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Central depressant action of cesium in mice.

Cesium chloride (CsCl) at several dose levels (1.25-20.0 mEq/kg IP) was administered acutely to albino mice whose behavior was compared with that in corresponding saline controls. Motor activity decreased and Straub tail occurred in a dose-related manner. Signs of autonomic disturbance, diarrhea, and salivation were seen with toxic doses. Subchronic administration of CsCl (5.0 mEq/kg/day IP for 7 days) exerted a phenothiazine-like effect in mice, reducing amphetamine-induced aggregation toxicity and enhancing pentobarbital-induced hypnosis. The antinociceptive action of morphine was unaltered by identical multiple administrations of CsCl. These results indicate a specific neurosuppressant action of CsCl on mouse CNS and suggest exploration of this alkali earth metal for antipsychotic-like activity.

Amphetamine↗

Tricyclic antidepressants and peripheral anticholinergic activity.

Peripheral anticholinergic activity of single acute doses of three tricyclic antidepressants (amitriptyline 50 mg, desipramine 50 mg, doxepin 100 mg) and placebo was assessed by several physiologic measures in normal male volunteers. Amitriptyline and doxepin produced similar significant depressions in salivary flow and finger sweating compared to placebo, while desipramine produced no change. Supine and standing blood pressures and standing pulse yielded significant differences among the drugs. Measures in at least three areas (salivation, perspiration, and pulse-blood pressure) offer a simple and reliable battery of tests for the peripheral autonomic effects of tricyclic antidepressants.

Adolescent↗

A histological study of the effects of different alpha-adrenergic and cholinergic agonists on the rat submandibular gland.

Rat submandibular glands were exposed to various sialagogues, including carbachol, clonidine, noradrenaline and cyclocytidine. The effects of these drugs were morphologically compared. Clonidine, which is an alpha-2-agonist, caused no depletion of granules in the serous cells examined. Noradrenaline and cyclocytidine, which are alpha-1-agonists, showed remarkable depletion of secretory granules in the serous cells. Carbachol caused visible and abundant salivation in the animals, but was found to produce only partial granular depletion of both serous and mucous cells. To induce experimentally a complete depletion of granular serous cells, cyclocytidine was found to be an excellent choice as a sialagogue with no side-effects on the cardiac and respiratory system.

Adrenergic alpha-Agonists↗

In vivo and in vitro actions of mammalian tachykinins.

Recently, two kassinin-like tachykinins have been isolated from mammalian nervous tissue. The potencies of these peptides, substance K (neurokinin alpha) and neuromedin K (neurokinin beta) were compared with those of substance P, eledoisin, and kassinin in various pharmacological systems in vivo and in vitro. In contracting the isolated guinea-pig ileum and rabbit jejunum the potencies of eledoisin, kassinin, substance K, and neuromedin K were 13-80% that of substance P. In the rat vas deferens substance K and neuromedin K potentiated the electrically induced contractions with potencies similar to those of eledoisin and kassinin; they were 46-236 times as potent as substance P. In stimulating salivation in the rat after intravenous injection, eledoisin, kassinin, and substance K were respectively 2.3, 1.3 and 0.33 times as potent as substance P. In contrast, neuromedin K exhibited negligible activity. Each peptide tested led to a short fall in blood pressure after intravenous injection in the rabbit, substance P being 12-250 times as potent as the other peptides. Substance P was 20 times as potent as substance K or neuromedin K in inducing vasodilatation in the rat hind paw in vivo. Of the peptides tested, only substance P (10 nmol/min) significantly increased the release of histamine from the rat isolated hindquarter preparation. The results are discussed with respect to several theories of tachykinin receptor heterogeneity.

Animals↗

Effect of intravenous atropine and methylatropine on heart rate and secretion of saliva in man.

Intravenous atropine sulphate (0.25, 0.40, 0.75 and 1.50 mg), atropine methylnitrate (0.08, 0.13 and 0.25 mg) and saline were given to 72 healthy medical students. The effects on heart rate and rhythm, systolic and diastolic blood pressure and salivary secretion were studied. Salivation was inhibited by all the doses of the two drugs. There was a clear dose-response relationship and methylatropine was about 3 times as potent as atropine. Heart rate was accelerated by 0.75 and 1.50 mg atropine, and 0.25 mg methylatropine, whereas 0.25 mg atropine and 0.08 and 0.13 mg methylatropine induced bradycardia, which was considered to be due to a peripheral action. It is suggested that the drugs act as partial agonists at muscarinic receptors. No clear effect on blood pressure was seen, except for the highest dose of atropine, after which the diastolic pressure was increased. 20 out of 59 subjects who received anticholinergics developed supra-ventricular arrhythmias; with both drugs periods of nodal rhythm were most common. They appeared shortly after the injection and usually lasted for a few minutes.

Adult↗

Effect of high doses of nicotine in pigs. I. Changes of the electrocardiogram.

Pigs in which venous catheters were positioned for long-term use were injected i.v. with high doses of nicotine in physiol. saline. The LD50 was 2.656 mg/kg body weight. Clinical symptoms were mainly: forced respiration, muscular tremor to tetanoid spasms, cyanosis of the skin, salivation and sometimes vomiting. The degree and duration of symptoms were dose-dependent. Ecg changes in anaesthesized pigs following intravenous nicotine injections of 0.126 mg/kg and 0.378 mg/kg at 15 minutes' interval were immediately commencing disturbances of the heart rate in form of bradycardia and asystolia. After 5 sec we observed extrasystoles, tachycardia, sino-auricular block and AV-block of first and second degree as well as a number of T- and P-changes. Changes of the ecg were observed generally for 10 to 15 min, however, the T-wave remained sometimes negative or biphasic-preterminal negative for some hours.

Animals↗

The relationship between motor and secretory behaviors in classical appetitive conditioning.

Three hungry dogs received pairings of food with an accessible, illuminated panel. This resulted in the dogs' approaching the lighted panel and salivating. Despite the similarity of these conditioning procedures to those used in a large body of research primarily with avians, however, the dogs did not physically contact the lighted stimulus panel. These results bear on several issues concerning the form and direction of classically conditioned behaviors.

Animals↗

Glycopyrrolate methobromide: 2. comparison with atropine sulphate in anaesthesia.

A double blind study of 98 patients was undertaken to compare the clinical usefulness of atropine and glycopyrrolate for pre-anaesthetic medication and their relative effectiveness in antagonizing the muscarinic effects of neostigmine methylsulphate given to reverse neuromuscular blockade. Intramuscular administration of atropine 0.4 mg or of glycopyrrolate 0.2 mg produced the same degree of dryness of the pharynx. However, glycopyrrolate was found to be a more potent antagonizer of the increased salivation induced by neostigmine. By intramuscular administration, both drugs produced the same degree of tachycardia, although atropine tended to cause no change in the pulse rate or even to produce bradycardia in a greater number of patients. Administered intravenously, atropine produced a more significant tachycardia in a large number of patients prior to neostigmine administration, although the protection against a decreased pulse rate from neostigmine is greater in those patients who received glycopyrrolate. It would appear, therefore, that glycopyrrolate is more effective in antagonizing the muscarinic effects of neostigmine methylsulphate.

Adolescent↗

Neuroleptic malignant-like syndrome: a complication of acute organophosphate poisoning.

We report a 60-yr-old woman with schizophrenia, who manifested a neuroleptic malignant (NM)-like syndrome after acute organophosphate poisoning (OPP). She attempted suicide by ingesting 40% emulsions of DMTP (S-2,3-dihydro-5-methoxy-2-oxo-1,3,4-thiadizol-3-yl-methyl O,O-dimethyl phosphorodithioate) 100 ml. On admission, she was unconscious and demonstrated convulsions, depressed respiratory movements, miosis and profuse salivation. Plasma cholinesterase concentration (842 IU.L-1) was very low and OPP was diagnosed. She was treated with gastric lavage, atropine and pralidoxime (PAM). By the seventh day after admission, symptoms of OPP disappeared and serum ChE had recovered to a sub-normal level. On the 13th day, she demonstrated coma, high fever (41.0 degrees C) and lead-pipe rigidity. Serum CPK was increased (1631 IU.L-1). Dantrolene sodium iv was administered for three days. Body temperature began to decrease in 24 hr, and her consciousness, muscle rigidity and other neurological symptoms returned to normal by the 16th day after admission. She was discharged from the hospital without sequelae 55 days after admission. We conclude that OPP can predispose to an NM-like syndrome and that dantrolene may be effective in the management.

Atropine↗

Nasal ketamine for paediatric premedication.

Ketamine in a dose of 6 mg.kg-1 was nasally administered in 86 healthy children (ASA I and II), aged from two to five years undergoing elective general, urological or plastic surgery, 20 to 40 min before the scheduled surgery time. These children were compared with 62 others, also aged from two to five years, in whom promethazine and meperidine, 1 mg.kg-1 of each, were injected im. Sedation was started as excellent in 48 and as adequate in 19 children in the ketamine group, compared with nine and 12 respectively in Group 2 (P < 0.05), while salivation was similar in both groups. We conclude that nasal ketamine is an alternative to im preanaesthetic sedation administration in children aged from two to five years.

Administration, Intranasal↗

Lipopolysaccharide-induced subsensitivity of protease-activated receptor-2 in the mouse salivary glands in vivo.

Protease-activated receptor-2 (PAR-2) acts as a modulator of multiple physiological/pathophysiological functions including salivary exocrine secretion. Given the supersensitivity of endothelial PAR-2 under endotoxaemia, we investigated if endotoxin/lipopolysaccharide (LPS) could alter the sensitivity of PAR-2 in the salivary glands. The in vivo salivation in response to i.v. administration of the PAR-2-activating peptide SLIGRL-NH2, but not of carbachol, gradually decreased 6-20 h after LPS administration in the mice. The LPS-induced hyporeactivity to the PAR-2 agonist was partially reversed by repeated administration of aprotinin, a non-specific protease inhibitor. PAR-2 mRNA levels in the salivary glands, as assessed by the semi-quantitative RT-PCR analysis, remained unchanged following LPS challenge. Our findings indicate that in contrast to the supersensitivity of endothelial PAR-2 as described previously, subsensitivity of PAR-2 in the salivary glands develops during the LPS-induced systemic inflammation, which might involve desensitisation of PAR-2 by endogenous proteases.

Animals↗

Cues paired with a low dose of alcohol acquire conditioned incentive properties in social drinkers.

RATIONALE: Drug-related cues may acquire incentive properties through classical conditioning. OBJECTIVE: The present study investigated whether arbitrary stimuli paired with a low dose of alcohol would evoke differential skin conductance, salivary, craving and attentional orienting responses compared to arbitrary stimuli paired with vehicle in a sample of social drinkers. METHODS: A discriminative classical conditioning procedure was employed, in which subjects repeatedly consumed two drinks, which differed in terms of the flavour of the drink and the colour of the glass in which it was administered. One of the drinks (CS+) always contained 0.2 g/kg ethanol in flavoured tonic water and the other drink (CS-) always contained flavoured tonic water only. Alcohol craving, amount of salivation, and skin conductance level were measured in response to CS+ and CS- during conditioning training. After conditioning training, the frequency with which subjects directed their attention to CS+ and CS- drinks and their choice of drinks was assessed. RESULTS: Comparable taste intensity ratings were given for alcohol and placebo drinks. Higher ratings of craving in the presence of CS+ and higher feelings of "lightheaded", "relaxed" and "contented" after consumption of the CS+ drink (compared with CS-) were observed over successive conditioning sessions. Skin conductance level was also higher in response to CS+ compared to CS-. After conditioning sessions were completed, subjects shifted their gaze more frequently towards CS+ than CS-, although they did not choose to consume more CS+ than CS- drinks when instructed to choose between them. CONCLUSIONS: These data suggest that conditioned responses to an arbitrary cue paired with alcohol will develop rapidly and provide further support for incentive salience theories of drug addiction.

Adolescent↗

Comparison of pramipexole and amisulpride on alertness, autonomic and endocrine functions in healthy volunteers.

RATIONALE: In a previous study in healthy volunteers, the anti-Parkinsonian drug pramipexole caused sedation and pupil dilatation, consistent with the stimulation of inhibitory D(2)/D(3) autoreceptors on the ventral tegmental area dopaminergic neurones. The sedation may be related to the removal of the dopaminergic excitation of the locus coeruleus (via the meso-coerulear pathway), whereas the pupil dilatation may be due to the removal of the dopaminergic excitation of the Edinger-Westphal nucleus (via a putative meso-pupillomotor pathway). OBJECTIVES: We investigated the hypothesis that amisulpride, a D(2)/D(3) receptor antagonist, would have effects opposite to those of pramipexole on alertness, pupillary and endocrine functions. MATERIALS AND METHODS: Pramipexole (0.5 mg), amisulpride (50 mg), and their combination were administered to 16 healthy males in a balanced, cross-over, double-blind design. Tests included measures of alertness (Pupillographic Sleepiness Test, critical flicker fusion frequency, visual analogue scales), pupillary functions (resting pupil diameter, light and darkness reflex responses), non-pupillary autonomic functions (heart rate, blood pressure, salivation, core temperature), and endocrine functions [blood concentrations of prolactin, growth hormone (GH) and thyroid stimulating hormone (TSH)]. Data were analysed by ANOVA. RESULTS: Pramipexole reduced alertness and pupillary light reflex response amplitude, tended to reduce core temperature, reduced prolactin levels and increased GH levels. Amisulpride reduced pupil diameter, increased the amplitude of the light reflex response and prolactin and TSH levels. CONCLUSIONS: The opposite effects of pramipexole and amisulpride on alertness, pupillary function and pituitary hormone levels are consistent with their interactions with inhibitory D(2)/D(3) receptors on VTA neurones and in the tuberoinfundibular system.

Adult↗

Behavioral effects of ketamine, an NMDA glutamatergic antagonist, in non-human primates.

RATIONALE: The dopamine hypothesis is the most widely investigated theory underlying schizophrenia and the mechanisms of action for antipsychotic drugs. However, recent studies call into question this proposal. Thus, the focus has turned towards other mechanisms, one of which has been glutamatergic systems. Phencyclidine (PCP), a potent NMDA receptor antagonist, causes a schizophrenic-like psychosis in normal volunteers and exacerbates psychotic symptoms in patients with schizophrenia. Ketamine, like PCP, is a non-competitive NMDA receptor antagonist, which is short acting and has been used as a dissociative anesthetic as well as a research tool in psychosis. OBJECTIVE: To clarify the role of NMDA antagonists further and to develop an animal model of these actions, ketamine was studied across a range of behaviors in Cebus monkeys. METHODS: Thirty-two (six male, 26 female) Cebus monkeys, which were previously sensitized to neuroleptics, were tested with a wide range of doses of ketamine that spanned the clinical effect range from threshold effects to full anesthesia. Behaviors scored included sedation/arousal, locomotor activity, extrapyramidal symptoms of parkinsonism and dystonia, as well as reactivity. RESULTS: Ketamine produced dose-related increases in parkinsonian bradykinesia and dystonia as well as salivation. There were dose-related decreases in locomotor activity and reactivity to environmental stimuli. These effects had short time courses and steep dose-response curves. CONCLUSIONS: These results suggest that ketamine-induced behavioral effects in non-human primates offer a model for studying a glutamatergic role in motor and mental function such as attention or perception.

Animals↗

Physiological and subjective responding to alcohol cue exposure in alcoholics and control subjects: evidence for appetitive responding.

36 alcoholic patients, recruited from a treatment program, and 20 non-alcohol abusing control subjects were tested for their reactions to alcohol and non-alcohol cues. The cue exposure paradigm included audio-visual (video), tactile, olfactory, and guided imagery cue components related to alcohol and non-alcohol beverages. Response measures were analyzed for significant difference based on alcohol and non-alcohol cue and patient type. Among the subjective ratings, alcohol cue specific increases in alcohol craving, desire to drink, alcohol-like high, positive drinking expectancies and alcohol-like withdrawal were seen in alcoholic subjects. Among the physiological measures, alcohol cue specific increases in salivation were seen in alcoholic subjects. Changes in heart rate, skin conductance and temperature were not specific to alcohol cues, or to alcoholic patients. The smelling of alcohol had the greatest impact on alcohol craving and skin conductance in alcoholic subjects. These findings demonstrate robust subjective effects, and weak physiological effects, in response to a multidimensional alcohol cue exposure paradigm. The response profile indicates cue reactivity in alcoholics as an appetitive based form of alcohol craving.

Adult↗

Hemodynamic and non-bronchial effects of ipratropium bromide.

Older anticholinergic agents such as stramonium and atropine have significant non-pulmonary effects. The non-pulmonary effects of a new quaternary anticholinergic, ipratropium bromide, have been studied both in the United States and abroad; these effects include inhibition of salivation, interference with micturition, and ocular effects such as pupil size, visual acuity, and intraocular pressure. Hemodynamic effects such as heart rate, blood pressure, and blood gas changes have also been studied. These evaluations have been performed in animals and in healthy and sick human subjects, following administration of ipratropium parenterally and by inhalation in a variety of dosage ranges. Ipratropium, a muscarinic inhibitor, would be expected to have effects similar to those of atropine. The most conspicuous result of these studies has been the low incidence of significant changes, even at high dose levels, when ipratropium bromide is administered by inhalation.

Aged↗

Relative secretory contributions of the three major salivary glands of the rat in response to substance P and super-sensitivity.

In vivo salivation in the rat in response to a range of intravenous doses of substance P was studied. The ducts of the parotid, submandibular and sublingual glands were cannulated. The secretory threshold dose of substance P, in microgram/kg, was 0.05-0.1 in the submandibular glands, 0.2 in the parotid glands and 0.2-0.5 in the sublingual glands. The maximal secretory response in all three types of glands was obtained at a dose level of 5-10 micrograms/kg. The total amount of saliva secreted at this dose level from the three pairs of glands was calculated to about 300 mg; the submandibular glands were responsible for 65 per cent, the parotid glands for 32 per cent and the sublingual glands for 3 per cent. Parasympathetic decentralization but not sympathetic denervation caused the sublingual glands to develop a super-sensitivity to substance P. The secretory effect of substance P was not exerted via cholinergic, alpha-adrenergic or beta-adrenergic receptors.

Animals↗

Amylase in parotid saliva of rats after sympathetic nervous decentralization.

The marked increase in the amylase secretion that occurs in parasympathetic saliva some days after sympathetic ganglionectomy occurred after decentralization also; hence, it results from lack of impulses from the central nervous system. It occurred whether salivation was evoked by activating muscarinic receptors with methacholine, peptidergic receptors with substance P or physalaemin, or alpha-adrenoceptors with phenylephrine. Unilateral operation affected to some degree the contralateral gland also.

Amylases↗