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The topography of amphetamine and scopolamine-induced hyperactivity: toward an activity print.

The increased locomotor activity induced by systemic injections of d-amphetamine or scopolamine in rats was studied in Digiscan Animal Activity Monitors. This multifactorial analysis of locomotion demonstrated that activity measures of horizontal (ambulatory), vertical (rearing), stereotypic, and rotational behaviors differed depending on dose and drug. The topographies of these activity variables may be unique for the dopaminergic and cholinergic systems underlying hyperactivity. These results are a first step toward a needed increase in the sophistication of behavioral pharmacological techniques, allowing for the development of specific activity prints for different classes of psychoactive agents.

Animals↗

Posttraining effects of amphetamine, chlorpromazine, ketamine, and scopolamine on the acquisition and extinction of the rabbit's conditioned nictitating membrane response.

Four experiments examined whether posttraining deliveries of drugs modified the performance of the rabbit's conditioned nictitating membrane response (NMR) during acquisition and extinction. The results show that ketamine accelerated, but that amphetamine, chlorpromazine, and scopolamine retarded, conditioning when the drugs were injected immediately after the completion of daily training sessions. However, all conditioning effects of the drugs were lost when their deliveries were delayed by 2 hr after the end of training. During extinction, the only drug that altered conditioned performance was ketamine. Specifically, ketamine retarded the rate of extinction when the drug was given immediately after training. However, delaying ketamine by 2 hr after training neutralized the drug's influence. These findings indicate that the NMR preparation should be useful in examining how the posttraining delivery of drugs influences associative processes in conditioning.

Animals↗

Chlordiazepoxide interactions with scopolamine and dizocilpine: novel cooperative and antagonistic effects on spatial learning.

The authors investigated the effects on spatial behavior of coadministrations of a benzodiazepine, chlordiazepoxide (CDP), with a noncompetitive N-methyl-d-aspartate receptor antagonist (NMDAR), dizocilpine (DZP), and a muscarinic cholinergic receptor antagonist, scopolamine (SCP). Rats solved the Morris swim task in 2 settings; 1 in which a hidden escape platform was always in the same location (performance) and a 2nd in which the platform had been moved to a different location (acquisition) for repeated daily sessions. CDP (3.0 mg/kg) administered alone did not disrupt escape latencies or swim path accuracies. SCP and DZP each impaired acquisition and performance in a dose-dependent manner. CDP coadministered with 0.3 mg/kg SCP impaired escape only in the acquisition setting and when coadministered with 1.0 mg/kg SCP selectively exacerbated the escape impairment in the acquisition setting. CDP ameliorated deleterious effects of DZP in both settings.

Analysis of Variance↗

Drugs, memory, and metamemory: a dose-effect study with lorazepam and scopolamine.

This experiment was designed to use the graded dose-related amnesia produced by the benzodiazepine lorazepam (1.0, 2.0 mg/70 kg, oral) and the anticholinergic scopolamine (0.3, 0.6 mg/70 kg, subcutaneous) as a tool to explore the cognitive and neurochemical mechanisms underlying metamemory in the judgment of learning paradigm, with a placebo-controlled independent groups design in healthy volunteers (n = 12/group). Results provide evidence for a pharmacological dissociation between effects on memory versus metamemory (relative accuracy of item-by-item monitoring) across a range of levels of memory performance and suggest that the drugs selectively impair those aspects of metamnemonic monitoring that require participants' awareness of their overall current state of functioning (absolute accuracy of prospective item-by-item monitoring, prospective global monitoring) but not those that rely solely on assessment of individual item characteristics (relative accuracy of item-by-item monitoring).

Administration, Oral↗

[Gly(14)]-Humanin improved the learning and memory impairment induced by scopolamine in vivo.

Humanin is a very recently discovered 24 amino acid linear polypeptide, which protects against cell death induced by either familial Alzheimer's disease mutant of amyloid precursor protein, presenilin-1 or presenilin-2 in vitro. However, it has remained uncertain whether humanin is a useful drug for the animal model of learning and memory deficit. In this study, we evaluated the effects of [Gly(14)]-humanin, a more potent humanin analogue, on the scopolamine HBr (1 mg kg(-1) s.c.)-induced impairment of spontaneous alternation behaviour in the Y-maze, an index of short-term memory in mice. [Gly(14)]-Humanin (1000 pmol 5 microl(-1) i.c.v.) reversed the impairment without affecting the number of arm entries. These results suggest that (I) [Gly(14)]-humanin is a beneficial drug for the impairment of learning and memory and (II) it modulates the learning and memory function mediated via cholinergic systems in mice.

Amino Acid Sequence↗

The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats.

The highly potent and selective 5-HT(6) receptor antagonist SB-271046 [5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide] has previously been demonstrated to improve retention significantly in a spatial water maze paradigm in adult rats. However, SB-271046 did not have any effect on task acquisition. As these apparently contradictory findings may be reconciled by a prime influence of SB-271046 on memory consolidation, the ability of this compound to reverse the discrete temporal action of a cholinergic antagonist in the 6-h period following passive avoidance training was investigated. SB-271046, given orally, by gavage, 30 min prior to training Wistar rats in a step-through, light-dark passive avoidance task, was found to reverse significantly the amnesia produced by administering scopolamine (0.8 mg/kg, intraperitoneal) in the 6-h post-training period. The effect was dose-dependent over a range of 3-20 mg/kg. Further, we investigated the cognition-enhancing effects of chronic SB-271046 administration (10 or 20 mg/kg/day; 40 days) on the acquisition and consolidation of a water maze spatial learning task in a population of 20-month-old Wistar rats with age-related learning deficits. Drug treatment progressively and significantly decreased platform swim angle and escape latencies over the five sequential trials on four consecutive daily sessions compared to vehicle-treated controls. SB-271046 also improved task recall as measured by significant increases in the searching of the target quadrant on post-training days 1 and 3, when the animals would have been substantially drug-free. This significant improvement of task recall suggests SB-271046, in addition to inducing symptomatic cognition-enhancing actions, also attenuates age-related decline in neural function.

Administration, Oral↗

Comparison of the effects of a selective muscarinic receptor antagonist and hyoscine (scopolamine) on motion sickness, skin conductance and heart rate.

AIMS: Hyoscine (scopolamine), which is effective in the prophylaxis of motion sickness, shows similar binding affinities to all of the five known muscarinic receptor sub-types. The effectiveness of hyoscine was compared with zamifenacin (UK-76654), which binds selectively to the muscarinic M3 and m5 receptors. METHODS: Eighteen subjects received hyoscine hydrobromide 0.6 mg, zamifenacin 20 mg, or placebo (double-blind cross-over design). Sessions were 1 week apart and the drug (oral) was given 90 min prior to a motion sickness test. Motion sickness was elicited by cross-coupled stimulation on a turntable. The rotational velocity was incremented by 2 degrees s-1 every 30 s, and a sequence (seq) of eight head movements of 45 degrees was completed every 30 s. Motion tolerance was assessed as the number of sequences of head movement required to achieve moderate nausea. Pulse rate was recorded before and at 1 and 2 h after drug administration. Skin conductance activity in the frequency band 0.005-0.48 Hz, an index of sweat gland activity, was measured using Ag/AgCl electrodes on the palmar surfaces of fingers and across the forehead. RESULTS: Both zamifenacin and hyoscine produced an increase in tolerance to the motion challenge (P < 0.01) with no significant difference between the two drugs (5.0 +/- 1.6 vs 5.7 +/- 1.6 seqs. respectively, mean +/- s.e.mean). Compared with placebo or zamifenacin, pulse rate fell following hyoscine administration (9 beats min-1, P < 0.01). Skin conductance was reduced following hyoscine compared with zamifenacin or placebo (P < 0.001). CONCLUSIONS: These results suggest that compounds with selective M3 and/or m5 antagonism possess activity against motion sickness. Antagonism at these receptors may be the basis of the anti-motion sickness action of hyoscine.

Adult↗

Donepezil reverses a mnemonic deficit produced by scopolamine but not by perforant path lesion or transient cerebral ischaemia.

The purpose of these studies were threefold. Firstly, to further characterize the effect of perforant path transection on a test of short-term memory: delayed matching (or nonmatching)-to-position [D(N)MTP]. Secondly, to evaluate the effect of a transient cerebral ischaemia in the same task. Both surgical procedures were chosen as they produce a CNS lesion similar to that described in Alzheimer's Disease (AD). Thirdly, the effect of the acetylcholinesterase inhibitor, donepezil (Aricept(R), E2020), on the resulting cognitive impairment was studied. Perforant path transection produced a robust, delay-dependent impairment of choice accuracy in rats performing either a delayed matching- or nonmatching-to-position task. Sample latency was also reduced following lesion, yet the lesion-induced impairment was not affected by increasing the response requirement at the sample stage. An 11-min period of transient ischaemia (two-vessel occlusion model) resulted in almost complete loss of hippocampal CA1 pyramidal cells and a delay-dependent impairment in DMTP performance. However, unlike perforant path lesions, this deficit was unstable and declined in magnitude over the experimental period. Increasing the delay interval restored this deficit. Donepezil, at doses that robustly attenuated a scopolamine (0.06 mg/kg s.c.)-induced DMTP accuracy impairment in naïve, unoperated rats, had no effect against either lesion-induced impairment. The results are considered in terms of the effectiveness of acetylcholinesterase inhibitors in noncholinergic-based preclinical cognitive models.

Alzheimer Disease↗

Effects of puerarin on scopolamine-, mecamylamine-, p-chloroamphetamine- and dizocilpine-induced inhibitory avoidance performance impairment in rats.

Puerarin at 10-50 mg/kg attenuated the mecamylamine- but not scopolamine-induced acquisition impairment of inhibitory avoidance performance in an inverse U-shape manner. p-Chloroamphetamine- and dizocilpine-induced acquisition impairment were reversed by puerarin at 25-50 mg/kg. Both piracetam, and tacrine attenuated impairment of inhibitory avoidance performance induced by all used drugs. Furthermore, puerarin, piracetam and tacrine alone did not alter step-through latency in the training trail but puerarin at 50 mg/kg and tacrine plus mecamylamine prolonged it in comparison with mecamylamine alone. From these results, we suggest that puerarin attenuated the deficits of inhibitory avoidance performance induced by mecamylamine, p-chloroamphetamine, and dizocilpine, the effects were related to increasing cholinergic activity via nicotinic but not muscarinic receptors, activating NMDA receptors, and decreasing serotonergic neuronal activity.

Amnesia↗

The use of prostaglandin F2 alpha and scopolamine-N-butylbromide in anorectal manometric diagnosis.

To improve the accuracy of diagnosis of Hirschsprung's disease by means of anorectal manometry, prostaglandin F2 alpha (PGF2 alpha) and scopolamine-N-butylbromide (Buscopan) were used. Normal rectoanal reflex was facilitated by PGF2 alpha in 6 out of 7 children and was abolished or markedly inhibited in 12 out of 13, when Buscopan was given. Obscure rectoanal reflexes in 7 normal neonates were clarified following the administration of PGF2 alpha. On the other hand, atypical rectoanal reflexes observed in 7 children with Hirschsprung's disease were unchanged with either PGF2 alpha or Buscopan. Therefore the use of PGF2 alpha or Buscopan facilitates the manometric diagnosis of Hirschsprung's disease. In 9 postoperative children with Hirschsprung's disease the reflexes were obscure. Five of these 9 reflexes became clear after the administration of PGF2 alpha and 4 remained unchanged. As the normal rectoanal reflex was enhanced by PGF2 alpha, the obscure reflex seen in the postoperative period can be positive or negative, using PGF2 alpha.

Adolescent↗

A descriptive study of an epidemic of poisoning caused by heroin adulterated with scopolamine.

OBJECTIVE: Adulterants, contaminants, and diluents are all examples of additives to street drugs. Some of these additives may be pharmacologically active; however, it is unusual for them to cause toxic side effects. In the spring of 1995, a new form of heroin appeared in New York City, spreading to other East Coast cities, that was adulterated with scopolamine. It caused severe anticholinergic toxicity in heroin users with patients often presenting to emergency departments in great numbers. This is a report of the demographics and clinical characteristics of the epidemic. METHODS: A combination of prospective and retrospective data collection from the New York City, New Jersey, Delaware Valley, and Maryland Poison Centers. The primary measurements were age, sex, route of drug use, vital signs, signs and symptoms, disposition, and treatment. RESULTS: Of the 370 cases reported to the participating poison centers, 129 were excluded from the final analysis because of insufficient data. Of the patients who used this product, 55% presented with signs and symptoms of heroin toxicity but then became severely agitated with anticholinergic symptoms when naloxone was used to reverse respiratory depression. Nasal insufflation was the route of administration in 34% of the cases. Seizures were rare (3%). Ninety percent required admission, and half were admitted to a critical care unit. CONCLUSIONS: Adulteration of street drugs can lead to toxic epidemics. Poison centers are essential for identification of these trends and are the primary source of information on diagnosis and treatment.

Adolescent↗

Combined pretrauma scopolamine and phencyclidine attenuate posttraumatic increased sensitivity to delayed secondary ischemia.

Fasted Wistar rats were given a mild level of traumatic brain injury (TBI) and then subjected to 6 min of transient forebrain ischemia 24 h posttrauma. One group was given simultaneous 1 mg/kg scopolamine and 4 mg/kg phencyclidine intraperitoneally (IP) 15 min before trauma and another group an equal volume of plasmalyte A solution. After 7 days of postinjury survival, placebo-treated rats demonstrated increased posttraumatic vulnerability to secondary ischemic CA1 neuronal death even 24 h after trauma. This finding confirmed that increased posttraumatic ischemic vulnerability persists for at least 24 h even following mild trauma. Combined muscarinic receptor and N-methyl-D-aspartate (NMDA) receptor coupled ion channel blockade given and present during the mild TBI statistically attenuated this enhanced secondary ischemic CA1 neuronal death and thus posttraumatic increased ischemic vulnerability. Placebo-treated rats had 335.3 +/- 93.6 CA1 neurons/10(6) microns 2 and drug-treated rats had 844.8 +/- 184.9 CA1 neurons/10(6) microns 2. This result suggests that muscarinic and/or NMDA receptor-mediated events confined to TBI and the early posttraumatic period are in part responsible for the phenomenon of increased posttraumatic ischemic vulnerability.

Animals↗

An analysis of lymphocyte 3H-N-methyl-scopolamine binding in neurological patients. Evidence of altered binding in Alzheimer's disease.

Muscarinic cholinergic receptors were analysed in lymphocyte membranes from 35 patients with early (n = 20) and late onset (n = 15) Alzheimer's disease (AD), 86 patients with other neurological disorders and 60 normal controls by the specific binding of 3H-N-methyl-scopolamine (3H-NMS). The number of binding sites of 3H-NMS (Bmax) was significantly decreased both in early and late onset AD groups as compared with age-matched controls, by 54% and 40%, respectively, whereas the apparent binding affinity (Kd) was the same in all disease and control groups. In addition, the average Bmax in early AD was significantly lower than in late AD. The density of the binding of 3H-NMS was also significantly lower in a subgroup of old subjects with Down's syndrome (DS), whereas no changes were found in younger individuals with DS or in patients with Parkinson's disease, whether they were demented or not, multi-infarct dementia, myasthenia gravis or epilepsy. In the AD group, the difference in binding sites was unrelated either to the severity of dementia or disease duration. Treatment of the patients with cholinergic agents did not alter the binding values in any of the examined group. We conclude that the alteration of lymphocyte muscarinic receptors is highly associated with AD, but whether this reflects the central cholinergic deficit in these patients is uncertain.

Adolescent↗

Effects of chlordiazepoxide and scopolamine, but not aging, on the detection and identification of conditional visual stimuli.

Our previous studies revealed impairments in the ability of aged rats to detect brief, rarely and unpredictably occurring stimuli. The failure of these impairments to interact with the effects of benzodiazepine receptor (BZR) ligands was attributed to low demands on stimulus-related information processing. Thus, in the present experiment, rats of different ages were trained to detect visual stimuli that were flashing at 20 Hz, or were constantly illuminated, for 8, 3, or 5 sec. Additionally, selection of the correct lever to report detection required the processing of propositional rules (e.g., flashing-go left; constant-go right), i.e., the identification of the stimulus. All measures of performance varied with stimulus duration. Subsedative doses of the BZR agonist chlordiazepoxide (CDP; 3.13, 4.69 mg/kg), similar to the effects of the muscarinic antagonist scopolamine (.025, 0.1 mg/kg), impaired response accuracy, increased the number of errors of omission and decreased response latencies. Animals aged 28 months omitted more trials following the administration of CDP than 12-month-old rats. Age did not produce main effects and did not interact with the effects of the drugs on response accuracy. It is speculated that, as stimuli had to be presented for relatively long periods of time (to maintain above chance-level discrimination performance), demands on detection remained too low to replicate previously documented effects of age. The demonstration of interactions between the effects of age and of BZR-ligands appears to depend on combined demands for stimulus detection and identification.

Aging↗

Premedication and high-dose fentanyl anesthesia for myocardial revascularization: a comparison of lorazepam versus morphine-scopolamine.

Using a randomized double-blind placebo-controlled experimental protocol, the authors compared two premedication regimens in 42 patients undergoing elective myocardial revascularization. Group L patients (n = 23) received lorazepam 0.06 mg/kg po 90 min preoperatively, while group M patients (n = 19) received morphine 0.1 mg/kg im, plus scopolamine 0.006 mg/kg im 60 min preoperatively. Anesthesia was induced with fentanyl 100 micrograms/kg and atracurium 0.50 mg/kg administered over 10 min. The treatment groups did not differ significantly with respect to the degree of sedation or anxiolysis achieved, or the rapidity of induction with fentanyl. Premedication significantly influenced the hemodynamic response to anesthetic induction. Hemodynamics were stable post-induction in group M, but cardiovascular depression was noted in group L. Control heart rate (HR) was lower in group L. The HR, arterial pressure, and cardiac index were significantly lower, following both induction and intubation, in group L. Following sternotomy hemodynamics were identical in both groups. Serum fentanyl concentration was significantly higher during intubation in group L, probably secondary to the pharmacokinetic consequences of a decreased CI. New electrocardiographic evidence of myocardial ischemia did not occur in either group. Based on their findings with fentanyl-at-racurium, and their review of the literature, the authors speculate that premedication exerts a significant hemodynamic effect during induction with other narcotic-relaxant combinations.

Anesthesia, Intravenous↗

Transdermal scopolamine decreases nausea and vomiting following cesarean section in patients receiving epidural morphine.

The authors evaluated the antiemetic properties of transdermal scopolamine (TDS) in healthy patients undergoing elective cesarean section and receiving epidural morphine for postoperative analgesia. Prior to administration of anesthesia, 203 patients had either TDS or a placebo study patch applied behind one ear. All patients were hydrated with lactated Ringer's solution iv and given 2.0% lidocaine with 1:200,000 epinephrine epidurally for surgical anesthesia. Following delivery of the infant, 4 mg of morphine sulphate was injected through the epidural catheter. After the operation patients were evaluated by "blinded" observers at 2, 4, 6, 8, 10, 24, and 48 h for nausea, vomiting, retching, pain relief, itching, and adverse effects. In addition, medications received were noted. No differences were found between the groups in terms of severity or incidence of pain, or requests for analgesic or antipruritic medication. Although there was no difference between the groups in the first 2 h, patients with TDS had significantly less nausea, vomiting, and retching than patients in the placebo group in each time interval between 2 and 10 h. Additionally, the TDS group required less antiemetic medication. There was no difference in the frequency of retching or vomiting between groups. Side effects were minimal and equal in both groups. The authors conclude that TDS results in a decreased incidence of nausea and vomiting in patients who have delivered by cesarean section and received epidural morphine. TDS appears safe for continuous antiemetic administration.

Administration, Cutaneous↗

Interleukin-6 affects scopolamine-induced amnesia, but not brain amino acid levels in mice.

We have previously shown that, after peripheral administration, different cytokines affect cognitive functions in mice. In this study, we evaluated the effects of mouse interleukin-6 (IL-6) on the classical behavioural test of scopolamine-induced amnesia for a passive avoidance response in the mouse. Pretraining i.p. administration of this cytokine (0.125 and 0.5 microgram/mouse) significantly reduced the amnesic action of the muscarinic receptor antagonist. As it is well known that brain amino acids are deeply involved in the modulation of cognitive processes we measured the levels of glutamine, aspartic acid, glutamic acid and GABA in the hippocampus and hypothalamus of mice treated with IL-6. At both doses which affected the cognitive functions, this cytokine had no effect on brain levels of measured amino acids. Neither nociceptive thresholds to a thermal stimulus, nor spontaneous locomotor activity were modified by the acute administration of IL-6 (0.5 microgram/mouse). Our data confirm previous observations indicating that peripheral administration of cytokines affects some, but not other brain functions and suggest the involvement of IL-6 in the central modifications induced by the immune activation.

Amino Acids↗