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We studied short-term effectiveness of transdermal scopolamine in a group of patients with unexplained syncope provoked during head-up tilt testing. This double-blind randomized trial of transdermal scopolamine demonstrated no significant effect of preventing vasovagal syncope.
In contrast to sleep studies of adult depressives that have consistently demonstrated abnormalities of sleep continuity, slow-wave sleep, and REM sleep, existing studies of depressed children and adolescents have been conflicting. Furthermore, only one study has explored the cholinergic regulation of sleep in early-onset depressives. In the present study, the electroencephalographic sleep of 20 adolescent outpatients with major depressive episodes and 13 normal control adolescents was obtained on two separate 2-night sessions, 1 night incorporating challenge with scopolamine. Depressed adolescents showed increased baseline phasic REM sleep measures, increased arousals, a trend toward reduced slow-wave sleep, and a greater difference in the change of first REM period density on the scopolamine night versus placebo night compared to controls. These findings support the continuity of some sleep abnormalities of depression into adolescence, and suggest that adolescent depression may be associated with alterations of cholinergic neurotransmission in some patients.
Using immunohistochemical technique, we investigated the regionally different roles of muscarinic receptors in the induction of HSP-70 by NMDA receptor antagonists. The administration of memantine and phencyclidine induced HSP-70 in the retrosplenial cortex of rat brain. Pretreatment with the muscarinic receptor antagonist scopolamine (0.1-1 mg/kg) blocked induction of HSP-70 in layer III of the retrosplenial cortex. However, induction of HSP-70 in layer V was augmented by scopolamine. These results suggest a regional difference in the mechanism of neurotoxicity induced by NMDA receptor antagonists.
The present study investigated the effects of the putative adenosine A1 receptor antagonist BIIP 20 ((S)-(-)-8-(3-oxocyclopentyl)-1,3-dipropyl-7H-purine-2,6-dione) on counteracting scopolamine-induced behavioral deficits in the rat in the passive avoidance paradigm. A single oral application of BIIP 20 (1 and 3 mg/kg) 90 min before the rats received the noxious stimulus significantly attenuated the scopolamine-induced deficits observed during the retention trial of this task.
The supercritical fluid extraction behaviors of hyoscyamine and scopolamine were investigated and found to be highly dependent upon the chemical nature of the compounds. Free bases of hyoscyamine and scopolamine were freely soluble in supercritical CO2 with increasing temperature and pressure; however, the salts of these alkaloids were not soluble under any experimental conditions. It was found that alkaline modifiers such as methanol basified with diethylamine could enhance the solubilities and extraction yields of these alkaloids from plant matrices as compared to other modifiers.
We examined memory improvement with respect to the effects of gastrin-releasing peptide (GRP) in male C57BL/6J mice under conditions of experimentally induced amnesia. GRP was administered following training in a one-trial passive avoidance test. In Experiment 1, the drug scopolamine (1 or 2 mg/kg, ip) was used to induce amnesia prior to training, and GRP (32 nmol/kg, ip) or saline (control) was administered immediately after training. Results indicate that GRP at this dose improved memory only when the dosage of scopolamine was relatively low (1 mg/kg). In Experiment 2, CO2-induced amnesia was employed. Mice were placed in a chamber filled with CO2 or air (control) immediately after acquisition training. Subsequently, they were administered either saline or GRP (32 nmol/kg, ip). Significantly longer light-dark latency was observed in all mice that received GRP (both experimental and control groups). In total, our results indicate that the effect of GRP at this dose on the improvement of impaired memory is dependent on the degree of impairment. Furthermore, because CO2-induced hypoxia is known to decrease acetylcholine release in the brain, our results also suggest that GRP and its receptor may interact with the cholinergic system in the central nervous system.
A combined treatment of a 3-day regimen of pCPA and low-dose scopolamine produced a significant deficit in the acquisition of a water maze task, which has been suggested as a model for the cognitive deficits of Alzheimer's disease. The putative cognition enhancers oxotremorine, captopril, ondansetron, and tacrine were used in attempts to alleviate the water maze impairment. The effects of oxotremorine were difficult to determine due to nonspecific motor effects causing alterations in swimming speed. No evidence for cognition-enhancing properties of captopril was found. Ondansetron showed a cognition-enhancing effect on one of 4 days, but only at a relatively high dose (1 mg/kg i.p.). Tacrine, however, alleviated the pCPA + scopolamine-induced cognitive deficit. This study may thus provide evidence for the usefulness of tacrine in treating spatial deficits in dementia.
CD-1 mice received daily subcutaneous injections of either cocaine (20 mg/kg or 40 mg/kg) or saline solution (0.9% NaCl) from postnatal days 2 to 15. Pups were tested on days 16-17 for learning and 24-h retention of a passive avoidance task, where entering a dark compartment was punished with a mild foot shock. Locomotor activity and general behaviour in an open field arena were assessed on day 21, following administration of either the muscarinic blocker scopolamine (0.8 mg/kg) or saline solution. In addition, immunostaining for the enzyme choline acetyltransferase (ChAT) was measured in different basal forebrain areas (medial septum, striatum, and nucleus basalis) on day 30. Cocaine treatment failed to affect either learning or retention capabilities. Nonetheless, neophobic behaviour during the learning session was enhanced in control nonpunished mice exposed to the 20-mg/kg dose. In the open field test, although baseline activity levels were unaffected by cocaine exposure, the 40-mg/kg cocaine-treated pups showed decreased sensitivity to the hyperkinetic effects of scopolamine. ChAT immunocytochemistry revealed a significant reduction of the number of ChAT-immunopositive neurons in the nucleus basalis but not in the other cholinergic basal forebrain regions.
The present study investigated the effects of scopolamine hydrobromide (SCOP: 0.06-1.0 mg/kg IP) and its quartenary analogue, scopolamine methylbromide (SCOPMB), on performance in a radial arm maze foraging task, to dissociate general drug-induced alterations of motor performance from measurement of impairments on more complex behaviors involving timing and memory. In this paradigm. rats are trained to free run a radial maze under an eight-alternative concurrent fixed-interval (FI) schedule of food reinforcement. The eight FIs (55 to 759 s) were assigned randomly to the arms of the maze, with a different pattern for each animal. SCOP produced dose-dependent degradation in response patterning and response rates in the concurrent FI schedules without significantly affecting the rates of arm entries or arm traversal latencies. The peripheral cholinergic antagonist, SCOPMB, generally produced small to moderate depressions in all measures with the exception of patterning of arm entries and pellets earned, but there were no clear dose-response relationships evident in the data. These results are consistent with the notion that central cholinergic mechanisms are involved in the mediation of complex conditioned behaviors.
The aim of the present experiments was to test the role played by the interaction of the selective H3 receptor antagonist, thioperamide, with the cholinergic, histaminergic, and serotonergic systems in modifying memory. The behavioral tests used (open-field and passive-avoidance repetition) were selected on the basis of the action displayed by thioperamide in these behavioral situations. Posttrial administration of thioperamide (5 mg/kg) resulted in an improvement in memory consolidation, as tested in the repetition of the open-field test, but repeated posttrial administration of thioperamide (2 or 5 mg/kg) had no effect in the repetition of passive avoidance test. Scopolamine (2 mg/kg) caused a deterioration in the memory processes in both tests: this effect was blocked by 2 mg/kg of thioperamide, which was itself ineffective in the test. These results may suggest that both the improvement in memory due to thioperamide and its antagonism of the amnestic effects of scopolamine are determined by activation of central cholinergic systems, due to thioperamide inhibition of H3 heteroreceptors. Diphenhydramine (2 or 10 mg/kg) was itself ineffective in the tests, but counteracted the memory improvement caused by thioperamide in the repetition of the open-field test. The effect of diphenhydramine is discussed in terms of interactions between histaminergic and cholinergic systems. Methysergide counteracted the effect of thioperamide in the open-field test only at a high dosage (50 mg/kg). The possible implication of serotonergic systems on the effects of the methysergide-thioperamide interaction in the memory process is discussed.
The visual recognition of rhesus monkeys was evaluated by means of a delayed nonmatching-to-sample task with trial-unique objects. Each daily session consisted of two lists of 20 objects each, which untreated animals were able to recognize at approximately 75% accuracy. When they were performing at this level reliably, doses of physostigmine (0.32, 1.0, 3.2, 10.0, 32.0, 56.0 micrograms/kg), scopolamine (1.0, 3.2, 5.6, 10.0, 17.8, 32.0 micrograms/kg), or saline were administered 20 min prior to the session. Physostigmine and scopolamine produced dose-related increases and decreases, respectively, in the number of objects correctly remembered. The systematic changes in performance support the view that cholinergic mechanisms contribute to recognition memory and suggest that tasks with trial-unique objects may be particularly useful for studying the mnemonic effects of cholinergic drugs.
The pre-test administration of beta-endorphin (0.05 microgram/mouse), oxotremorine sesquifumarate (5.0 micrograms/mouse), or beta-endorphin plus oxotremorine enhanced retention test performance of a conditioned emotional response in mice. The effects were blocked by scopolamine. Scopolamine had no effect of its own. The data suggest that the retention enhancement caused by beta-endorphin may involve the secondary activation of cholinergic mechanisms.
Several reports have indicated that, under different experimental conditions, the administration of histamine H(3)-receptor antagonists exerts procognitive effects by activating central histaminergic transmission. In the present study the action of thioperamide, a H(3)-receptor blocker, is investigated on consolidation and recall mechanisms of the rat place recognition memory. The animals have been tested on a two-trial delayed comparison paradigm in a Y-maze. Thioperamide enhances the memory retention when administered intraperitoneally (i.p.) post-acquisition (0.7 and 5.0 mg/kg are ineffective, whereas the dose of 2.0 mg/kg improves memory) but does not affect the rat performance when injected 45 min prior to the testing trial. The post-acquisition effect of thioperamide is time-dependent since the administration of the drug 30 min after the end of the training trial has no effect on memory. In addition, thioperamide reverses the amnesia induced by the post-acquisition treatment with 0.02 mg/kg i.p. of scopolamine (SCOP). The procognitive effect of thioperamide is not modified by the contemporary administration of pyrilamine, an histamine H(1)-receptor antagonist. On the contrary, the blockade of H(2)-receptors by zolantidine 10 mg/kg reverses both the effect of thioperamide alone and the drug action on the scopolamine-induced memory deficit. The results indicate that the neuronal histamine released in consequence of the post-acquisition thioperamide treatment improves place recognition memory through the activation of postsynaptic H(2)-receptors.
In this series of experiments, we examined the ability of post-training glucose injections to improve memory of the Balb/cAnNCrlBR strain of mice for a bar-pressing task. We could not replicate this effect which has been demonstrated in many other strains of mice including Balb/cbyJ, a related strain. We found that the Balb/cAnNCrlBR strain of mice is also much less sensitive to the disrupting effects produced by pre- or post-training injections of the competitive cholinergic antagonist scopolamine. This strain also shows altered glucoregulation compared to the Balb/cbyJ strain. The absence of glucose effects on memory in Balb/cAnNCrlBR mice appears to be associated with decreased sensitivity to cholinergic antagonists. These results can be contrasted with previous ones obtained in a related strain, the Balb/cbyJ, in which glucose was shown to improve memory while scopolamine could easily disrupt memory processes. Taken together, these data provide additional indirect support for the hypothesis that glucose improvement of memory is closely linked to a functional interaction with central cholinergic systems. The comparison of these two strains could be the basis for a useful animal model to investigate the relationship between age-related changes in memory and central cholinergic function.
Twelve young rabbits (3-6 months; Oryctolagus cuniculus) were classically conditioned in a trace jaw movement paradigm (300 ms tone, 450 ms trace, 200 ms intraoral water) after implantation of electrodes into area CA1 of dorsal hippocampus. Rabbits were divided into two groups and administered either 0.5 mg/kg scopolamine hydrobromide (HBr) or 0.5 mg/kg scopolamine methylbromide (MBr) subcutaneously before daily training sessions. Rabbits given HBr took significantly more trials to reach a behavioral criterion of eight conditioned responses in any nine consecutive trials than rabbits given MBr (P = 0.03). Conditioned, but not unconditioned, rhythmic jaw movement responses of the HBr group were of a lower frequency (Hz) than those of MBr rabbits (P = 0.02). The magnitude of hippocampal conditioning-related responses across the first 3 days of training was significantly smaller for HBr rabbits than for MBr rabbits (P = 0.02). These effects of central cholinergic blockade are similar to those reported for undrugged aging rabbits trained in the same paradigm (Seager MA, Borgnis RL, Berry SD. Neurobiol. Aging 1997;18(6):631 639).
Recently, a receptor for the angiotensin II(3-8) (Ang IV) hexapeptide, was discovered in the hippocampus, suggesting a possible role in learning. The present study utilized intracerebroventricularly (icv) infused scopolamine hydrobromide (scop) to disrupt spatial learning in the circular water maze, followed by the Ang IV analog norleucine1-Ang IV (Nle1-Ang IV), to restore normal performance. Rats were icv pretreated with either scop or artificial cerebrospinal fluid (aCSF) followed by either icv injected Nle1-Ang IV or aCSF, and then behaviourally tested. During acquisition training, each animal's latency to locate the platform, path distance, speed, and efficiency ratios were measured. A probe trial was conducted on the final day of training and the time spent in the target quadrant and the number of crossings over the former location of the platform (annulus crossings) were observed. The results indicate that those animals treated with scop followed by aCSF performed poorly during acquisition training as compared with controls. In contrast, those animals that received scop followed by Nle1-Ang IV attained equivalent latencies, distances, and efficiency ratios to find the platform as those achieved by controls. There were no observed differences in swimming speed, thus arguing against drug-induced motor impairment. During the probe trial, animals treated with scop followed by aCSF spent less time in the target quadrant and made fewer annulus crossings as compared to controls, while the scop, Nle'-Ang IV treated animals performed equivalently to controls. These results suggest that Nle1-Ang IV acts to counteract the disruption of spatial learning induced by scopolamine.
Transdermal devices are now marketed for the delivery of systemic medications through the skin. This report confirms delayed hypersensitivity to scopolamine, the active ingredient in Transderm-Scop. Patch testing with structurally related alkaloids suggests the active antigenic site on the scopolamine molecule. The mechanism of drug delivery by the transdermal device is discussed, along with the features that make this an attractive method of drug administration. Dermatologists should be familiar with these devices, since broader future applications can be expected.
The object of this work was to determine whether the changes in field activity and neuronal excitability recorded in the hippocampus during eyeblink classical conditioning are induced by the cholinergic input, and their relationships with the conditioned response performance. The pyramidal layer field activity, its response to fornix stimulation and eyelid responses were recorded during paired tone-air puff presentations, under scopolamine (25, 50 and 100 microg/kg) or saline administration, following well-established eyeblink conditioning in a trace paradigm in cats. Scopolamine impaired behavioral performance, and, in the hippocampus, disrupted conditioned stimulus-evoked field potential, high frequency shift in field activity, and paired presentation-induced hyperexcitability. These findings indicate that the cholinergic input participates in hippocampal information processing in a way that allows precise conditioned response performance and memory trace formation.