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Nonhippocampal muscarinic receptors are required for nonspatial working memory.

The effects of scopolamine on nonspatial working memory were examined in rats with hippocampal lesions and sham operations. Performance was examined using a continuous conditional discrimination task in an operant box. Choice accuracy measured nonspatial working memory. Response bias, delay interval responses, and response probability measured response preference, stimulus control, motivation, and sensorimotor ability. Scopolamine (0.05, 0.075, 0.1, and 0.15 mg/kg) or methylscopolamine (0.1 mg/kg) was injected (I.P.) 15 min prior to behavioral testing. In both control and hippocampal lesioned groups, choice accuracy declined as the delay interval increased. Scopolamine, but not methylscopolamine, produced a dose-dependent impairment of choice accuracy (interaction of Dose x Delay) in both groups. The scopolamine-induced impairment was not different between the control and hippocampally lesioned rats. Response bias, delay interval responses, and response probability were not affected by scopolamine except at the highest dose, which increased delay interval responses. The results suggest that central muscarinic receptors outside the hippocampus are important for working memory of nonspatial stimuli.

Animals↗

The role of the dorsal raphe-serotonergic system and cholinergic receptors in the modulation of working memory.

The present study investigated the role of the dorsal raphe-serotonergic system and its interaction with muscarinic or nicotinic receptors in the modulation of working memory and motor activity by assessing the effects of serotonin lesion with pCA and cholinergic receptor blockade on the performance of rats in a working memory (delayed non-matching to position, DNMTP) task. The pCA lesion did not impair the choice accuracy or motor activity of rats in the DNMTP-task. The lower dose of scopolamine (0.075 mg/kg) impaired percent correct responses already at the shortest delay which is not indicative of a working memory impairment per se. Scopolamine also disrupted motor activity markedly. The effects of scopolamine 0.075 mg/kg on the choice accuracy were aggravated by pCA treatment. Furthermore, the effects of N-methylscopolamine (0.150 mg/kg) were comparable with scopolamine. The higher dose of mecamylamine (3.0 mg/kg) also interfered with motor activity and it decreased the choice accuracy. The performance disruption induced by mecamylamine was not as severe as that seen with scopolamine. Mecamylamine did not reveal any interaction with the serotonergic lesion. Hexamethonium slightly decreased the percent correct responses, while not interfering with motor activity of rats. The present results suggest that: (i) lesion of serotonergic fibers with pCA does not significantly impair the choice accuracy or interfere with motor activity of rats; (ii) the blockade of cholinergic receptors does not impair working memory per se, but disrupts motor activity, and (iii) pCA lesion of serotonergic fibers aggravates the non-mnemonic choice accuracy impairment induced by central muscarinic blockade, while not interacting with the cholinolytics in modulation of motor activity.

Animals↗

No evidence for involvement of angiotensin II in spatial learning in water maze in rats.

There is increasing evidence suggesting angiotensin II (AII) may inhibit memory formation in a range of conditioned avoidance and habituation learning tasks in rodents. We were interested to determine if AII might also play an inhibitory role in spatial learning. Angiotensin-converting enzyme (ACE) inhibitors, which block the formation of AII from AI, improve acquisition and/or retention of basal performance inhibited by the muscarinic receptor antagonist, scopolamine, in conditioned avoidance and habituation tasks. In hooded Wistar rats, over 5 days of training in a water maze neither the ACE inhibitor, ceranapril 5 and 50 micrograms/kg/day, nor the ACE inhibitor, ramipril 2 and 10 mg/kg/day, altered the increase in path length produced by administration of scopolamine 0.75 mg/kg/day. In probe trails (without platform), on the last day of training, ceranapril 50 micrograms/kg produced a 35% further deterioration in performance in the scopolamine-treated rats (P < 0.02). Administration of the substrate, renin, that leads to AII formation, did not alter water maze performance over 5 days of training. The angiotensin receptor antagonist, losartan, has been shown to improve basal and scopolamine-impaired performance in a habituation task and reverse the inhibition in long-term potentiation produced by diazepam. However, neither losartan 10 and 30 mg/kg/day nor ramipril 2 and 10 mg/kg/day reversed diazepam-impaired (3 mg/kg/day) acquisition of the spatial memory task over 5 days of training. These studies suggest AII does not inhibit spatial learning in rats in the constant platform position water maze task nor does it mediate the inhibitory effects of scopolamine or diazepam in this task.

Angiotensin II↗

Effect of active fragments of arginine-vasopressin on the disturbance of spatial cognition in rats.

The effect of arginine8-vasopressin (AVP1-9) and its metabolite C-terminal fragments on the scopolamine-induced disruption of spatial cognition were investigated using an 8-arm radial maze task in rats. AVP1-9 (10 micrograms/kg s.c.) markedly improved the disruption of spatial cognition by treatment with scopolamine (0.5 mg/kg i.p.), and 60% of the rats recovered to a normal level. The main metabolite of AVP1-9, AVP4-9 (0.5 and 1 ng/kg s.c.) also significantly improved the scopolamine-induced deficit of spatial memory. The activity of AVP4-9 was determined to be about 10000 fold greater than that of AVP1-9. An intracerebroventricular (i.c.v.) injection of 10 fg of AVP5-8, however, showed a lower activity. Both AVP6-8 and AVP5-7, which are both metabolites of AVP5-8, demonstrated no activity. The scopolamine-induced disruption of spatial memory was found to improve after a microinjection of AVP4-9 (1 fg) into the ventral hippocampus (VH) region, but not into the dorsal hippocampus (DH). In an in vivo microdialysis study, the scopolamine-induced acetylcholine (ACh) release from the VH was slightly potentiated by treatment with AVP4-9 (10 fg i.c.v.). In addition, an AVP4-9 analogue, No. 302, which is a synthetic hexapeptide and has a longer half-life, also demonstrated a markedly improved effect, which had a 10-fold higher activity than that with AVP4-9. AVP4-9 is the most potent activity of all the endogenous metabolites of the AVP1-9 and the new synthetic AVP4-9 analogue, No. 302 (obtained from Nippon Chemiphar Co.), substituting Ser for Cys-Cys in hexapeptide, has higher activity than that of AVP4-9. These results indicated [Ser6] hexapeptide has an important role in behavioral activity. Based on these results, it is possible that AVP1-9 and its metabolite AVP4-9 could, thus, be useful in treating cholinergic dysfunction diseases, such as Alzheimer's disease. Hexapeptide may play an important role in improving the spatial memory by promoting the release of ACh in the VH region.

Acetylcholine↗

Effects of the kappa-opioid dynorphin A(1-13) on learning and memory in mice.

The effects of intracerebroventricular administration of dynorphin A(1-13) on scopolamine- and pirenzepine-induced amnesia were investigated in mice by observing the step-down-type passive avoidance response and spontaneous alternation performance. The pre- or post-training, or preretention administration of dynorphin A(1-13) (0.3-10 micrograms) alone failed to affect the passive avoidance response, while scopolamine (1 mg/kg) significantly inhibited it. Dynorphin A(1-13) (1 microgram) given 15 min before training and retention tests, but not immediately after training, significantly improved the scopolamine (1 mg/kg)-induced impairment of passive avoidance response, indicating the anti-amnesic effects of dynorphin A(1-13). A lower dose (1 mg/kg) of the kappa-opioid receptor antagonist (-)-(1R,5R,9R)-5,9-diethyl-2-(3-furyl-methyl)-2'-hydroxy-6,7-benzomorpha n reversed the anti-amnesic effects of dynorphin A(1-13) (1 microgram). In contrast, although dynorphin A(1-13) (1, 3 and 10 micrograms) did not influence spontaneous alternation performance, scopolamine (1 mg/kg) and the muscarinic M1 receptor antagonist pirenzepine (3 micrograms) markedly decreased spontaneous alternation performance. Dynorphin A(1-13) (3, 5.6 and/or 10 micrograms) significantly improved the scopolamine (1 mg/kg)- and pirenzepine (3 micrograms)-induced impairment of spontaneous alternation performance. The improving effects of dynorphin A(1-13) (3 micrograms) were almost completely reversed by pretreatment with nor-binaltorphimine (4 micrograms), a kappa-selective opioid receptor antagonist. These results suggest that the stimulation of kappa-opioid receptors improves memory dysfunctions resulting from the blockade of muscarinic M1 receptors.

Analgesics, Opioid↗

Effects of piracetam on the performance of rats in a delayed match-to-position task.

1. The influence of acute and chronic treatment with piracetam on spatial working memory of rats was examined. A new version of an operant chamber "delayed match-to-position task" was used, in which the animals had to visit one randomly baited box out of three boxes ("choice boxes") in a front panel. Hereafter a delay period began, in which the subjects had to visit an alcove in the back panel ("reference box"). At the end of the delay the animals should return to the front panel and choose the same choice box that was baited before the delay, thereby obtaining a reward. 2. Rats were trained to a stable level of performance, measured as per cent correct responses during sessions of 20 trials. Additionally, the time spent between leaving the choice box and entering the reference box was recorded. Results were obtained from a single group of rats tested repeatedly under different experimental conditions. 3. Injections of scopolamine (0.6 mg/kg) significantly reduced the percentage of correct choices and increased the time spent to reach the reference box. The impairment of correct choices was reversed after chronic treatment with piracetam (250 mg/kg). However, the same treatment did not reverse the effect of scopolamine on the time performance. 4. Scopolamine also induced an increase of repetitive errors (a measure of perseverance), and the chronic treatment with piracetam caused full reversal of this increase. These results represent the first observation of a piracetam induced reversal of scopolamine impairments in a working memory test. 5. In normal animals not treated with scopolamine, acute injection of piracetam had no effect compared to saline injected controls, but chronic treatment with the nootropic significantly enhanced working memory performance. The drug did not affect the time used to reach the reference box.

Animals↗

Involvement of striatal cholinergic receptors in reaction time and fixed-interval responding in rats.

In the present study the effects of intrastriatal scopolamine injections (0, 3, and 10 microg) were evaluated in two operant tasks. The first task tested the reaction time performance of rats, while the other task measured responding in a temporal discrimination test (fixed-interval 30 s). In the reaction time task, in which the rats had to hold down a lever during a variable interval, blockade of striatal muscarinic receptors resulted in a decrease in the total number of trials that the rats completed. Scopolamine also decreased the proportion of anticipatory responses, i.e., premature releases of the lever. The reaction time was not affected after scopolamine infusions. In the temporal discrimination task, the number of emitted responses was decreased after scopolamine infusions. However, the number of trials completed in the fixed interval task was not affected by scopolamine. It was concluded that the striatal cholinergic neurons are involved in organization of motor responses.

Animals↗

Effect of Indian Hypericum perforatum Linn on animal models of cognitive dysfunction.

The effect of a standardised 50% ethanolic extract of Indian Hypericum perforatum (IHp) was investigated for its putative nootropic activity on various experimental paradigms of learning and memory, viz. transfer latency (TL) on elevated plus-maze, passive avoidance (PA), active avoidance (AA), scopolamine and sodium nitrite induced amnesia (SIA & NIA) in albino rats. Pilot studies indicated that single dose administration of IHp had little or no acute behavioural effects, hence the extract of IHp was administered orally at two dose levels (100 and 200 mg/kg, p.o.), once in daily for three consecutive days, while piracetam (500/kg, i.p.), a clinically used nootropic agent, was administered acutely to rats as the standard drug. Control rats were treated with equal volume of vehicle (0.3% carboxymethyl cellulose (CMC)). IHp and piracetam when given alone shortened the TL on day 1, 2, 9 and also antagonised the amnesic effects of scopolamine and sodium nitrite on the TL significantly. IHp had no significant per se effect on the retention of the PA in rats. Only the higher dose (200 mg/kg, p.o.) produced a significant reversal of scopolamine induced PA retention deficit but no significant reversal was observed with sodium nitrite. Piracetam showed significant per se facilitatory effect on PA retention and also reversed the scopolamine and sodium nitrite induced impaired PA retention. In the AA test, IHp in both the doses, and piracetam, facilitated the acquisition and retention of AA in rats and the IHp effects were found to be dose dependent. Both the doses of IHp and piracetam significantly attenuated the scopolamine and sodium nitrite induced impaired retention of AA. These results indicate a possible nootropic action of IHp, which was qualitatively comparable with that induced by piracetam.

Amnesia↗

Stimulation of alpha-1 adrenergic receptors facilitates spatial learning in rats.

The present experiments were designed to examine the effects of alpha-1 adrenergic stimulation and inhibition on memory encoding and to investigate whether the alpha-1 adrenergic and muscarinic cholinergic systems interact in the regulation of spatial navigation behavior in the Morris water maze test and we also studied the effects of D-cycloserine, a partial agonist at the glycine binding site on the N-methyl-D-aspartate (NMDA) receptor complex, on the performance of scopolamine-treated rats in this task. Pre-training subcutaneous administration of St-587 (a putative alpha-1 agonist) at 1000 micrograms kg-1 or 1500 micrograms kg-1 improved water maze navigation to a hidden platform. Prazosin (an alpha-1 antagonist), 300-2000 micrograms kg-1, did not significantly impair the spatial navigation performance. Pre-training administration of prazosin 1000 micrograms kg-1, but not 300 micrograms kg-1, slightly potentiated the deficit in water maze navigation seen after scopolamine (200 micrograms kg-1, pre-training intraperitoneal injection). Pre-training administration of St-587 at a dose 1500 micrograms kg-1, but not 500 micrograms kg-1, slightly ameliorated the scopolamine-induced (200 micrograms kg-1) impairment in performance of rats. Pre-training administration of prazosin at doses 300 or 1000 micrograms kg-1 or St-587 at doses 500 micrograms kg-1 or 1500 micrograms kg-1 did not have any significant influence on the scopolamine-induced (200 micrograms kg-1) increase of swimming speed. Furthermore, D-cycloserine at the dose of 300 micrograms kg-1 but not 1000 or 3000 micrograms kg-1 reversed the scopolamine (200 micrograms kg-1)-induced deficit in acquisition of the water maze task but not the increase in motor output (increased swimming speed). These results indicate that the stimulation of alpha-1 adrenoceptors may facilitate the encoding of new information. These findings suggest that alpha-1 adrenergic mechanisms do not participate or at least are not the most critical part of the noradrenergic system in the interaction between noradrenaline and muscarinic receptors in the modulation of learning and memory. In addition, these results suggest that D-cycloserine may be effective in alleviating states of central cholinergic hypofunction.

Adrenergic alpha-1 Receptor Agonists↗

Effects of a muscarinic antagonist on various components of female sexual behavior in the rat.

The effects of the muscarinic antagonist scopolamine on lordosis, solicitation, pacing, approach, attractivity, and activity were evaluated in ovariectomized rats brought into sexual receptivity with estrogen and progesterone. Systemic (1 mg/rat) or intraventricular (10 micrograms bilaterally) administration of scopolamine significantly reduced the incidence of lordosis and solicitation behaviors and disrupted typical pacing of sexual contacts with a stimulus male. In addition, females avoided contact with a stimulus male, but not a stimulus female, following intraventricular infusion of scopolamine. The levels of general activity and frequencies of sexual contacts were similar in females treated intraventricularly with scopolamine and vehicle solutions. Consequently, scopolamine disrupted various components of sexual behavior, including lordosis, solicitation, pacing, and approach, without altering female attractivity or general activity.

Animals↗

Environmentally induced analgesia: age-related decline in a neurally mediated, nonopioid system.

In order to examine the function of an endogenous system of pain inhibition during aging, rats (3, 14, and 24 months old) were exposed to 90 s of hind-paw shock. To investigate the pharmacology and anatomy involved in the production of hind-paw shock induced analgesia, the effects of naltrexone (7 mg/kg), scopolamine (5 mg/kg), and adrenalectomy were examined. Results revealed that there was an age-related reduction in the degree of analgesia produced by hind-paw shock. Naltrexone and adrenalectomy did not alter the analgesia elicited by hind-paw shock. Scopolamine reduced the analgesia produced by hind-paw shock, and the effectiveness of scopolamine blockage declined with age. The results of a second experiment demonstrated that the effect of scopolamine was specific to the analgesia induced by hind-paw shock because scopolamine was ineffective in modifying the analgesia produced by a different stressor (cold water). These results suggest that the decline in hind-paw shock induced analgesia is the result of an alteration in the function of the cholinergic system.

Adrenalectomy↗

An assessment and comparison of the effects of oxotremorine, D-cycloserine, and bicuculline on delayed matching-to-sample performance in rats.

The effects of a muscarinic antagonist (scopolamine), a muscarinic agonist (oxotremorine), an agonist at the N-methyl-D-aspartate receptor site (D-cycloserine), and a GABAa antagonist (bicuculline) on working memory were compared using rats performing a delayed matching-to-sample task. When administered on their own, oxotremorine, D-cycloserine, and bicuculline had no effect on performance in the current task. When administered concurrently with scopolamine, oxotremorine (at 1 dose) and bicuculline (at 2 doses) improved accuracy (in terms of percentage correct) by ameliorating the scopolamine-induced increase in response bias. None of the drugs, however, were successful in ameliorating the scopolamine-induced impairment in bias-free recognition performance per se (as measured by Log d). Therefore, none of the drugs examined were able to fully ameliorate all aspects of the memory impairment caused by scopolamine.

Animals↗

Anticholinergic medication in diagnostic endoscopy of the upper gastrointestinal tract.

The effects of two different forms of anticholinergic medication on endoscopic quality and patient discomfort were studied in 235 consecutively observed out-patients. Patients were randomized to receive either scopolamine i.v. and placebo transdermally, saline i.v. and saline transdermally, or placebo i.v. and scopolamine transdermally. No differences could be observed between the groups with respect to gastric motor function or endoscopic quality (as judged by the endoscopist), or discomfort during endoscopy (as judged by the patient). Transdermally applied scopolamin resulted in a significant increase (2p = 0.002) in post-endoscopy discomfort due to dryness of the mouth. The findings speak against the use of i.v. scopolamine (20 mg) or transdermally applied scopolamine (0.5 mg) in endoscopy of the upper gastrointestinal tract.

Administration, Cutaneous↗

Increased anticholinergic sensitivity following closed skull impact and controlled cortical impact traumatic brain injury in the rat.

Evidence suggests that prolonged memory deficits in several neurodegenerative diseases are attributable to deficits in central cholinergic neurotransmission. In traumatic brain injury (TBI), such cholinergic deficits also may contribute to prolonged memory disturbances. This study determined whether moderate magnitudes of TBI produced by controlled cortical impact and mild magnitudes of experimental TBI produced by a new closed head impact technique in rats would produce an enhanced vulnerability to the memory disruptive effects of scopolamine, a muscarinic cholinergic receptor antagonist. Water maze performance was used to determine changes in cholinergic hippocampal function following TBI. In the first experiment, rats received a moderate level of TBI by means of a controlled cortical impact. A Morris water maze task assessed spatial memory function on days 30-34 postinjury. During the 5 day assessment period, statistical analyses showed a group main effect for swim latency. Subsequent post hoc analyses indicated that injured rats had significantly longer latencies on days 30 and 31 (p < 0.05, injury vs sham controls). By days 32-35, injured rats showed no statistically significant deficits in spatial memory performance. On day 35, scopolamine (1 mg/kg, IP) was injected into injured rats and sham-injured rats 15 min prior to being retested in the maze. Results showed that although the scopolamine had no effects on the performance of the sham-injured rats, the same dose significantly (p < 0.05) increased the latency to find the hidden platform in the injured group. In the second experiment, rats received a mild concussive closed head impact. Water maze performance was assessed on days 8-12 postinjury. No significant water maze performance deficits were observed. On day 13, injured and uninjured rats were pharmacologically challenged with scopolamine (1 mg/kg) and retested. Similar to the first experiment, injured rats manifested a significantly greater (p < 0.05) sensitivity to scopolamine than sham controls. The results from both experiments suggest that concussive and more severe levels of TBI can produce an enhanced vulnerability to disruption of cholinergically mediated memory function, even when memory function appears normal in the absence of secondary challenges. These data demonstrate that covert deficits can persist after the recovery of normal function. These deficits may be attributable to a decrease in the ability of cholinergic neurons to function properly. These data also provide important insights into features of receptor-coupled disturbances that could contribute to the maintenance of enduring cognitive deficits following TBI.

Acetylcholine↗

Working memory failure by combined blockade of muscarinic and beta-adrenergic transmission in the rat hippocampus.

INTRAHIPPOCAMPAL administration of the muscarinic acetylcholine receptor antagonist scopolamine at a dose of 3.2 micrograms/side significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points) in the working memory task with a three-panel runway setup, whereas 0.32 microgram/side scopolamine did not affect working memory errors. The beta-adrenoceptor antagonist propranolol (10 mg/kg, i.p.) had no effect on working memory error, but it produced a significant increase in working memory errors when administered in combination with intrahippocampal scopolamine at the behaviourally ineffective dose (0.32 microgram/side). The increase in working memory errors induced by intrahippocampal administration of 0.32 microgram/side scopolamine to rats treated with 10 mg/kg propranolol was decreased by concurrent injection of the cholinesterase inhibitor physostigmine (3.2 micrograms/side). D-Cycloserine (the partial agonist at the glycine bindings site on the NMDA receptor/channel complex) at a dose of 10 micrograms/side reduced the increase in working memory errors induced by intrahippocampal 0.32 microgram/side scopolamine combined with 10 mg/kg propranolol. These results suggest that neural mechanisms regulated cooperatively by hippocampal muscarinic and beta-adrenergic transmission underlie working memory performance, and that modification of NMDA function contributes to such interactive regulation of working memory processes in the hippocampus.

Adrenergic beta-Antagonists↗

Alpha-sialyl cholesterol reverses AF64A-induced deficit in passive avoidance response and depletion of hippocampal acetylcholine in mice.

1. The effect of alpha-sialyl cholesterol (alpha-SC; alpha-D-N-acetylneuraminyl cholesterol) on disturbances of the central cholinergic system induced by ethylcholine mustard aziridinium ion (AF64A) and by scopolamine were studied by means of a step-down passive avoidance response and locomotor activities in mice. The levels of acetylcholine (ACh) in certain regions of the brain were measured to assess the neurochemical recovery promoted by alpha-SC. 2. Treatment with AF64A (2.5, 5 and 10 nmol, i.c.v.) impaired the 24 h retention latencies of animals in a dose-dependent manner, and scopolamine (0.5 mg kg-1, i.p.) also impaired the retention performance. Administration of alpha-SC (1 and 4 mg kg-1, p.o.) once daily for 13 days improved the retention performance in AF64A-treated animals in a dose-dependent manner, but not in the scopolamine-treated animals. 3. Treatment with AF64A (2.5, 5 and 10 nmol, i.c.v.) and scopolamine (0.5 mg kg-1, i.p.) increased vertical and horizontal locomotor activities. alpha-SC dose-dependently attenuated the increase in locomotor activities induced by 2.5 nmol of AF64A, but not the locomotor activities caused by 5 or 10 nmol of AF64A, or scopolamine (0.5 mg kg-1, i.p.). 4. The deficit retention performance of AF64A-treated animals was associated with depletion of ACh levels in the hippocampus, but not in the septum or cerebral cortex. Administration of alpha-SC to AF64A-treated animals dose-dependently reversed the depletion of ACh levels in the hippocampus. 5. The results indicate that alpha-SC had significant effects after oral administration of AF64A-treated animals. The behavioural recovery promoted by alpha-SC may be based on the reversal of ACh depletion in the hippocampus.

Acetylcholine↗

Pharmacological but not physiological modulation of cortical acetylcholine release by cholinergic mechanisms in the nucleus basalis magnocellularis.

The role of muscarinic transmission in the activation of cholinergic neurons ascending to the neocortex from the nucleus basalis magnocellularis (NBM) was investigated. The release of acetylcholine (ACh) from the neocortex of urethane-anesthetized rats was measured using microdialysis, and a second microdialysis probe was inserted into the NBM to apply drugs to the NBM and to measure ACh release from this area. Cholinergic neurons in the NBM were activated synaptically by stimulating the pedunculopontine tegmentum (PPT). Systemically administered scopolamine greatly increased the PPT stimulation evoked cortical release of ACh when the cortical probe was perfused with the cholinesterase inhibitor neostigmine. PPT stimulation evoked release was also high when the cortical probe was perfused with atropine plus neostigmine, but it was not increased any further by systemic scopolamine or by scopolamine perfused through the NBM probe. When neostigmine was perfused through the NBM probe, PPT stimulation evoked cortical ACh release was halved, but the release was restored when the NBM solution also contained scopolamine. The resting release of ACh within the NBM was increased by local neostigmine, but evoked release in the NBM was large only in the presence of local scopolamine. Both of these increases were blocked by perfusion of the NBM with tetrodotoxin. These results suggest that muscarinic transmission within the NBM does not control the activation of cholinergic neurons under physiological conditions, when the diffusion of ACh is limited by its hydrolysis. However, when ACh is allowed to diffuse to a wider area, it may inhibit the release of an excitatory transmitter, probably glutamate, via presynaptic muscarinic receptors.

Acetylcholine↗

Botulinum toxin effect on salivary flow rate in children with cerebral palsy.

OBJECTIVE: To investigate the effectiveness of botulinum neurotoxin (BoNT) type A in reducing salivary flow rate in children with cerebral palsy (CP) with severe drooling. METHODS: During a controlled clinical trial, single-dose BoNT injections into the submandibular salivary glands were compared with scopolamine treatment. Forty-five school-aged children were included. Salivary flow rates from all major glands were obtained at baseline and compared with measurements during the interventions. Basic statistics consisted of analysis of difference scores. RESULTS: Compared with baseline, the mean decrease in submandibular flow was 25% during scopolamine and 42% following BoNT injections. The difference scores were significant with maximum reductions 2, 4, and 8 weeks following BoNT. Of all children, 95% responded during scopolamine. Response rates for BoNT were significantly lower and varied from 69% at 2 weeks to 49% at 24 weeks after injection (the end of the study). Four patients discontinued scopolamine therapy because of side effects. Only incidentally mild side effects were reported from BoNT. CONCLUSIONS: Intraglandular BoNT injections significantly reduce salivary flow rate in the majority of drooling CP children, demonstrating high response rates up to 24 weeks. The procedure is simple to perform, effective, and safe when ultrasound guidance is used. The anticholinergic effect of BoNT exceeds that of scopolamine. As anticholinergic drugs are frequently contraindicated because of side effects, BoNT injections offer an alternative in the treatment of drooling.

Adolescent↗