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PubMed1994

Role of cholinergic neurotransmission in the amygdala on performances of passive avoidance learning in mice.

To clarify the role of cholinergic neurons in the amygdala on learning and memory, scopolamine was injected topically into the bilateral amygdala of mice, and the ability to perform two types of passive avoidance tasks (step-through and step-down) was investigated. On the first day mice performed the learning trial and on the second day their retention was tested. Scopolamine (0.5 or 1 microgram/site) was injected bilaterally into the amygdala 30 min before or immediately after the learning trial or 30 min before the testing trial. Scopolamine impaired the performance ability of the mice dose-dependently only when it was injected 30 min before the learning trial. The results coincided well with the effect of scopolamine injected intraperitoneally. Taken together, these results suggest that the site of action for scopolamine to cause anterograde amnesia is the amygdala, and that cholinergic neurons projecting to the amygdala play an important role in memory acquisition in the two passive avoidance tasks.

Amygdala↗
PubMed2006

Daidzein activates choline acetyltransferase from MC-IXC cells and improves drug-induced amnesia.

The choline acetyltransferase (ChAT) activator, which enhances cholinergic transmission via an augmentation of the enzymatic production of acetylcholine (ACh), is an important factor in the treatment of Alzheimer's disease (AD). Methanolic extracts from Pueraria thunbergiana exhibited an activation effect (46%) on ChAT in vitro. Via the sequential isolation of Pueraria thunbergiana, the active component was ultimately identified as daidzein (4',7-dihydroxy-isoflavone). In order to investigate the effects of daidzein from Pueraria thunbergiana on scopolamine-induced impairments of learning and memory, we conducted a series of in vivo tests. Administration of daidzein (4.5 mg/kg body weight) to mice was shown significantly to reverse scopolamine-induced amnesia, according to the results of a Y-maze test. Injections of scopolamine into mice resulted in impaired performance on Y-maze tests (a 37% decreases in alternation behavior). By way of contrast, mice treated with daidzein prior to the scopolamine injections were noticeably protected from this performance impairment (an approximately 12%-21% decrease in alternation behavior). These results indicate that daidzein might play a role in acetylcholine biosynthesis as a ChAT activator, and that it also ameliorates scopolamine-induced amnesia.

Amnesia↗
PubMed2000

The preclinical pharmacological profile of WAY-132983, a potent M1 preferring agonist.

Muscarinic M1 preferring agonists may improve cognitive deficits associated with Alzheimer's disease. Side effect assessment of the M1 preferring agonist WAY-132983 showed significant salivation (10 mg/kg i.p. or p.o.) and produced dose-dependent hypothermia after i. p. or p.o. administration. WAY-132983 significantly reduced scopolamine (0.3 mg/kg i.p.)-induced hyperswimming in mice. Cognitive assessment in rats used pretrained animals in a forced choice, 1-h delayed nonmatch-to-sample radial arm maze task. WAY-132983 (0.3 mg/kg i.p) significantly reduced scopolamine (0.3 mg/kg s.c.)-induced errors. Oral WAY-132983 attenuated scopolamine-induced errors; that is, errors produced after combining scopolamine and WAY-132983 (to 3 mg/kg p.o.) were not significantly increased compared with those of vehicle-treated control animals, whereas errors after scopolamine were significantly higher than those of control animals. With the use of miniosmotic pumps, 0.03 mg/kg/day (s.c.) WAY-132983 significantly reduced AF64A (3 nmol/3 microliter/lateral ventricle)-induced errors. Verification of AF64A cholinotoxicity showed significantly lower choline acetyltransferase activity in the hippocampi of AF64A-treated animals, with no significant changes in the striatal or frontal cortex. Cognitive assessment in primates involved the use of pretrained aged animals in a visual delayed match-to-sample procedure. Oral WAY-132983 significantly increased the number of correct responses during short and long delay interval testing. These effects were also apparent 24 h after administration. WAY-132983 exhibited cognitive benefit at doses lower than those producing undesirable effects; therefore, WAY-132983 is a potential candidate for improving the cognitive status of patients with Alzheimer's disease.

Animals↗
PubMed2003

Muscarinic blockade slows and degrades the location-specific firing of hippocampal pyramidal cells.

The firing of rat hippocampal pyramidal cells is determined both by the animal's location and by the state of the hippocampal EEG. Because cholinergic transmission plays a role in EEG activity, we expected that its modification would alter place cell activity. We therefore investigated the effects on place cell activity of blocking muscarinic transmission with intracerebroventricular injections of scopolamine. Scopolamine reduced both the rate of place cell discharge inside firing fields and the spatial coherence of the fields; discharge outside of the fields also showed small increases. After injections, fields were shifted farther from their previous location than for saline controls, indicating reduced reproducibility after muscarinic blockade. Scopolamine increased the time rats were stationary, but changes in place cell activity persisted even after analysis was restricted to periods of walking, suggesting that the behavioral changes cannot account for the cell discharge changes. The scopolamine effects were dose dependent to an extent that varied between different measures. The firing rates of interneurons showed only a minor trend to decrease after scopolamine. Nevertheless, the spatial coherence of interneuron firing patterns was reduced, consistent with the recent demonstration that their positional firing is mediated by the location-specific firing of pyramids (Marshall et al., 2002). These results demonstrate that acetylcholine enhances positional firing patterns in the hippocampus. Muscarinic blockade weakens the positional firing of most place cells and therefore renders them less useful for precise representation of the environment. This effect may underlie the difficulties in spatial learning and problem solving caused by abnormalities of cholinergic transmission.

Acetylcholine↗
PubMed1992

Effect of FR121196, a novel cognitive enhancer, on the memory impairment of rats in passive avoidance and radial arm maze tasks.

Passive avoidance performance was impaired in young rats by scopolamine (1.0 mg/kg) or by nucleus basalis magnocellularis lesions and in aged rats (24-26 months old). FR121196[N-(4-acetyl-1-piperazinyl)-4-fluorobenzenesulfonamide+ ++], a newly introduced cognitive enhancer, ameliorated the failure in memory retention with bell-shaped dose-response curves in doses ranging from 0.1 to 10 mg/kg. Similar dose-response curves also were obtained with methamphetamine (0.1-10 mg/kg), whereas physostigmine (0.01-1.0 mg/kg) attenuated the amnesia in scopolamine-treated rats, but hardly affected that in nucleus basalis magnocellularis-lesioned or aged rats. In radial arm maze tasks, behavioral indices of spatial memory, such as first correct choices and number of errors, were impaired by an injection of scopolamine (0.5 mg/kg) or by lesions of the medial septum or fimbria-fornix. FR121196 ameliorated the scopolamine-induced memory deficit with a bell-shaped dose-response curve, whereas methamphetamine had the opposite effect. These two drugs had little effect on memory deficits brought about by medial septum or fimbria-fornix lesioning, whereas physostigmine ameliorated these deficits in scopolamine-treated and medial septum-lesioned rats, but not in fimbria-fornix-lesioned rats. Behavioral studies using Animex demonstrated that FR121196, in contrast with methamphetamine, does not increase locomotor activities in rats up to a dose of 10 mg/kg. These results are discussed in relation to the cholinergic and dopaminergic mechanisms of memory.

Aging↗
PubMed2003

Cholinergic activity enhances hippocampal long-term potentiation in CA1 during walking in rats.

Long-term potentiation (LTP) at the basal-dendritic synapses of CA1 pyramidal cells was induced by a single 200 Hz stimulation train (0.5-1 sec duration) in freely behaving rats during one of four behavioral states: awake-immobility (IMM), walking, slow-wave sleep (SWS), and rapid eye movement sleep (REM). Field EPSPs generated by basal-dendritic excitation of CA1 were recorded before and up to 1 d after the tetanus. After a tetanus during any behavioral state, basal-dendritic LTP was >170% of the baseline for the first hour after the tetanus and decayed to approximately 120% 1 d after. LTP induced during walking was significantly larger than that induced during IMM, SWS, or REM, which had similar LTP magnitudes. To test the hypothesis that septohippocampal cholinergic activity enhanced LTP during walking as compared with IMM, rats were either pretreated with muscarinic cholinergic antagonist scopolamine or injected with IgG192-saporin in the medial septum to selectively lesion cholinergic septohippocampal neurons. Pretreatment with scopolamine decreased the LTP induced during walking but did not affect that induced during IMM, such that the difference between the LTP induced during walking and IMM was abolished after scopolamine. Rats injected with IgG192-saporin showed no difference in the LTP induced during walking and IMM, and scopolamine did not reduce the LTP during walking. In contrast, sham-lesion rats showed larger LTP induced during walking than IMM, and the LTP induced during walking was attenuated by scopolamine. This is the first demonstration of an enhancement of hippocampal LTP by physiologically activated cholinergic inputs.

Animals↗
PubMed1989

Pharmacologic discrimination between receptor heterogeneity and allosteric interaction: resultant analysis of gallamine and pirenzepine antagonism of muscarinic responses in rat trachea.

The antagonism of muscarinic receptor-mediated contraction of rat trachea by a range of muscarinic antagonists was quantified by Schild and resultant analysis. Dose-response curves to carbachol, muscarine and oxotremorine were shifted to the right by gallamine and pirenzepine in a parallel manner with no change in maximal response ostensibly indicating simple competitive inhibition. However, Schild analysis indicated differences in the blockade and estimated pKb values with each agonist for both gallamine and pirenzepine. This suggested either that the responses to these three agonists were mediated by a heterogeneous receptor population in this tissue or that the blockade produced by gallamine and by pirenzepine was not competitive. Further Schild analysis with the muscarinic antagonists scopolamine, atropine, 4-diphenylacetoxy-N-methyl piperidine methiodide and (11 [(2-[(diethylamino)methyl]-1-piperidinyl]acetyl)-5,11- dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine 6-one) with carbachol, muscarine and oxotremorine indicated simple competitive antagonism of a homogeneous population of muscarinic receptors. Therefore, the competitivity of binding of atropine, gallamine and pirenzepine with the scopolamine binding site was measured with the recently reported technique of resultant analysis. With this method the effect of various concentrations of the test antagonist on the antagonism produced by specified concentrations of the reference antagonist scopolamine was measured and the equilibrium dissociation constant of the test antagonist-receptor complex estimated. These data indicated that atropine and scopolamine bind to a common binding site on the muscarinic receptor, but that scopolamine and both gallamine and pirenzepine bind to mutually exclusive sites. This result is mine and pirenzepine are allosteric modulators of muscarinic receptors which bind at sites other than that utilized by agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Allosteric Regulation↗
PubMed1985

Evaluation of antimotion sickness drug side effects on performance.

This project has employed a computerized pursuit meter which has a high correlation with operational performance (2) to test the principal antimotion sickness drugs. Proficiency scores on the pursuit meter task were improved over placebo scores in subjects with d-amphetamine 10 mg and 5 mg, the combination of promethazine 25 mg plus scopolamine 0.4 mg with d-amphetamine 10 mg, and the combination of scopolamine 1 mg with d-amphetamine 10 mg. Scores were not significantly different from placebo scores in tests with scopolamine 0.25 mg, 0.5 mg, or 0.6 mg; marezine 50 mg; meclizine 50 mg; or dimenhydrinate 50 mg. This was also true for the combination of scopolamine 1 mg with d-amphetamine 5 mg, and that of promethazine 25 mg with d-amphetamine 10 mg. A statistically significant decrement of performance scores was seen with scopolamine 1 mg or 0.8 mg, and with promethazine 25 mg oral or 25 mg I.M. The combination of promethazine 25 mg with scopolamein 0.4 mg, and that of promethazine 25 mg oral plus 25 mg I.M. with d-amphetamine 10 mg, also gave significant decrements from placebo scores. These results indicate that selected doses and combinations of antimotion sickness drugs can be used without loss of operational proficiency.

Adolescent↗
PubMed1983

Effects of oral phosphatidylcholine on mouse brain choline and acetylcholine.

Oral phosphatidylcholine (PC) in a dose of 250 mg/kg choline equivalent, was given 1, 2, 4, 8, 12, and 24 hr prior to brain assay to groups of fasted mice. The animals were then killed by focused microwave irradiation to the head and brain choline (Ch) and acetylcholine (ACh) assayed by chemical demethylation using gas chromatography-nitrogen phosphorous (GC-NP) detection. Mouse brain Ch levels increased significantly at 4 (P less than .001) and 8 (P less than .01) hr after PC administration. However, there was no change in mouse brain ACh. When this experiment was repeated in a second series of animals at 1, 3, 6, and 12 hr pretreatment with PC, only the 6 hr pretreatment showed a significant increase in brain Ch (P less than .01). The effects of PC administration to alter the known ACh depleting effects of scopolamine were also determined by giving PC orally 4 hr before and scopolamine, 0.1, 0.32, and 1 mg/kg, one hr before microwave irradiation. The known depleting effects of scopolamine pretreatment on brain ACh were confirmed (P less than .001). A large dose (1 mg/kg) of scopolamine also caused a decrease in brain Ch (P less than .001). Pretreatment with PC reversed the depletion of brain Ch induced by scopolamine but had no effect on depleted brain ACh. The results indicate that, although mouse brain Ch can be increased by oral PC, there is no effect on mouse brain ACh.

Acetylcholine↗
PubMed1982

Pirenzepine does not discriminate between pre- and postsynaptic muscarine receptors in the guinea-pig small intestine.

The effects of pirenzepine and scopolamine on presynaptic muscarine receptors (mediating inhibition of acetylcholine release) and postsynaptic receptors (mediating smooth muscle contraction) were compared in the myenteric plexus-longitudinal muscle preparation of the guinea pig. The preparation was preincubated with 3H-choline and subsequently superfused with Tyrode's solution. Field stimulation (1 Hz; 2 min) caused an outflow of 3H-acetylcholine that was depressed by the muscarinic agonist oxotremorine. Both pirenzepine and scopolamine produced shifts to the right of the concentration-response curve for the inhibitory effect of oxotremorine. Similarly, in contraction experiments, pirenzepine and scopolamine competitively antagonized the responses to oxotremorine. From the dose ratios pA2 values for pre- and postsynaptic effects were calculated. The presynaptic pA2 values for pirenzepine (6.90) and scopolamine (9.07) did not differ significantly from the respective postsynaptic pA2 values (6.66 and 9.40). Thus, pirenzepine like scopolamine does not distinguish between muscarine receptors that mediate contraction and those which mediate inhibition of acetyl-choline release.

Acetylcholine↗
PubMed1994

Anticholinergic drugs: effects on oxygen consumption and energy expenditure.

Premedication has been shown to affect both oxygen consumption (VO2) and energy expenditure (EE). The metabolic responses to anticholinergic drugs have not been studied. In this study the effects of anticholinergic drugs on VO2 and EE (calculated from the measured rates of VO2 and carbon dioxide production [VCO2]: EE [kcal/d] = 3.581 x VO2 [L/d] + 1.448 x VCO2 [L/d] - 32.4) were measured in six healthy female volunteers. They were given intramuscular atropine (15 micrograms/kg), glycopyrrolate (8 micrograms/kg), scopolamine (8 micrograms/kg), and placebo in a random double-blind cross-over design. The consecutive sessions were at least 1 wk apart for each subject. VO2 and EE were measured using an indirect calorimetry (Deltatrac). Cardiovascular responses were assessed using standard noninvasive monitoring. Plasma drug concentrations were analyzed using a sensitive modification of radioreceptor assay. Subjective responses were measured with visual analog scale (VAS). Atropine and glycopyrrolate induced a significant increase in heart rate with a simultaneous decrease in pressure rate quotient (PRQ), while scopolamine caused a significant decrease in heart rate with a simultaneous increase in PRQ. Scopolamine significantly decreased both VO2 and EE, whereas glycopyrrolate increased VO2. Atropine had no significant effect on metabolic variables. Only scopolamine induced sedation in this study. In conclusion, atropine, glycopyrrolate, and scopolamine differ not only in their cardiovascular and central nervous system effects, but also in their effects on metabolism.

Adult↗
PubMed1993

MK-801 impairs recognition memory in rhesus monkeys: comparison with cholinergic drugs.

Both N-methyl-D-aspartate (NMDA) and cholinergic receptors are thought to participate in processes of learning and memory. The effects of the noncompetitive NMDA antagonist ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) MK-801 on recognition memory in rhesus monkeys performing a computer-automated version of delayed nonmatching-to-sample DNMS were compared to those of the cholinergic compounds physostigmine and scopolamine. In the sample phase of the test, 20 symbols were presented sequentially every 30 sec on a color monitor fitted with a touch-sensitive screen. These symbols were then presented again in the same order as before, but each symbol was now paired with a different novel symbol. A monkey was rewarded with a food pellet if it touched the symbol in the sample phase and the previously unseen symbol in the choice phase. Physostigmine (3.2, 10 and 32 micrograms/kg), scopolamine (3.2, 10, 17.8 and 32 micrograms/kg) or MK-801 (3.2, 10 and 32 micrograms/kg) was injected i.m. 20, 20 and 30 min before testing, respectively. The highest doses of both MK-801 and scopolamine significantly impaired performance. In addition, scopolamine, but not MK-801, prolonged response latency, whereas MK-801, but not scopolamine, increased response bias. Physostigmine produced a small but significant increase in correct responses at the intermediate dose, but not at the highest dose. These results suggest that both the glutamatergic and the cholinergic systems participate in visual recognition memory in monkeys, though probably by different mechanisms.

Animals↗
PubMed1994

Effects of disrupting the cholinergic system on short-term spatial memory in rats.

The effects of disrupting the muscarinic or nicotinic systems on short-term spatial memory were investigated using a delayed matching to position (DMTP) procedure. Rats were trained on the DMTP until stability and then divided into two groups: one group was implanted with an indwelling cannula aimed at the lateral ventricle. The cannulated group received injections of selective muscarinic antagonists (pirenzepine, M1; AFDX 116, M2; UH-AH 37, M1/M3) or hemicholinium-3 (a choline uptake inhibitor). The remaining animals were treated with conventional muscarinic antagonists (scopolamine, methyl scopolamine) or nicotinic channel blockers (mecamylamine, hexamethonium). Scopolamine, methyl scopolamine and UH-AH 37 disrupted all performance parameters in a non-specific but dose related manner. Pirenzepine disrupted accuracy in a delay, but not dose dependent manner, and exerted no other negative effects on performance. Hemicholinium-3-induced performance deficits showed some elements of effects seen following pirenzepine and scopolamine (delay dependent effects on accuracy, some negative effects on other motoric aspects of performance). AFDX 116 and hexamethonium had no significant effects on performance with respect to control. Mecamylamine reduced accuracy and increased response latencies at the highest dose tested. These data indicate that muscarinic antagonists are more effective at disrupting mnemonic performance than nicotinic blockers, and moreover, that distinct muscarinic receptors may have differential effects on cognitive performance.

Animals↗
PubMed2002

Antagonistic effects of antimuscarinic drugs on alpha 1-adrenoceptors.

We previously observed that noradrenaline (NA)-induced contraction of the portal vein of rabbit was relaxed by the antimuscarinic drugs of atropine sulfate, but not scopolamine hydrobromide. In the present study we examined the possible effect of the antimuscarinic drugs of atropine sulfate, scopolamine hydrobromide, p-fluoro-hexa-hydro-sila-difenidol ( p-F-HHSiD, the M(3)-receptor antagonist) and pirenzepine (the M(1)-receptor antagonist) on alpha(1)-adrenoceptor (AR). Atropine and p-F-HHSiD relaxed the alpha(1)-AR agonist methoxamine-induced contraction of the rabbit portal vein in a concentration-dependent manner; however, scopolamine and pirenzepine had no such inhibitory effect. Radioligand binding studies with the alpha(1)-AR ligand 2-[2-(4-hydroxy-3-[(125)I]iodo-phenyl)ethylaminomethyl]-alpha-tetralone ([(125)I]HEAT) in membrane preparations from mouse whole brain showed that atropine (p K(i)=5.33) and p-F-HHSiD (p K(i)=5.88) had higher affinities than scopolamine (p K(i)=3.17) and pirenzepine (p K(i)<2.70). Furthermore, atropine and p-F-HHSiD had higher affinities for all human cloned alpha(1)-ARs than scopolamine and pirenzepine. The results show that the antimuscarinic drugs atropine and p-F-HHSiD have a direct but weak antagonistic activity against alpha(1)-ARs.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1990

The interaction of acetylcholinergic and serotonergic neural systems on performance in a continuous non-matching to sample task.

The interactions of cholinergic and serotonergic neural systems were investigated in a working memory, continuous non-matching-to-sample task in an operant chamber. Each rat was injected (i.p.) with scopolamine and/or methysergide. The serotonergic system was destroyed by p-chloroamphetamine (PCA) injection. Scopolamine, but not PCA, impaired response accuracy. The effects of methysergide and scopolamine together were not different from scopolamine alone. Scopolamine had a significantly smaller effect on choice accuracy in PCA-treated than in untreated rats.

Acetylcholine↗
PubMed2004

Phosphodiesterase inhibition by sildenafil citrate attenuates the learning impairment induced by blockade of cholinergic muscarinic receptors in rats.

We examined whether treatment with sildenafil citrate (the active compound of Viagra), a cyclic nucleotide phosphodiesterase type 5 inhibitor (PDE5), would reverse the learning impairment induced by cholinergic muscarinic (mACh) receptor blockade [0.75 mg/kg scopolamine HCl, intraperitoneal (i.p.) injections]. Rats were pretrained in a one-way active avoidance of foot shock in a straight runway and the next day received 15 training trials in a 14-unit T-maze. Performance in this maze paradigm requires accurate responding to avoid mild foot shock and has been shown to be sensitive to aging and to impairment in central cholinergic systems. Intraperitoneal (i.p.) injections of scopolamine or saline and sildenafil or vehicle were given 30 and 15 min before training, respectively. The combined treatment conditions were as follows: saline+vehicle (control), scopolamine (0.75 mg/kg)+vehicle, and scopolamine (0.75 mg/kg)+sildenafil (1.5, 3.0, or 4.5 mg/kg). Behavioral measures of performance included deviations from the correct pathway (errors), run time from start to goal, shock frequency, and duration. Statistical analysis revealed that scopolamine impaired maze performance and that sildenafil (3.0 mg/kg) significantly attenuated this impairment in a dose-dependent manner. These results suggest that sildenafil citrate may serve as a cognitive enhancer for therapeutic treatment of cholinergic dysfunction in age-related cognitive decline and Alzheimer's dementia (AD).

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2004

The interactive effects of nicotinic and muscarinic cholinergic receptor inhibition on fear conditioning in young and aged C57BL/6 mice.

Both normal aging and age-related disease, such as Alzheimer's disease, have diverse effects on forebrain-dependent cognitive tasks as well as the underlying neurobiological substrates. The purpose of the current study was to investigate if age-related alterations in the function of the cholinergic system are associated with memory impairments in auditory-cued and contextual fear conditioning. Young (2-3 months) and aged (19-20 months) C57BL/6 mice were administered scopolamine (0.1, 0.3, 0.5, or 1.0 mg/kg), a muscarinic cholinergic receptor antagonist, mecamylamine (1.0 and 2.0 mg/kg), a nicotinic cholinergic receptor antagonist, both scopolamine and mecamylamine (0.1 and 1.0 mg/kg, respectively), or saline prior to training. Training consisted of two white-noise CS (85 dB, 30 s)-footshock US (0.57 mA, 2 s) presentations. Testing occurred 48 h post-training. Scopolamine administration impaired contextual and cued fear conditioning in young and aged mice, although the aged mice were less sensitive to disruption by scopolamine. Mecamylamine did not disrupt conditioned fear in the young or aged mice. Scopolamine and mecamylamine co-administration, at doses sub-threshold for disrupting fear conditioning with separate administration, disrupted contextual and auditory-cued fear conditioning in the young mice, indicating that in the young mice the muscarinic and nicotinic cholinergic processes interact in the formation and maintenance of long-term memories for conditioned fear. Co-administration of both antagonists did not disrupt fear conditioning in the aged mice, indicating that age-related alterations in the cholinergic receptor subtypes may occur.

Aging↗
PubMed2001

Apparent capacity of cardiac muscarinic receptors for different radiolabeled antagonists.

Muscarinic receptors in sarcolemmal membranes, digitonin-solubilized extracts, and purified preparations from porcine atria have revealed a shortfall in the apparent capacity for N-[3H]methylscopolamine, which was only about 75% of that for [3H]quinuclidinylbenzilate. Since binding at near-saturating concentrations of [3H]quinuclidinylbenzilate was inhibited fully at comparatively low concentrations of unlabeled N-methylscopolamine, the data are inconsistent with the notion that [3H]quinuclidinylbenzilate binds selectively to a subclass of distinct, non-interconverting, and mutually independent sites. The discrepancy is resolved by adjusting the specific activity of N-[3H]methylscopolamine to account for unlabeled scopolamine that was identified in some batches of the radioligand. Also, there was no shortfall in capacity when N-[3H]methylscopolamine was devoid of scopolamine, and the predicted effect was obtained when pure N-[3H]methylscopolamine was supplemented with known amounts of scopolamine. A small discrepancy in the levels of scopolamine estimated pharmacologically and by mass spectrometry can be attributed largely to a difference in the efficiency of ionization between scopolamine and N-methylscopolamine. Different capacities for different radioligands are not uncommon with muscarinic and other G protein-coupled receptors, and in some cases the effect may have been due wholly or in part to an unlabeled impurity. Binding data can be mechanistically ambiguous, particularly when acquired only at graded concentrations of the radioligand. The predicted effects of an unlabeled impurity mimic or resemble those of alternative scenarios such as sequestration behind a hydrophobic barrier, a nucleotide-regulated interconversion from one state of affinity to another, and cooperativity between interacting sites.

Animals↗

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