following intravenous injection. Scopolamine is initially delivered to brain in a perfusion-directed pattern. After 30 to 60 min, activity is lost preferentially from cerebral structures with low muscarinic receptor density including the cerebellum and thalamus. Activity continues to accumulate throughout a 2 h postinjection period in receptor-rich areas including cerebral cortex and the basal ganglia. The late regional concentration of [11C]scopolamine does not, however, accurately parallel known differences in muscarinic receptor numbers in these receptor-rich areas. Tracer kinetic analysis of the data, performed on the basis of a three-compartment model, provides receptor binding estimates in good agreement with prior in vitro measurements. Kinetic analysis confirms significant contributions of ligand delivery and extraction to the late distribution of [11C]scopolamine, reconciling the discrepancy between receptor levels and tracer concentration. Finally, a novel dual-isotope method for rapid chromatographic processing of arterial blood samples in radiotracer studies is presented. The combination of rapid chromatography and compartmental analysis of tracer distribution should have broad utility in future in vivo studies with short-lived radioligands.

Brain↗
PubMed2000

Low doses of 8-OH-DPAT prevent the impairment of spatial learning caused by intrahippocampal scopolamine through 5-HT(1A) receptors in the dorsal raphe.

1. We studied the effects of low doses of 8-OH-DPAT, a 5-HT(1A) receptor agonist, on the impairment of spatial learning caused by scopolamine injected into the CA1 region of the dorsal hippocampus of rats performing a two-platform spatial discrimination task. 2. Bilateral injections of 4 microg (in 1 microl) of scopolamine into the CA1 region of the dorsal hippocampus 10 min before each training session impaired choice accuracy with no effect on choice latency and errors of omission. 3. Administered subcutaneously 20 min before each training session, 8-OH-DPAT 10 and 30 (but not 3) microg kg(-1) did not modify choice accuracy but prevented the impairment by intrahippocampal scopolamine. 4. Injection of 1.0 microg (in 0.5 microl) of WAY 100635, a 5-HT(1A) receptor antagonist, into the dorsal raphe 5 min before scopolamine had no effect on choice accuracy and latency or errors of omission and did not modify the effect of scopolamine, but completely antagonized the effect of 10 and 30 microg kg(-1) 8-OH-DPAT on scopolamine-induced impairment of choice accuracy. 5. The results confirm previous findings that stimulation of presynaptic 5-HT(1A) receptors in the dorsal raphe attenuates the deficit of spatial learning caused by blockade of cholinergic excitatory input on hippocampal pyramidal cells. 6. Drugs that stimulate presynaptic 5-HT(1A) receptors such as 5-HT(1A) receptor partial agonists may be useful in the symptomatic treatment of human memory disturbances associated with loss of cholinergic innervation to the hippocampus.

8-Hydroxy-2-(di-n-propylamino)tetralin↗