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PubMed2001

Kainic acid-induced substantia nigra seizure in rats: behavior, EEG and metabolism.

RATIONALE: In order to clarify the role of substantia nigra pars reticulata (SNr) upon the development of epileptic seizure, kainic acid (KA) was injected into a unilateral SNr. MATERIALS AND METHODS: Wistar rats weighing 250-350 g were used. A stainless-steel cannula and depth electrode were inserted stereotaxically into the left substantia nigra pars reticulata (SNr). At 7 days after surgery, 1.0 microg of KA was injected into the left SNr. Experiment 1: In eight rats, behavior and electroencephalograms (EEG) were continuously recorded for about 30 h, and intermittently monitored following 1 month. Experiment 2: Two hours after KA injection into SNr, rats demonstrated status epilepticus. Then, 100 microCi/kg of [(14)C]2-deoxyglucose (2-DG) was intravenously injected in seven rats, and the rats were processed for autoradiographic study. RESULTS: Changes in behavior and EEG: On EEG, a secondary generalized seizure status was observed at about 70 min after KA injection. In video, limbic seizure manifestations such as salivation were observed as a initial symptom and followed by rolling and generalized tonic seizures. [(14)C]deoxyglucose autoradiographic study demonstrated increased local cerebral glucose metabolism in the medial and lateral septal nucleus, substantia nigra, hippocampus, parietal cortex, piriform cortex, medial and lateral geniculate nucleus, anterodorsal, lateral and ventral nucleus of the thalamus, amygdala and midbrain reticular formation. SUMMARY: The result suggested that the substantia nigra played an important role in the secondary generalization in the substantia nigra seizure model due to the decreased function of the GABAergic projection system induced by an excessive epileptic excitation of SNr.

Action Potentials↗
PubMed2002

Characterization of a new muscarinic receptor antagonist PNU-171990 in guinea pig, cat and human smooth muscle.

The present study was done to characterize a new compound, PNU-171990, 2-diisopropyl aminoethyl 1-phenylcyclopentane carboxylate hydrochloride, with functional smooth muscle selectivity at least as high as tolterodine. In vitro homogenates of guinea pig cerebral cortex, parotid gland, heart, urinary bladder, and Chinese hamster ovary (CHO) cells expressing human muscarinic m(1)-m(5) receptors PNU-171990 did not show selectivity for any subtype (pK(i), 7.72-8.64). PNU-171990 caused a parallel shift in the concentration-response curve for carbachol-induced contraction of smooth muscle from guinea pig bladder (pK(B), 7.65), guinea pig ileum (pK(B), 8.48), and human ileum (pK(B), 7.10). In vivo PNU-171990 inhibited urinary bladder contraction with a significantly lower ID(50) than on the salivary secretion (206 and 706 nmol/kg, respectively, P<0.05). In conclusion, PNU-171990 is a competitive and potent muscarinic receptor antagonist in vitro with a numerically better selectivity ratio for the bladder contraction over salivation in vivo than tolterodine.

Adult↗
PubMed2002

The subtypes of muscarinic receptors for neurogenic bladder contraction in rats.

We evaluated in vivo functional selectivity profiles for muscarinic M(2) and M(3) subtypes of four muscarinic antagonists: Compound A (a novel muscarinic receptor antagonist with M(2)-sparing antagonistic activity), darifenacin, (a muscarinic M(3) receptor antagonist); methoctramine (a muscarinic M(2) receptor antagonist) and tolterodine (a nonselective muscarinic receptor antagonist), and compared the inhibition potency on distention-induced bladder contraction in rats. In an in vivo functional study, Compound A (0.03-10 mg/kg, i.v.) showed antimuscarinic activity with high selectivity for M(3) (salivation) over M(2) (bradycardia) (>100-fold). Darifenacin (0.01-0.3 mg/kg, i.v.) showed only slight selectivity for M(3) over M(2) (3.7-fold). Methoctramine (0.003-1 mg/kg, i.v.) showed the reverse selectivity profile (0.077-fold). Tolterodine (0.003-0.3 mg/kg, i.v.) showed less selectivity (1.2-fold). Compound A at M(3) inhibitory doses (0.1 and 0.3 mg/kg, i.v.) showed inhibition in a distention-induced neurogenic bladder contraction model, and its maximal inhibitory effects were about 60% at an even higher dose (3 mg/kg). Methoctramine at M(2) inhibitory doses (0.03 and 0.1 mg/kg, i.v.) did not significantly affect distention-induced bladder contraction. When tolterodine and darifenacin caused inhibition of distention-induced bladder contraction, its maximal inhibitory effects were similar to that of Compound A. Therefore, these findings suggest that Compound A would be an excellent pharmacological tool to give a better understanding of which subtypes of muscarinic receptors act in bladder function so far, and muscarinic M(3), but not M(2), receptors mainly mediate the cholinergic component of distention-induced bladder contraction.

Animals↗
PubMed2003

Comparative behavioural effects of typical and atypical antipsychotic drugs in rhesus monkey.

Behavioural effects of typical and atypical antipsychotic agents were compared in unrestrained rhesus monkey (Macaca mulatta) living in social colonies. The behaviours were categorized as social, solitary and abnormal. They were studied with the help of video cameras fixed in the observation chamber. The behavioural effects were recorded on videotape and analyzed for significant changes. Chlorpromazine (2.5-10 mg/kg, i.m.), haloperidol (0.01-0.04 mg/kg, i.m.), risperidone (0.05-0.2 mg/kg, p.o.) and clozapine (5-20 mg/kg, p.o.) induced significant alterations in parameters of social and solitary behaviour. Chlorpromazine produced a marked decrease in locomotor activity whereas haloperidol showed marked extrapyramidal effects. Risperidone produced minimal extrapyramidal effects and sedation compared to haloperidol and chlorpromazine. Clozapine had intermediate extrapyramidal effects similar to those of chlorpromazine but it produced hypersalivation and dose-related sedation. Thus, risperidone had advantages over the other antipsychotics used in this study because it did not produce salivation, had minimal extrapyramidal effects and caused less sedation. These antipsychotic drugs produced many behavioural effects in the rhesus monkey that were similar to their clinically observed effects. A study of behavioural effects in the monkey can thus be a useful predictive tool in the preclinical development of new antipsychotics.

Administration, Oral↗
PubMed1997

Anti-tremor activity of talipexole produced by selective dopamine D2 receptor stimulation in cynomolgus monkeys with unilateral lesions in the ventromedial tegmentum.

The anti-tremor activity of talipexole (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine dihydrochloride, B-HT 920 CL2, Domin), a non-ergot dopamine D2 receptor agonist which possesses alpha 2-adrenoceptor agonistic and 5-HT3 receptor antagonistic properties, was examined in monkeys with a unilateral lesion in the ventromedial tegmentum. Talipexole dose dependently suppressed the tremor and had ED50 values of 34 micrograms/kg s.c. and 84 micrograms/kg p.o. The anti-tremor effect of talipexole occurred at much lower doses than that of an ergot dopamine receptor agonist, bromocriptine (2-bromo-alpha-ergocryptine mesilate, ED50; 2.5 mg/kg s.c.), and talipexole acted synergistically in combination with L-DOPA (3,4-dihydroxyphenylalanine). In ventromedial tegmentum-lesioned monkeys, anti-tremor doses of talipexole did not cause emetic behavior, but had sedative effects. Conversely, monkeys given bromocriptine exhibited oral movement, salivation and vomiting when anti-tremor effects were observed, but not marked sedative behavior at any of the doses investigated. During repeated administration of talipexole (a daily dose of 50 micrograms/kg s.c. for 21 days), the extent and duration of the anti-tremor effect did not change, but those of the sedative effect decreased gradually. The anti-tremor effect of talipexole was significantly suppressed by sulpiride, but not by SCH 23390 (7-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) or yohimbine, while the sedative effect was inhibited by sulpiride and yohimbine. The main metabolites of talipexole had no anti-tremor or sedative effects. These results indicate that talipexole exerts its anti-tremor activity via selective dopamine D2 receptor stimulation.

Administration, Oral↗
PubMed1998

Unexpected antipsychotic-like activity with the muscarinic receptor ligand (5R,6R)6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane .

(5R,6R)6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3 .2.1]octane (PTAC) is a potent muscarinic receptor ligand with high affinity for central muscarinic receptors and no or substantially less affinity for a large number of other receptors or binding sites including dopamine receptors. The ligand exhibits partial agonist effects at muscarinic M2 and M4 receptors and antagonist effects at muscarinic M1, M3 and M5 receptors. PTAC inhibited conditioned avoidance responding, dopamine receptor agonist-induced behavior and D-amphetamine-induced FOS protein M5 expression in the nucleus accumbens without inducing catalepsy, tremor or salivation at pharmacologically relevant doses. The effect of PTAC on conditioned avoidance responding and dopamine receptor agonist-induced behavior was antagonized by the acetylcholine receptor antagonist scopolamine. The compound selectively inhibited dopamine cell firing (acute administration) as well as the number of spontaneously active dopamine cells (chronic administration) in the limbic ventral tegmental area (A10) relative to the non-limbic substantia nigra, pars compacta (A9). The results demonstrate that PTAC exhibits functional dopamine receptor antagonism despite its lack of affinity for the dopamine receptors and indicate that muscarinic receptor partial agonists may be an important new approach in the medical treatment of schizophrenia.

Animals↗
PubMed1998

Effects of SR 141716A after acute or chronic cannabinoid administration in dogs.

The effects of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1H-pyrazole-3-carboxamide HCl (SR 141716A), a specific cannabinoid receptor antagonist, were assessed in the dog static ataxia test after either acute treatment with two cannabinoid receptor agonists, delta9-tetrahydrocannabinol and arachidonylethanolamide (anandamide), or chronic treatment with delta9-tetrahydrocannabinol. As previously reported, acute intravenous (i.v.) injected delta9-tetrahydrocannabinol produced dose-dependent cannabinoid effects, including marked static ataxia, prancing, loss of muscle tone, and incoordination. The behavioral profile of anandamide was distinctly different in that it produced a loss of muscle tone and considerable sedation with little static ataxia, prancing, or incoordination. Despite these qualitative differences between the two agonists, SR 141716A blocked the acute behavioral effects of both drugs indicating a cannabinoid receptor mechanism of action. Interestingly, SR 141716A was able to precipitate a withdrawal syndrome in delta9-tetrahydrocannabinol-tolerant dogs, but failed to produce any observable effects in dogs receiving chronic vehicle injections. Acute toxicity caused by anandamide, which was not blocked by SR 141716A, precluded conducting dependence studies with this drug. The delta9-tetrahydrocannabinol precipitated withdrawal syndrome included diarrhea, vomiting, excessive salivation, decreases in social behavior, and increases in restless behavior and trembling. This is the first demonstration of a precipitated withdrawal syndrome in a non-rodent species.

Animals↗
PubMed1985

Aedes aegypti: model for blood finding strategy and prediction of parasite manipulation.

Aedes aegypti mosquitoes salivate during intradermal probing of vertebrate prey before ingesting blood (Griffiths and Gordon 1952). Nonsalivating mosquitoes locate blood more slowly; this difference was ascribed to an anti-platelet activity found in the mosquito's saliva (Ribeiro et al. 1984). Mosquitoes infected with Plasmodium gallinaceum suffer pathology that specifically impairs saliva anti-hemostatic activity but without reducing volume of output (Rossignol et al. 1984). The complexity of the feeding apparatus of mosquitoes provides opportunity for a variety of strategies in which pathogens may produce specific lesions that enhance their transmission, but the variables that affect the duration of probing by mosquitoes have not been defined. We sought to resolve this complexity by identifying and quantifying relevant parameters of probing behavior. Mosquitoes thrust their mouthparts repeatedly through their host's skin while searching for blood. Female A. aegypti thrust at 7-sec intervals. If this search results in success, feeding ensues. Alternatively, the mosquito "desists," the mouthparts stylets are withdrawn, and the mosquito attempts to feed at another site. Even after previous desistance, the probability of finding blood remains undiminished. Functions for the probability of feeding success and desistance over time were derived using data from observations on 300 mosquitoes. The probability of feeding success was interpreted as being a function of the density of vessels in the skin, their geometric distribution, and the conditions locally affecting hemostasis. During each probe, the probability of desisting increased linearly with time, and after desisting once, mosquitoes tended to desist more rapidly. A model was developed incorporating Monte Carlo simulation which closely fit observed data. By changing values for the several parameters of the probability functions, we predicted modes in which parasites may manipulate their hosts to enhance transmission, both to and from the vector. In particular, parasite strategies in the vector would include induced salivary pathology; increased duration of probing thrusts; decreased desistance time; and inhibited phagoreception. Predicted parasite strategies in the reservoir host would include increased skin vascular volume and impaired host hemostasis. Our model supports the hypothesis of a mutualistic interaction of malaria and mosquitoes.

Aedes↗
PubMed2000

Salivary proteins of aphids, a pilot study on identification, separation and immunolocalisation.

Salivary proteins (SPs) of Schizaphis graminum, Acyrthosiphon pisum and Myzus persicae were studied after probing and feeding on different artificial diets. Salivary sheaths as well as apical lumps of saliva were found, presumably representing subsequently excreted saliva of different types. Phenoloxidase, pectinase and peroxidase activities were detected by staining the enzyme-converted products, thus confirming these enzyme activities found earlier by others. Proteinase and cellulase were not found. SPs in three major SDS-PAGE bands, at 154 and 66/69 kDa, were collected in fluid diets (soluble fraction) and as sheath material (solid fraction) attached to the membranes covering these diets. Proteins of both fractions presumably represented the enzymatic activities found, although this could not be proven. The lack of electrophoretic mobility of the undenaturated (isoelectrofocusing and PAGE) active proteins meant that they could not be separated, whereas the mobile denaturated (SDS-PAGE) proteins had lost their enzyme activity. Polyclonal antibodies, anti-SP154 and anti-SP66/69, both cross-reacted to most salivary proteins in Western blots. They also reacted to sheath material and to the principal salivary glands. For further studies of saliva some monoclonal antibodies were developed. The complexity of salivation and the relation of the results obtained to the behaviourally known secretion periods is discussed.

Journal Article↗
PubMed2000

Evidence that dilation of isolated salivary ducts from the tick Dermacentor variabilis (Say) is mediated by nitric oxide.

We used pharmacological methods to test the hypothesis that female Dermacentor variabilis salivary ducts dilated when dopamine-stimulated and that dilation was nitric oxide-mediated. Stimulation with dopamine resulted in an increased diameter (19.7%) compared to unstimulated ducts (P<0.005). Pretreatment with L-NAME, an inhibitor of nitric oxide synthase, or cytochalasin D abolished the dilation. Addition of L-arginine to L-NAME-treated ducts partially restored the ability to dilate. A cuticular coil composed of a series of concentric rings ran the length of the duct adjacent to the epithelial cell layer. In stimulated ducts, the center-to-center periodicity of these rings increased from 0.59 µm in unfed ducts to 1.0 µm from partially fed ducts (P<0.05). When the ducts from partially fed females were stimulated with dopamine, the periodicity increased further to 1.75 µm (P<0.05), suggesting the coils moved further apart in response to stimulation. Prominent folds lining the lumen of unstimulated ducts were less pronounced in stimulated preparations, suggesting that the cuticle stretches, thereby increasing lumen size. Actin was localized in epithelial cells as a honeycomb pattern that we suggest links the epithelial cells to the rings. Together, these data support the following hypothesis: stimulated ducts dilated during fluid production; dilation involved an actin-based system, and was mediated by nitric oxide. Dilation of the duct may enhance its role as a reservoir for saliva produced by the acini during the period between imbibition and salivation.

Journal Article↗
PubMed1997

Pearls and perils in the management of prolonged, peculiar, penetrating esophageal foreign bodies in children.

BACKGROUND/PURPOSE: Most retained esophageal foreign bodies (FB) are identified soon after ingestion and are easily extracted. A minority of FB ingestions are not identified for weeks to years and present significant problems for retrieval. The purpose of this study was to describe the diagnostic and therapeutic strategies needed to care for children who have chronic esophageal FBs. METHODS: Five children were identified as having retained esophageal FBs 2 months to 2 years after ingestion. During the same 3-year period, 100 children who had acute FBs were identified and had their foreign bodies removed endoscopically. The average age of the children was 3 years (range, 2.4 to 3.5). RESULTS: The average age of the five children identified in this study was 3 years. The items ingested included coins, a heart pendant, a clothespin spring, and a toy soldier. Complications from chronically retained foreign bodies were bronchoesophageal fistula, mediastinitis, esophageal diverticulum, and lobar atelectasis. One patient died from an aortoesophageal fistula. In all children, endoscopic removal was attempted. Barium esophagram was then performed, and foreign bodies were eventually removed via right thoracotomy. CONCLUSIONS: Long-retained esophageal FBs are extremely morbid and life threatening. History most often identifies excess salivation, new onset asthma, and/or recurrent upper respiratory infections. Three diagnostic adjuncts are helpful in identifying the presence of a long retained FB: (1) Chest x-ray (PA and lateral), (2) barium swallow, and (3) esophagoscopy. Indications for thoracotomy for removal of foreign body include (1) Poor endoscopic visualization of FB because of inflammatory tissue and (2) Herald bleeding during endoscopy.

Aorta, Thoracic↗
PubMed2000

Association of L-DOPA with recovery following Ayurveda medication in Parkinson's disease.

Ayurveda, the Indian system of traditional medicine, uses a concoction of several spices, herbs and minerals for the treatment of diseases. In a clinical prospective study we have evaluated the efficacy of Ayurveda treatment (a concoction in cow's milk of powdered Mucuna pruriens and Hyoscyamus reticulatus seeds and Withania somnifera and Sida cordifolia roots) in 18 clinically diagnosed (with a mean Hoen and Yahr value of 2.22) parkinsonian patients. As per Ayurveda principles, 13 patients underwent both cleansing (for 28 days) and palliative therapy (56 days), 5 patients underwent palliative therapy alone (84 days). Only the former group showed significant improvement in activities of daily living (ADL) and on motor examination as per UPDRS rating. Symptomatically, they exhibited better response in tremor, bradykinesia, stiffness and cramps as compared to the latter group. Excessive salivation worsened in both the groups. Analyses of powdered samples in milk, as administered in patients, revealed about 200 mg of L-DOPA per dose. The study establishes the necessity of cleansing therapy in Ayurveda medication prior to palliative therapy. It also reveals contribution of L-DOPA in the recovery as observed in Parkinson' disease following Ayurveda medication.

Female↗
PubMed2001

Evidence for specific analgesic activity of a muscarinic agonist selected among a new series of acetylenic derivatives.

The central and peripheral effects of a series of Oxotremorine/Oxotremorine-M derivatives, previously characterized as muscarinic agonists in isolated preparations, were investigated in in vivo experiments. The molecules were tested for their antinociceptive activity (formalin licking and acetic acid writhing tests) and for their ability to induce tremor in mice. Peripheral cholinergic effects such as salivation, bradycardia, hypotension and intestinal hypermotility were studied in anaesthetized rats. All of the acetylenic compounds acted as muscarinic analgesics displaying the same order of potency shown in in vitro studies. The Oxotremorine-like subset showed a clearer distinction between doses producing antinociception and doses exerting undesirable central/peripheral side effects compared to the Oxotremorine-M derivatives. The most promising profile was displayed by the isoxazolin-3-one Oxotremorine-like derivative (compound 1a), which was characterized by a wider therapeutic window than that of the parent molecule Oxotremorine. Indeed, it produced atropine-sensitive analgesia (ID50 about 0.1 mg/kg i.p.) in the absence of tremorogenic (EC50 2.73 mg/kg i.p.) and cardiovascular effects while lethality occurred only at higher doses (LD50 19 mg/kg i.p.). These results suggest that such a derivative could be a candidate for further development of selective muscarinic analgesics.

Acetylene↗
PubMed2001

Catecholamines in human saliva.

Catecholamines are readily detectable in human saliva but their origin is unclear. Norepinephrine (NE) was stable in saliva stored at 4 degrees for 2 hours but 11 +/- 3% degraded after storage at 25 degrees for 1 hour. We intravenously infused 3H-NE into humans and measured levels of 3H-NE and its metabolites in both saliva and forearm venous plasma (a site whose plasma NE levels reflect both local uptake and release of NE). 3H-NE levels in saliva continued to rise for 1 hour even though forearm plasma levels had plateaued by 5 min. By 65 min into the infusion the ratio of 3H-NE:non-radioactive NE was similar in saliva and forearm venous plasma. The ratio of NE:epinephrine (E) was similar in saliva and forearm venous plasma at all time points. Chewing induced salivation, and at least tripled the amount of NE, E and 3H-NE released into saliva per minute, but decreased their concentration in saliva by as much as one half. Saliva NE level was unaltered after 15 min of standing but was increased by 31% after 1 hour of upright posture. Our data imply that the NE present in human saliva comes from both the bloodstream and from salivary sympathetic nerves. The finding that diffusion of blood NE into saliva takes roughly 1 hour to complete suggests that NE in saliva is a poor index of acute changes in sympathetic activity.

Adult↗
PubMed1997

In vivo pharmacology of butylthio[2.2.2] (LY297802 / NNC11-1053), an orally acting antinociceptive muscarinic agonist.

Butylthio[2.2.2] (LY297802 / NNC11-1053) is a mixed muscarinic cholinergic receptor agonist/antagonist that produces antinociception in mice and rats. As such, butylthio[2.2.2] may have therapeutic utility in the treatment of pain. Butylthio[2.2.2] was fully efficacious in the mouse grid shock, writhing, tail-flick and hot plate tests with ED50 values ranging from 1.5 to 12.2 mg/kg after oral administration. In contrast, the ED50 values for morphine ranged from 7.3 to 72 mg/kg after oral administration. Scopolamine was a competitive antagonist of the antinociceptive effects of butylthio[2.2.2]. Butylthio[2.2.2] did not produce either salivation or tremor at therapeutic doses; rather, there was a 50- to >100-fold separation between therapeutic doses and doses which produced side-effects. Butylthio[2.2.2] had high affinity for muscarinic receptors, but little if any affinity for other neurotransmitter receptors or uptake sites. In isolated tissues, butylthio[2.2.2] was an agonist with high affinity at M1 receptors in rabbit vas deferens, an antagonist at M2 receptors in guinea pig atria as well as an antagonist at M3 receptors in guinea pig urinary bladder. Although it has been suggested that M1 receptors mediate the antinociceptive effects of muscarinic agonists, M1 efficacy is not a requirement for antinociception, and, in vivo, the antinociceptive effects of muscarinic agonists are blocked by the intrathecal administration of pertussis toxin, indicating the involvement of m2 or m4 receptors. Since butylthio[2.2.2] is an M2 antagonist, antinociception is therefore most likely mediated by m4 receptors. Butylthio[2.2.2] is currently undergoing clinical development as a novel analgesic.

Administration, Oral↗
PubMed1998

A bridging study of LU 25-109 in patients with probable Alzheimer's disease.

Lu 25-109 is a functionally selective partial M1 agonist with M2/M3 antagonist properties. This double-blind, placebo-controlled, two-part, inpatient bridging study was designed to evaluate the safety and tolerability of multiple oral doses of Lu 25-109 in patients with Alzheimer's Disease(AD), and to determine the maximum tolerated dose (MTD) in this population. In the first part of the study, the fixed-dose MTD was to be determined in five consecutive panels of 6 patients each (4 Lu 25-109/2 placebo). Doses for the five panels were 100, 125, 150, 200, and 225 mg tid for 7 days. Cholinergic adverse events such as increased salivation, dizziness, and gastrointestinal symptoms were observed at all doses studied. The dosing of fixed-dose panels was discontinued after 3 days at 200 mg tid due to unacceptable gastrointestinal adverse events. Thus, 150 mg tid was defined as the fixed-dose MTD. The second part of the study, conducted in a single panel of 8 patients (6 Lu 25-109/2 placebo), was designed to determine if patients could tolerate higher doses of Lu 25-109 when administered on a titration regimen. Patients were to receive doses that were 50%, 75%, 100%, 125%, and 150% of the fixed dose MTD, with dose increases every five days. The first dose, 75 mg tid, was very well-tolerated; however, as in the first phase of the study, patients did not tolerate the 200 mg tid dose. Thus, the titration regimen employed did not improve the overall tolerability of Lu 25-109.

Aged↗
PubMed1999

Cholinergic facilitation of trace eyeblink conditioning in aging rabbits.

The hippocampus is importantly involved in learning and memory, and is severely impacted by aging. In in vitro hippocampal slices, both the post-burst afterhyperpolarization (AHP) and spike-frequency accommodation are reduced in hippocampal pyramidal neurons after hippocampally-dependent trace eyeblink conditioning, indications of increased cellular excitability. The AHP results from the activation of outward potassium currents, including sI(AHP) and muscarine-sensitive I(M). The AHP is significantly increased in aging hippocampal neurons, potentially contributing to age-associated learning deficits. Compounds which reduce the AHP and spike-frequency accommodation could facilitate learning in normal aging or in age-associated dementias such as Alzheimer's disease. The cholinesterase inhibitor metrifonate enhances trace eyeblink conditioning by aging rabbits and reduces the AHP and accommodation in hippocampal CA1 neurons in a dose-dependent manner. These reductions are mediated by muscarinic cholinergic transmission as they are blocked by atropine. Hippocampal neurons from metrifonate treated but behaviorally naive rabbits were more excitable and not desensitized to the effects of metrifonate since the AHP and accommodation were further reduced when metrifonate was bath applied to the neurons. These observations suggest that the facilitating effect of chronic metrifonate on acquisition of hippocampally dependent tasks is mediated at least partially by increasing the baseline excitability of CA1 pyramidal neurons. The issue of whether learning can be facilitated with muscarinic cholinergic agonists, in addition to cholinesterase inhibitors, was addressed by training aging rabbits during intravenous treatment with the M1 agonist CI1017. A dose-dependent enhancement of acquisition was observed, with rabbits receiving 1.0 or 5.0 mg/ml CI1017 showing comparably improved learning rates as those receiving 0.5 mg/ml or vehicle. Sympathetic side effects, mainly excess salivation, were seen with the 5.0 mg/ml dose. Post-training evaluations suggested that the effective doses of CI1017 were enhancing responsivity to the tone conditioned stimulus. These studies suggest that muscarinic cholinergic neurotransmission is importantly involved in associative learning; that learning in aging animals may be facilitated by enhancing cholinergic transmission; and that the facilitation may be mediated through actions on hippocampal neurons.

Acetylcholine↗
PubMed1999

Nitric oxide modulates salivary amylase and fluid, but not epidermal growth factor secretion in conscious rats.

The involvement of the L-arginine/NO pathway in the control of salivary fluid, amylase and epidermal growth factor (EGF) secretion was investigated in conscious rats. For the collection of saliva, an oesophageal cannula was implanted. To obtain steady secretion, submaximal carbachol background infusion was given. Different treatments included NO synthase inhibitor N(G)-nitro-L-arginine (NOLA; with or without phentolamine, propranolol), L-arginine, D-arginine and NO donor 3-morpholinosydnonimine (SIN-1) administration. Volume, amylase activity and EGF output in the secreted fluid were determined in 30 min mixed saliva samples. Carbachol infusion alone produced a modest, sustained salivary fluid and amylase secretion. NOLA (30 mg/kg) further increased both fluid (p<0.001) and amylase outputs (p<0.001). These latter effects were prevented by L-arginine but not by D-arginine or by phentolamine. Propranolol administration decreased both fluid and amylase secretion below the carbachol plateau, and NOLA did not modify this suppressed secretory rate. SIN-1 did not alter either volume or amylase secretion. Interestingly, NOLA given without carbachol did not modify salivation. Neither carbachol nor NOLA changed salivary EGF output. The present results suggest that the L-arginine/NO pathway has a modulatory role in the cholinergic control of salivary amylase secretion, but not in EGF output. The mechanisms of inhibitory action of NO on salivary fluid and amylase secretion remain to be identified.

Amylases↗