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Induction and resetting of REM sleep rhythm in normal man by arecholine: blockade by scopolamine.

Arecholine, a cholinergic muscarinic agonist, was administered intravenously 35 min after sleep onset in eight normal volunteers who had been pretreated with either methscopolamine or scopolamine, muscarinic receptor blockers that do not and do cross the blood--brain barrier, respectively. Following pretreatment with methscopolamine, arecholine shortened the REM latency and increased the number of REM periods without altering the duration of individual REM periods or altering the REM--REM intervals. Pretreatment with scopolamine blocked the effects of arecholine. The results support the hypothesis that cholinergic muscarinic mechanisms are involved in the timing but not the duration of REM sleep.

Adult↗

Scopolamine, morphine, and brain-stem auditory evoked potentials in awake monkeys.

The effects of scopolamine and morphine sulfate on brain-stem auditory evoked potentials (BAEPs) were studied in 10 rhesus (Macaca mulatta) monkeys. Study drugs were given intravenously to unanesthetized animals and BAEPs recorded at 3-min and 30-min intervals after administration of 0.1 mg/kg and 0.32 mg/kg of scopolamine and 15 min after administration of 3.2 mg/kg morphine at the end of the experiment. No significant change in either latency or amplitude of different components of BAEPs was observed.

Animals↗

A novel nitrate ester reverses the cognitive impairment caused by scopolamine in the Morris water maze.

The objective of this study was to test the hypothesis that activation of soluble guanylyl cyclase and increased cGMP formation in the brain would improve task acquisition in cognitively impaired animals. We evaluated the effects of a novel nitrate ester, GT 715 (2,3-dinitrooxy-(2,3-bis-nitrooxypropyldisulfanyl)-propane), in scopolamine-induced impairment of task acquisition in the Morris water maze. GT 715 improved task acquisition in scopolamine-pretreated animals in a time- and dose-dependent manner, whereas the prototypical nitrate ester, glyceryl trinitrate (GTN), was ineffective. GT 715 also was more effective and more potent than GTN for activation of hippocampal guanylyl cyclase. The results of this study therefore suggest that stimulation of cerebral soluble guanylyl cyclase activity may be an effective strategy to improve learning and memory performance in individuals in whom cognitive abilities are impaired by injury, disease, or ageing.

Animals↗

Scopolamine reduces the P35m and P60m deflections of the human somatosensory evoked magnetic fields.

Acetylcholine (ACh) is a potent neuromodulator in the brain with multiple, complex effects on neuronal function, most of which are mediated by muscarinic receptors. Generally, the most significant effect is excitation of pyramidal neurones and facilitation of responses to afferent stimulation. Much of the information on the ACh effects comes from studies utilizing in vitro or anesthetized in vivo preparations, while fewer data are available from awake animals or humans. We studied human somatosensory evoked magnetic fields (SEFs), which reflect summated postsynaptic currents in pyramidal neurones in area 3b, and in the opercular somatosensory cortex, when cholinergic transmission was modulated either by a central (scopolamine, 0.3 mg, i.v.) or peripheral (glycopyrrolate, 0.2 mg, i.v.) muscarinic antagonist. A randomized, double-blind, cross-over design was employed. SEFs were elicited by right median nerve stimulation at the wrist with constant-current pulses above motor threshold. The first excitatory cortical response from area 3b (N20m) was not affected by the central muscarinic blockade, while later P35m and P60m deflections were significantly reduced. The responses from the opercular somatosensory cortex showed some tendency toward reduction, but no significant alterations. The results show that somatosensory cortical processing can be modulated by muscarinic transmission at a relatively early stage. Relative membrane hyperpolarization of pyramidal neurons due to scopolamine (caused by blocking an ACh-induced tonic depolarization) is discussed as a possible mechanism underlying the observed effects.

Adult↗

The use of transdermal scopolamine to control drooling. A case report.

Drooling is a serious social handicap experienced by some neurologically impaired patients. No one method has been identified to control drooling for all patients, however, anticholinergic drugs recently have been utilized. In the case study described, transdermal scopolamine patches were found to be effective for controlling drooling in a traumatic brain-injured patient for whom more conservative methods failed. From a baseline saliva flow rate, saliva flow decreased an average of 30% with one-patch and 59% with two-patch dosing. No significant side effects were observed with treatment, and the decrease in drooling was maintained for a 4-month period. Although transdermal scopolamine may represent one acceptable facet of long-term treatment, it must be stressed that efficacy is variable across patient populations and that treatment approaches must be individualized.

Administration, Cutaneous↗

Scopolamine attenuates tinnitus-related plasticity in the auditory cortex.

High doses of salicylate induce a temporary hearing deficit and a temporary subjective tinnitus in humans and animals. In animals, salicylate suppresses activity in the ascending auditory system but generates activity and plasticity in the auditory cortex and central amygdala. In addition to changes in the auditory system evoked by hearing impairment, enhanced stress may be crucial for the salicylate-induced alterations in the auditory cortex. The central amygdala responds to stress, and may influence cortical excitability and plasticity through cholinergic mechanisms. We investigated whether salicylate-induced plasticity in the auditory cortex is prevented by blocking cortical cholinergic receptors with the muscarinic antagonist scopolamine. Scopolamine suppresses salicylate-induced plasticity in the auditory cortex and, therefore, may be effective in suppressing the tinnitus sensation.

Animals↗

Cholinergic modulation of visual attention and working memory: dissociable effects of basal forebrain 192-IgG-saporin lesions and intraprefrontal infusions of scopolamine.

Two experiments examined the effects of reductions in cortical cholinergic function on performance of a novel task that allowed for the simultaneous assessment of attention to a visual stimulus and memory for that stimulus over a variable delay within the same test session. In the first experiment, infusions of the muscarinic receptor antagonist scopolamine into the medial prefrontal cortex (mPFC) produced many omissions but did not impair rats' ability to correctly detect a brief visual stimulus. However, these animals were highly impaired in remembering the location of that stimulus following a delay period, although in a delay-independent manner. In the second experiment, another group of animals with selective 192 IgG-saporin lesions of the nucleus basalis magnocellularis (nBM) were not impaired under conditions of low-attentional demand. However, when the stimulus duration was reduced, a significant memory impairment was observed, but similar to the results of the first experiment, the nBM-lesioned animals were not impaired in attentional accuracy, although aspects of attention were compromised (e.g., omissions). These findings demonstrate that (1) cortical cholinergic depletion produces dissociable deficits in attention and memory, depending on the task demands, (2) delay-independent mnemonic deficits produced by scopolamine are probably due to impairments other than simple inattention, and (3) working memory deficits are not simply dependent on attentional difficulties per se. Together, these findings implicate the nBM cortical cholinergic system in both attentional and mnemonic processing.

Acetylcholine↗

Double-blind comparison of transdermal scopolamine, droperidol and placebo against postoperative nausea and vomiting.

Since transdermal scopolamine (TS) seems effective against seasickness, we compared its antiemetic effect with intravenous droperidol (DHBP), our routine antidote for postoperative emesis. Ninety-six female patients (ASA I-II) scheduled for short-stay surgery were randomly allocated to three study groups after giving their informed consent. The three groups were as follows: TS adhesive, delivering 140 micrograms initially and 5 micrograms/h thereafter + placebo 0.5 ml i.v. 5 min before the end of surgery; transdermal placebo adhesive preoperatively + DHBP 0.5 ml (1.25 mg) i.v. 5 min before the end of surgery; transdermal placebo + 0.5 ml placebo i.v. as indicated above. Oxycodone i.m. and glycopyrrolate i.v. were given for premedication together with the test adhesive. Anaesthesia was induced with thiopental and maintained with nitrous oxide and oxygen, enflurane, vecuronium and fentanyl. Neostigmine and glycopyrrolate were administered for reversal. In the recovery room no differences in nausea or vomiting were observed between the groups. Sedation was significantly more marked (P less than 0.15-0.0001) after DHBP than after either TS or the given DHBP and 6% of those given the placebo (P less than 0.05). During the following 24 h nausea was reported more by the placebo patients (25) than by those on TS (20) or DHBP (15) (P less than 0.05). However, actual vomiting on the ward did not differ between the groups. Visual disturbances were more frequent after TS (P less than 0.01). We conclude that prophylactic transdermal scopolamine does not diminish postoperative emetic sequelae.

Administration, Cutaneous↗

Control of drooling with transdermal scopolamine in a child with cerebral palsy.

Transdermal scopolamine patches (1.5 mg) were used to control drooling in a two-year-old boy with severe spastic quadriparetic cerebral palsy and developmental delay. He responded well to the continuous scopolamine therapy, with a decrease in drooling, and a secondary decrease in respiratory distress and frequency of suctioning. No significant side-effects were noted.

Administration, Cutaneous↗

The effects of scopolamine on event-related potentials in a continuous recognition memory task.

Event-related potentials (ERPs) were recorded during a task requiring continuous recognition memory for visually-presented words. Twelve subjects each performed the task twice, once following the administration of scopolamine, and once after receiving a saline placebo. In the placebo condition, correctly detected "old" words (i.e., words that had been presented once before during the task) evoked more positive-going ERPs than did "new" words. Scopolamine caused a substantial impairment in task performance, but did not reduce the size of these old-word/new-word ERP differences. It is concluded that old/new ERP effects are unlikely to reflect cholinergically-mediated neural activity underlying normal recognition memory.

Adult↗

Recurrent classic migraine attacks following transdermal scopolamine intoxication.

A 20 year old male naval crew-member suffering from sea sickness was treated with transdermal scopolamine (TS). After 5 months of continuous treatment, he developed scopolamine intoxication followed by the appearance of recurrent classic migraine attacks. He had never suffered from headache or migraine prior to TS intoxication. The migraine attacks comprised a prodrome of apathy, bad mood and loss of appetite lasting several hours. An aura of scintillating spots, left arm numbness and paresthesias lasting several minutes was followed by a severe throbbing unilateral headache with photophobia, sonophobia and nausea. After one year of repeated follow-up examination, he continued to suffer from the attacks once every 10 to 14 days, with no identified precipitating factors. We are not aware of similar cases in the medical literature. Although it is not possible to establish TS intoxication as a causal effect of the appearance of classic migraine in our patient, the temporal association and clinical course are very supportive of this assumption. Central nervous system neurotransmitter imbalance of cardiovascular alterations may possibly be implicated.

Administration, Cutaneous↗

Effect of transdermal scopolamine on heart rate variability in patients with severe coronary heart disease.

A decrease in cardiac parasympathetic tone is a recognized finding in patients with ischemic heart disease, correlating closely with disease severity and overall survival. The aim of this study was to assess whether transdermal scopolamine (Tds), which increases parasympathetic tone in healthy volunteers, increases vagal tone in patients with severe CAD and whether it might have an antiischemic effect. Fifteen patients (10 men, aged 55 +/- 8 years) with three-vessel CAD, but with no prior MI and preserved ventricular function, underwent 24-hour Holter monitoring and exercise testing before and after wearing a scopolamine patch for 24 hours. Time-domain measures of heart rate variability (HRV) and the total number and duration of ischemic episodes were obtained from the Holter recordings for each patient. Tds significantly (P < 0.05) increased the values of all HRV measures. Tds also reduced the total number of ischemic episodes (from 273 to 159, P < 0.05) and their total duration (from 136 to 46 min per patient, P < 0.05). Tds also increased treadmill exercise duration from 293 +/- 101 to 345 +/- 95 seconds (P < 0.05) and the time to 1-mm ST depression from 177 +/- 105 to 244 +/- 128 seconds (P < 0.02), while maximum ST depression was reduced from 2.86 +/- 0.6 to 2.3 +/- 0.3 (P < 0.05). No significant side effects were observed. Tds modifies the autonomic balance in patients with severe CAD toward a condition associated with a better prognosis. It may also be useful as an adjunctive treatment for ischemic heart disease.

Administration, Cutaneous↗

Enhancement of memory retrieval and attenuation of scopolamine-induced amnesia following administration of 5-HT3 antagonist ICS 205-930.

Experimental evidence suggests an important role of serotonin in the process of learning and memory. The present study investigated the effect of 5HT3-receptor antagonist (ICS 205-930) on retrieval of a previously learned aversive habit in the mouse. The effect of ICS 205-930 on scopolamine (3 mg/kg) induced amnesia was also studied. ICS 205-930 (1, 10 & 100 micrograms/kg) produced a dose-dependent increase in latency to cross into the dark chamber. The scopolamine induced memory impairment was significantly attenuated by ICS 205-930 (10 micrograms/kg). These results suggest that memory deficits may be susceptible to attenuation with non-cholinergic treatments.

Amnesia↗

Toxic effect of scopolamine eye drops in children.

Five children, admitted with acute psychotic reactions after use of Scopolamine eye drops 0.2%, are presented. The predominant symptoms were visual hallucinations, strange behaviour, and restlessness. In one case peripheral symptoms were observed. Recovery was complete in 24 h. Prescription of Scopolamine eye drops should be followed by information of possible adverse effects. Cyclopentolate might be used instead.

Acute Disease↗

Attenuation of scopolamine-induced and age-associated memory impairments by the sigma and 5-hydroxytryptamine(1A) receptor agonist OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1H]-quinolinone monomethanesulfonate).

Sigma and 5-HT(1A) receptor stimulation can increase acetylcholine (ACh) release in the brain. Because ACh release facilitates learning and memory, we evaluated the degree to which OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1H]-quinolinone monomethane sulfonate), a novel sigma and 5-HT(1A) receptor agonist, can augment ACh release and improve learning impairments in rats due to cholinergic- or age-related deficits. Single oral administration of OPC-14523 improved scopolamine-induced learning impairments in the passive-avoidance task and memory impairment in the Morris water maze. The chronic oral administration of OPC-14523 attenuated age-associated impairments of learning acquisition in the water maze and in the conditioned active-avoidance response test. OPC-14523 did not alter basal locomotion or inhibit acetylcholinesterase (AChE) activity at concentrations up to 100 microM and, unlike AChE inhibitors, did not cause peripheral cholinomimetic responses. ACh release in the dorsal hippocampus of freely moving rats increased after oral delivery of OPC-14523 and after local delivery of OPC-14523 into the hippocampus. The increases in hippocampal ACh release were blocked by the sigma receptor antagonist NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine). Thus, OPC-14523 improves scopolamine-induced and age-associated learning and memory impairments by enhancing ACh release, due to a stimulation of sigma and probably 5-HT(1A) receptors. Combined sigma/5-HT(1A) receptor agonism may be a novel approach to ameliorate cognitive disorders associated with age-associated cholinergic deficits.

Acetylcholine↗

Human serial learning: enhancement with arecholine and choline impairment with scopolamine.

Arecholine (4 milligrams), a cholinergic agonist, and choline (10 grams), a precursor of acetylcholine, significantly enhanced serial learning in normal human subjects. The subjects received methscopolamine prior to both arecholine and placebo injections. Conversely, scopolamine (0.5 milligram), a cholinergic antagonist, impaired learning and this impairment was reversed by arecholine and choline and the impairment after scopolamine were inversely proportional to the subject's performance on placebo; that is, "poor" performers were more vulnerable to both the enhancing effect of cholinergic agonist and precursor and the impairment after cholinergic antagonist than "good" performers.

Acetylcholine↗

M2 muscarinic ([3H]N-methyl scopolamine) binding in micropunches of rat ventricular myocardium: characterization and modification by progesterone.

A new technique is outlined for the characterization and quantification of M2 muscarinic binding sites (receptors) in micropunches (1 mm diam.), cut from slices (350 microns), of fresh cardiac tissue using the hydrophilic antagonist [3H]N-methyl scopolamine. The use of this water-soluble ligand allows us to label, and quantify, M2 receptors on the cell surface of intact cells contained within the micropunch. We believe that cardiac micropunches offer a simple but powerful approach to the investigation of membrane receptor regulation in tissue that largely retains the in vivo cytoarchitecture. Specific binding is reversible, stereospecific, saturable, of high affinity, and has the drug specificity typical of an M2 muscarinic receptor. In rat left ventricle, Bmax was 151.2 +/- 10.3 fmol/mg protein while KD was 1.0 +/- 0.1 nM. Nonspecific binding of the ligand was very low, varying from 2.8% (at 0.27 nM) to 7.7% (at 3.58 nM). This micropunch assay was used to determine that progesterone can compete with the muscarinic ligand for the M2 receptor in vitro (IC50 = 50 x 10(-6) M). The steroids estradiol and testosterone, as well as ouabain, were without effect. Progesterone inhibited [3H]N-methyl scopolamine binding competitively (KD reduced from 1.9 to 4.3 nM) without affecting the rate of association of the ligand. However, progesterone induced a rapid dissociation of the ligand from its receptor. We conclude that the micropunch assay described here is suitable for the continued study of sex hormone effects on cardiac function.

Animals↗

Effects of Jen-San-Yaung-Jung-Tang on scopolamine-induced amnesia in rats.

The effect of Jen-San-Yaung-Jung-Tang (YJT) on scopolamine (SCOP)-induced amnesia was investigated in a step-through passive avoidance task in rats. It was observed that YJT (0.5 and 1.0 g/kg) significantly improved SCOP-induced amnesia and did not change the horizontal activity and pain threshold. YJT at 0.5 and 1.0 g/kg also did not change SCOP-treated horizontal activity and pain threshold. Furthermore, the antiamnesic effect of YJT at 1.0 g/kg on the SCOP-induced amnesia was augmented by physostigmine, but was not altered by neostigmine or scopolamine N-methylbromide. These results suggest that the antiamnesic effect of YJT could only be related to the memory-related process, and to an increase in central cholinergic neuronal activity.

Amnesia↗