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PubMed2004

Free operant and discrete trial performance of mice in the nine-hole box apparatus: validation using amphetamine and scopolamine.

RATIONALE: To determine the suitability of the nine-hole box to characterise mouse performance on a free operant task and a discrete trials task, and to validate the tests by probing whether d-amphetamine and scopolamine modify performance of the task as predicted. OBJECTIVES: To demonstrate the functionality and efficiency of the mouse nine-hole box for the evaluation of performance under fixed- (FR) and progressive-ratio (PR) operant schedules, as well as under a three-choice visual discrimination task and subsequent reversals of the task. In addition, sensitivity of the apparatus was assessed using pharmacological challenges. METHODS: C57BL/6J were tested on CRF, FR5, FR10, FR20, and a modified PR3 schedule. Behavioural response to d-amphetamine sulphate (0.1, 0.3, and 2.0 mg/kg for FR and 0.1, 0.3, and 1.0 mg/kg for PR) was assessed. In a separate group of mice trained on a three-choice visual discrimination task, the task was reversed (light+, dark+, light+, dark+) 3 times to determine acquisition and reversal of the visual discrimination rule. Scopolamine hydrobromide was examined in this paradigm with the reversal task, and was used to determine learning acquisition and rule reversal learning. RESULTS: Mice rapidly acquired the FR and PR schedules, as well as both three-choice visual discrimination procedures in the nine-hole box. d-Amphetamine significantly reduced performance on the FR5 and FR10 schedules as shown by the reduction in the number of rewarded responses and the increases in various latency measurements. As expected, d-amphetamine induced an increase in the break point and eliminated the pauses that occurred on high ratio schedules under the PR3 paradigm. Pretreatment of scopolamine decreased accuracy in the three-choice visual discrimination task. CONCLUSIONS: The nine-hole box is an effective tool to assess operant behaviours in mice following pharmacological manipulation validating the utility of this apparatus for the behavioural evaluation of drug-induced and transgenic models of neurodegenerative disorders.

Amphetamine↗
PubMed1997

Mecamylamine- or scopolamine-induced learning impairment: ameliorated by nefiracetam.

Nefiracetam is undergoing preclinical and clinical tests as a cognition-enhancing drug in Alzheimer's disease (AD). Nicotinic cholinergic receptors are lost in AD, and nicotinic as well as muscarinic cholinergic receptors are involved in the modulation of eyeblink conditioning. Experiments were carried out using young rabbits to examine the effect of nefiracetam on cholinergic antagonists to nicotinic (mecamylamine) and muscarinic (scopolamine) receptors. Rabbits were tested for 15 days in the 750 ms delay eyeblink classical conditioning paradigm in paired and explicitly unpaired conditions. Nefiracetam at a dose of 15 mg/kg significantly ameliorated the effects of 0.5 mg/kg mecamylamine, and nefiracetam at a dose of 10 mg/kg significantly ameliorated the effect of 1.5 mg/kg scopolamine. The vehicle alone and nefiracetam alone groups performed similarly to the groups treated with mecamylamine or scopolamine and nefiracetam. Reversal by nefiracetam of a nicotinic as well as a muscarinic cholinergic antagonist indicates that the drug may affect deficits specific to AD.

Animals↗
PubMed2004

Transdermal scopolamine use for post-rhytidectomy sialocele.

BACKGROUND: Post-rhytidectomy sialocele is a rare complication. The usual treatment uses prolonged drainage. The use of antisialogogues has been described previously, but has potential side effects. Transdermal scopolamine SCOPODERM TTS is indicated for the prevention of motion sickness and also has antisialogugue action. METHODS: An interventional case report is presented. RESULTS: The application of transdermal scopolamine SCOPODERM TTS resulted in resolution of a post-rhytidectomy sialocele within 6 days. CONCLUSION: Transdermal scopolamine delivery should be considered as an option for the treatment of post-rhytidectomy parotid fistulas.

Administration, Cutaneous↗
PubMed1991

The effects of scopolamine on sleep and mood in depressed patients with a history of alcoholism and a normal comparison group.

In order to determine the effect of an anticholinergic agent on mood and sleep, scopolamine (0.4 mg IM) was administered before bedtime for three consecutive nights to 10 depressed patients (8 with a history of alcohol abuse) and 10 normal comparison subjects. The patients had a small, statistically significant antidepressant response on the second morning of treatment. Scopolamine inhibited rapid eye movement (REM) sleep and prolonged REM latency equally in depressed patients and the normal comparison group. Partial tolerance to the REM inhibiting effect of scopolamine developed between the first and third night of treatment. A REM rebound occurred during recovery nights. These results are consistent with concepts relating central cholinergic mechanisms to the control of REM sleep. Compared with controls, patients showed a greater increase in Stage 2 and Stage 2% and a lesser and increase in Delta (Stage 3 and 4) sleep % and Stage 4% on the first night of treatment. Further, well-controlled studies are needed to determine whether anticholinergic drugs possess clinically significant antidepressant effects.

Adult↗
PubMed1995

Effects of scopolamine infusions into the anterior and posterior cingulate on passive avoidance and water maze navigation.

We examined the role of anterior and posterior cingulate cortical muscarinic receptors in water maze spatial learning and passive avoidance. Pretraining and posttraining trial scopolamine (a mixed a muscarinic acetylcholine antagonist) infusions into the anterior cingulate cortex dose dependently (3 no effect; 10 and 30 micrograms impaired) impaired passive avoidance performance. Pretesting infusion into the anterior cingulate had no effect on passive avoidance. Scopolamine infusion into the anterior cingulate did not impair spatial navigation. On the contrary, scopolamine (3 micrograms no effect, 10 and 30 micrograms impaired) infusions into the posterior cingulate before daily training trials impaired water maze navigation to a hidden platform, but did not affect navigation to a visible escape platform or passive avoidance. Posttraining and pretesting infusion into the posterior cingulate did not impair WM spatial navigation. The present results indicate that muscarinic acetylcholine receptor antagonist may modulate passive avoidance performance via cholinergic receptors located in anterior cingulate cortex and the ability to develop a spatial navigation strategy via muscarinic receptors located in posterior cingulate.

Analysis of Variance↗
PubMed1976

Differential attenuation of some effects of haloperidol in rats given scopolamine.

In a series of pharmacological tests the ability of 0.6 mg/kg of the anticholinergic scopolamine to decrease the effectiveness of the neuroleptic heloperidol varied widely. Most severely attenuated was production of catalepsy followed in order of decreasing interference by inhibition of amphetamine-induced rotation, inhibition of amphetamine- or apomorphine-induced stereotyped behavior, inhibition of conditioned avoidance responding and lastly attenuation of the haloperidol-induced increase in striatal HVA. By use of such a relatively low dose of scopolamine the behavioral effects of heloperidol were dissociated from effects on dopamine turnover in the striatum. If behavioral tests in animals can be related to the clinical effects of neuroleptic drugs, those effects of haloperidol severely reduced by scopolamine may be related to extrapyramidal effects.

Amphetamine↗
PubMed1989

Atropine- and scopolamine-resistant subtypes of muscarinic receptors in the rabbit aorta.

Tritiated acetylcholine ([3H]ACh) binds specifically to different muscarinic binding sites in the rabbit aorta. The binding of [3H]ACh to endothelial membranes was displacable by nanomolar concentrations of scopolamine but only by micromolar concentrations of atropine and homatropine. The reverse was true for smooth muscle membranes, i.e. [3H]ACh binding was displacable by nanomolar concentrations of atropine and homatropine but only by micromolar concentrations of scopolamine. Pirenzepine, AF-DX 116 and 4-diphenyl-acetoxy-N-methylpiperidine methobromide (4-DAMP) displaced the binding of [3H]ACh from both tissues in the nano- to micromolar range. Our findings indicate that endothelial receptors are characterised by a high affinity for scopolamine, which possesses a scopine base, and that muscle binding sites have a high affinity for antagonists possessing a tropine base (atropine, homatropine). Both the endothelial and smooth muscle binding sites have a low affinity for AF-DX 116, indicating that they are not of the cardiac type.

Animals↗
PubMed1990

Effects of azaprophen, scopolamine and trihexyphenidyl on schedule-controlled behavior, before and after chronic physostigmine.

The effects of the muscarinic acetylcholine receptor antagonists, azaprophen (0.3-10.0 mg/kg), scopolamine (0.01-3.0 mg/kg) and trihexyphenidyl (0.3-10.0 mg/kg) were examined in rats using a VI 18 s schedule of food reinforcement, before and after chronic physostigmine administration. All three compounds produced dose-dependent decreases [corrected] in the rate of responding. Scopolamine was more potent than trihexyphenidyl which was equipotent to azaprophen. All three compounds antagonized the response rate-decreasing effects of physostigmine in a dose-dependent fashion. Following 43 consecutive daily administrations of physostigmine (0.4 mg/kg), partial tolerance developed to its response rate-decreasing effects. When the three antagonists were again examined (alone and in combination with physostigmine), their effects were generally unchanged. These results further characterize the behavioral effects of azaprophen, scopolamine and trihexyphenidyl. These results also suggest that tolerance to physostigmine's effects can be mediated through behavioral rather than pharmacological mechanisms.

Acetylcholine↗
PubMed1992

L-alpha-glycerylphosphorylcholine antagonizes scopolamine-induced amnesia and enhances hippocampal cholinergic transmission in the rat.

The effects of L-alpha-glycerylphosphorylcholine (alpha-GPC) on scopolamine-induced memory impairment and on brain acetylcholine (ACh) synthesis and release were investigated in rats. Oral administration of alpha-GPC 3 h before the behavioural test prevented the learning impairment induced by scopolamine given 30 min before the acquisition of a passive avoidance response. Similarly, retrograde amnesia induced by scopolamine, given immediately after acquisition training, was also completely reversed by the drug. These effects were dose-dependent with a maximum at 300 mg/kg. The mechanism of action of this compound was investigated by measuring hippocampal ACh synthesis and release both in vivo by means of the microdialysis technique and in vitro in tissue slices. alpha-GPC dose dependently increased ACh release with a maximum at 300 mg/kg. In addition, i.v. injection of [14C]alpha-GPC resulted in [14C]ACh formation. The data suggest that the behavioural effects of alpha-GPC may be related to its property to increase hippocampal ACh synthesis and release.

Acetylcholine↗
PubMed1993

Impairment of working memory induced by scopolamine in rats with noradrenergic DSP-4 lesions.

In a working memory task with a three-panel runway set-up, DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine), a noradrenergic neurotoxin, at 50 mg/kg i.p. given 14 days before testing, had no effect on the number of errors (attempts to pass through two incorrect panels of the three-panel gates at four choice points). Working memory errors were significantly increased by scopolamine, a muscarinic receptor antagonist, at 0.32 mg/kg i.p. given 20 min before testing, whereas errors were not affected by the 0.1 mg/kg dose. In rats with noradrenergic DSP-4 lesions, 0.1 mg/kg scopolamine significantly increased the number of working memory errors. However, DSP-4 at 50 mg/kg and scopolamine at 0.1 mg/kg whether they were administered alone or in combination had no effect on reference memory errors. These results suggest that noradrenergic deficits aggravate the working memory impairment induced by blockade of muscarinic receptors.

Animals↗
PubMed1995

Dynorphin A-(1-13) potently improves scopolamine-induced impairment of passive avoidance response in mice.

The effects of intracerebroventricular administration of dynorphin A-(1-13) on scopolamine-induced amnesia were investigated in mice by using a step-down type passive avoidance task. The pre- or post-training, or pre-retention administration of dynorphin A-(1-13)(0.3-10 micrograms) alone failed to affect step-down latency of the passive avoidance response, while scopolamine (1 mg/kg) significantly shortened step-down latency. Dynorphin A-(1-13)(1 microgram) given 15 min before training and retention tests but not immediately after training significantly improved the scopolamine (1 mg/kg)-induced shortening of step-down latency of the passive avoidance response, indicating antiamnesic effects of dynorphin A-(1-13) (1 microgram). A lower dose (1 mg/kg) of the kappa-opioid receptor antagonist, (-)-(1R,5R,9R)-5,9-diethyl-2-(3-furyl-methyl)- 2'-hydroxy-6,7-benzomorphan, reversed the anti-amnesic effects of dynorphin A-(1-13) (1 microgram). These results suggest that the antiamnesic effects of dynorphin A-(1-13) depend on the timing of drug treatments.

Amnesia↗
PubMed1995

(S)-WAY 100135, a 5-HT1A receptor antagonist, prevents the impairment of spatial learning caused by intrahippocampal scopolamine.

Scopolamine, 3.75 micrograms/microliters infused bilaterally into the CA1 region of the dorsal hippocampus 10 min before each training session, impaired choice accuracy but had no effect on choice latency or errors of omission in rats trained in a two-platform spatial discrimination task. Administered subcutaneously at 3 and 10 mg/kg 30 min before each training session, N-tert-butyl-3-4-(2-methoxyphenyl)piperazin-1-yl-2-phenylpropanami de dihydrochloride ((S)-WAY 100135), a 5-HT1A receptor antagonist, prevented the impairment of choice accuracy induced by intrahippocampal scopolamine. No subcutaneous dose of (S)-WAY 100135 by itself modified the acquisition of spatial learning. Administered into the dorsal hippocampus 15 min before each training session, (S)-WAY 100135 at doses of 0.2, 1 and 5 micrograms/microliters did not affect the acquisition of spatial learning but dose dependently prevented the impairment of choice accuracy caused by scopolamine, 3.75 micrograms/microliters infused into the same area. These findings suggest that blockade of 5-HT1A receptors can compensate the loss of cholinergic excitatory input on pyramidal cells, probably by favouring the action of other excitatory transmitters.

Animals↗
PubMed1987

Effects of treatment with scopolamine and naloxone, singly and in combination, on amygdala kindling.

Scopolamine and naloxone were administered singly and in combination to different groups of rats undergoing electrical kindling of the amygdala. Scopolamine significantly reduced the maximal seizure stage attained during 15 drug sessions and increased the total number of afterdischarges required to kindle a generalized convulsion. Naloxone had a similar but weaker and nonsignificant effect. The results confirm that antagonism of muscarinic receptors by scopolamine retards amygdala kindling.

Amygdala↗
PubMed1993

Two-step epoxidation of hyoscyamine to scopolamine is catalyzed by bifunctional hyoscyamine 6 beta-hydroxylase.

In several solanaceous plants, hyoscyamine is first hydroxylated at the 6 beta-position, and then epoxidized to scopolamine. We expressed hyoscyamine 6 beta-hydroxylase (H6H) in Escherichia coli as a fusion protein with maltose-binding protein. The crude cell extract from the bacterium that expressed the soluble fusion protein showed a strong hydroxylase activity and a weak epoxidase activity. When 100 microM of hyoscyamine was fed to the recombinant bacterium, the alkaloid was first converted to 6 beta-hydroxy hyoscyamine, and then to scopolamine, which was almost the only alkaloid found in the culture after one week. Therefore, H6H catalyzes two consecutive reactions that oxidize hyoscyamine to scopolamine.

ATP-Binding Cassette Transporters↗
PubMed1994

Metabolic effects of scopolamine and physostigmine in human brain measured by positron emission tomography.

Two of the more consistent findings in Alzheimer's disease are depressions in frontal and temporoparietal glucose metabolism and a loss of cholinergic neurons in the nucleus basalis of Meynert. Nonetheless, cholinergic replacement strategies have had only minimal therapeutic successes. Whether this situation reflects the limited contribution of cholinergic deafferentation to the intellectual decline or the meager ability of the pharmaceuticals tested to exert their intended pharmacologic action remains unclear. To address this question, the distribution of cerebral abnormalities found in untreated Alzheimer patients, as revealed by positron emission tomography following 18F-fluorodeoxyglucose, were compared with the pattern of functional changes produced by drugs that block or stimulate cholinergic function. Physostigmine was administered to 6 Alzheimer patients to increase brain cholinergic neurotransmission. The anticholinergic scopolamine, given to normal volunteers, was administered to 6 age-matched controls. These data were compared to those obtained from the same subjects while receiving placebo. Amnestic doses of the anticholinergic, scopolamine increased glucose metabolism by up to 20% (p < 0.001) in all brain regions studied, except thalamus. This response contrasted with the metabolic reductions of up to 17% (p < 0.01), especially in parietal and frontal association cortices, occurring in unmedicated Alzheimer patients. Maximum tolerated doses of the anti-cholinesterase, physostigmine, rather than tending to normalize abnormalities in these patients, further reduced cerebral metabolism (p < 0.01) and increased metabolism in thalamus in a pattern inversely correlated (p < 0.001) with that produced by scopolamine. These results fail to support a cholinergic basis for the abnormal metabolic pattern in Alzheimer's disease.

Aged↗
PubMed1991

Induction of cognitive impairment by scopolamine and noncholinergic agents in rhesus monkeys.

In primates, treatment with scopolamine impairs performance of a spatial delayed response task in a way which mimics deficits seen spontaneously in aged primates and demented patients. Despite their efficacy in reversing scopolamine induced disruption, the effects of cholinergic agonists on cognition in aged primates and dements are unimpressive, suggesting that other neurotransmitter systems are also involved in this type of deficit. We have induced a scopolamine-like impairment of spatial delayed response performance in rhesus monkeys using phencyclidine (0.1-0.2 mg/kg i.m.), lorazepam (0.4-0.6 mg/kg s.c.) or tetrahydrocannabinol (1-4 mg/kg p.o.), but not amphetamine (0.1-0.4 mg/kg i.m.), yohimbine (0.1-1.0 mg/kg i.m.) or morphine (2-4 mg/kg i.m.). Our findings suggest that disruption of specific neurotransmitter systems other than acetylcholine may contribute importantly to cognitive decline in aging and dementia.

Amphetamine↗
PubMed1994

Scopolamine effects on the pressor response to thyrotropin-releasing hormone in humans.

Thyrotropin-releasing hormone (TRH) produces a marked pressor effect, which may be mediated by central cholinergic neurons, which in turn enhance sympathetic nervous system activity. In this study, 22 subjects (10 patients with Alzheimer's disease and 12 elderly controls) were administered IV scopolamine or placebo prior to administration of IV high-dose TRH (0.5 mg/kg). Systolic blood pressure was less on the day scopolamine was administered prior to TRH administration, as compared with placebo (F[1,20] = 6.12, p < 0.02). Results indicate that the pressor effect of TRH is attenuated by scopolamine, indicating a role of the cholinergic system in this response in humans.

Aged↗
PubMed1995

Scopolamine prevents the development of sensitization to methamphetamine.

The cholinergic neurotransmission has been implicated in various forms of neural plasticity such as kindling and learning. The present study examined the effects of scopolamine, a muscarinic cholinergic antagonist, on the development of behavioral sensitization to methamphetamine (MA). Rats treated with MA (1 mg/kg, sc) for 10 days indicated significantly enhanced motor activity when tested with MA (0.5 mg/kg) after a 7-8 day withdrawal, indicating the development of behavioral sensitization. Pretreatment with scopolamine (3 mg/kg) prior to MA administration prevented the development of the phenomenon. Rats treated with scopolamine alone showed no difference in the motor activity compared to those treated with saline. These results suggest that stimulation of muscarinic cholinergic receptors plays a role in the development of behavioral sensitization.

Animals↗