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Peripheral treatment with cholinergic or adrenergic agonists results in salivation and the possibility of synergy between cholinergic and adrenergic efferent mechanisms in the control of salivation has been proposed. Central injections of the cholinergic agonist pilocarpine also induce salivation, while the effects of central injections of noradrenaline (norepinephrine) are not known. Here (a) the effects of intracerebroventricular (i.c.v.) injection of noradrenaline on the salivation induced by i.c.v. or intraperitoneal (i.p.) injection of pilocarpine and (b) the receptors involved in the effects of central noradrenaline on pilocarpine-induced salivation were investigated. Male Holtzman rats with a stainless-steel guide cannula implanted into the lateral ventricle were used. Rats were anaesthetized with tribromoethanol (200mg/kg body weight) and saliva was collected on small, preweighed cotton balls inserted into the animal's mouth. Noradrenaline (40, 80 and 160 nmol/1 microl) injected i.c.v. reduced the salivary secretion induced by pilocarpine (0.5 micro mol/1 microl) injected i.c.v.. Noradrenaline (80 and 160 nmol/1 microl) injected i.c.v. also reduced the salivation induced by pilocarpine (4 micromol/kg) injected i.p. Previous treatment with the alpha(2)-adrenergic receptor antagonists RX 821002 (40, 80 and 160 nmol/1 microl) or yohimbine (160 and 320 nmol/1 microl) abolished the inhibitory effect produced by i.c.v. injection of noradrenaline on pilocarpine-induced salivation in rats. Prazosin (alpha(1)-adrenergic receptor antagonist) injected icv did not change the effect of noradrenaline on pilocarpine-induced salivation. Prior icv injection of only RX 821002 (80 or 160 nmol/1 microl) or yohimbine (320 nmol/1 microl) increased pilocarpine-induced salivation. The results show that (1) contrary to its peripheral effects, noradrenaline acting centrally inhibits cholinergic-induced salivation in rats; (2) central mechanisms involving alpha(2)-adrenergic receptors inhibit pilocarpine-induced salivation.
The M(1) and M(3) subtypes are the major muscarinic acetylcholine receptors in the salivary gland and M(3) is reported to be more abundant. However, despite initial reports of salivation abnormalities in M(3)-knockout (M(3)KO) mice, it is still unclear which subtype is functionally relevant in physiological salivation. In the present study, salivary secretory function was examined using mice lacking specific subtype(s) of muscarinic receptor. The carbachol-induced [Ca(2+)](i) increase was markedly impaired in submandibular gland cells from M(3)KO mice and completely absent in those from M(1)/M(3)KO mice. This demonstrates that M(3) and M(1) play major and minor roles, respectively, in the cholinergically induced [Ca(2+)](i) increase. Two-dimensional Ca(2+)-imaging analysis revealed the patchy distribution of M(1) in submandibular gland acini, in contrast to the ubiquitous distribution of M(3). In vivo administration of a high dose of pilocarpine (10 mg kg(-1), s.c.) to M(3)KO mice caused salivation comparable to that in wild-type mice, while no salivation was induced in M(1)/M(3)KO mice, indicating that salivation in M(3)KO mice is caused by an M(1)-mediated [Ca(2+)](i) increase. In contrast, a lower dose of pilocarpine (1 mg kg(-1), s.c.) failed to induce salivation in M(3)KO mice, but induced abundant salivation in wild-type mice, indicating that M(3)-mediated salivation has a lower threshold than M(1)-mediated salivation. In addition, M(3)KO mice, but not M(1)KO mice, had difficulty in eating dry food, as shown by frequent drinking during feeding, suggesting that salivation during eating is mediated by M(3) and that M(1) plays no practical role in it. These results show that the M(3) subtype is essential for parasympathetic control of salivation and a reasonable target for the drug treatment and gene therapy of xerostomia, including Sjögren's syndrome.
We determined the effects of moxonidine and rilmenidine 20 nmol (alpha(2)-adrenergic and imidazoline receptor agonists) injected into the medial septal area (MSA) on the pilocarpine-induced salivation, when injected intraperitoneally (i.p.), of male Holtzman rats weighing 250-300 g, with stainless-steel cannula implanted into the MSA. The rats were anesthetized with zoletil 50 mg kg(-1) b.wt. (tiletamine chloridrate 125.0 mg and zolazepan chloridrate 125.0 mg) into quadriceps muscle intramuscularly (IM), saliva was collected using pre-weighed small cotton balls inserted in the animal's mouth. The pre-treatment with moxonidine injected into the MSA reduced the salivation induced by pilocarpine (1 mg kg(-1)) injected i.p. (12+/-3 mg min(-1)) vs. control (99+/-9 mg min(-1)). The pre-treatment with rilmenidine 40 nmol also reduced the salivation induce by pilocarpine injected i.p. (20+/-5 mg min(-1)) vs. control (94+/-7 mg min(-1)). Idazoxan 40 nmol (imidazoline receptor antagonist) injected into the MSA previous to moxonidine and rilmenidine partially blocked the effect of moxonidine and totally blocked the rilmenidine effect in pilocarpine-induced salivation injected i.p. (60+/-8 and 95+/-10 mg min(-1), respectively). Yohimbine 40 nmol (alpha(2)-adrenergic receptor antagonist) injected into the MSA previously to moxonidine and rilmenidine partially blocked the moxonidine effect but produced no change on the rilmenidine effect on i.p. pilocarpine-induced salivation (70+/-6 and 24+/-6 mg min(-1), respectively). Injection of these alpha(2)-adrenergic and imidazoline agonists and antagonists agents i.p. produced no change on i.p. pilocarpine-induced salivation. These results show that central, but not peripheral, injection of alpha(2)-adrenergic and imidazoline agonists' agents inhibit pilocarpine-induced salivation. Idazoxan, an imidazoline receptor antagonist, totally inhibits the rilmenidine effect and partially inhibits the moxonidine effect on pilocarpine-induced salivation. Yohimbine produced no change on rilmenidine effect but partially inhibited the moxonidine effect. Both of these antagonists when injected into the MSA previous to pilocarpine i.p. potentiated the sialogogue effect of pilocarpine. The results suggest that alpha(2)-adrenergic/imidazoline receptor of the MSA when stimulated blocked pilocarpine-induced salivation in rats when injected intraperitonially. These receptors of the medial septal area have an inhibitory mechanism on salivary secretion.
A method of quantitatively measuring tachykinin-induced salivation in conscious, male, Sprague-Dawley rats is described. Salivation is quantified by determining the weight of a preweighed, absorbant foam cube after it has been used to swab the oral cavity of a tachykinin challenged rat. Salivation is induced by intravenous (i.v.) injection of sialogogues (microgram/kg) via the lateral tail vein. Measurements are made immediately after injection. Substance P (Sub.P), Sar9, Met (O2) 11Substance P (Sar9 Sub.P), a selective neurokinin (NK) 1 receptor agonist, Physalaemin and Eledoisin are equipotent sialogogues as determined by this method. Neurokinin A (NKA), the endogenous NK2 receptor agonist, is 0.27 (0.14-0.46) times as potent as Sub. P, while (Suc-[Asp6, MePhe8]Substance P(6-11), (senktide), a selective NK3 receptor agonist, only induced salivation at 300 microgram/kg. Acetylcholine (Ach) is only 0.006 (0.002-0.012) times as potent as Sub.P. Treatment with the neurokinin antagonist [D-Arg1, D-Trp7,9 Leu11]-Substance P (spantide) dose-dependently inhibits Sub. P stimulated salivation. Atropine dose-dependently inhibits Ach induced salivation but is inactive against Sub.P-induced salivation. These data are consistent with literature values and indicate that this method provides a simple, quantitative model, free of any possible anesthetic side effects, for the measurement of neurokinin stimulated salivation and the assessment of potential neurokinin antagonists in vivo.
Salivation induced by intraperitoneal (i.p.) injections of pilocarpine (cholinergic agonist) is reduced by intracerebroventricular (i.c.v.) injections of moxonidine (alpha(2) adrenergic and imidazoline receptor agonist). In the present study, we investigated the involvement of central alpha(2) adrenergic receptors in the inhibitory effect of i.c.v. moxonidine on i.p. pilocarpine-induced salivation. Male Holtzman rats with stainless steel cannula implanted into the lateral ventricle (LV) were used. Saliva was collected using pre-weighted small cotton balls inserted into the animal's mouth under ketamine (100 mg x kg(-1)) anesthesia. Salivation was induced by i.p. injection of pilocarpine (4 micromol x kg(-1)). Pilocarpine-induced salivation was reduced by i.c.v. injection of moxonidine (10 nmol) and enhanced by i.c.v. injections of either RX 821002 (160 nmol) or yohimbine (320 nmol). The inhibitory effect of i.c.v. moxonidine on pilocarpine-induced salivation was abolished by prior i.c.v. injections of the alpha(2) adrenergic receptor antagonists, RX 821002 (160 nmol) or yohimbine (160 and 320 nmol). The alpha(1) adrenergic receptor antagonist prazosin (320 nmol) injected i.c.v. did not change the effect of moxonidine on pilocarpine-induced salivation. The results suggest that moxonidine acts on central alpha(2) adrenergic receptors to inhibit pilocarpine-induced salivation, and that this salivation is tonically inhibited by central alpha(2) adrenergic receptors.
1. Salivation has been studied in the submandibular gland of the rabbit. A very slow spontaneous salivation took place when all possibility of nerve influence had been excluded. Salivation was not due to ultrafiltration.2. The ;spontaneous' saliva had a mean K concentration of 148 mM and Na concentration of 46 mM. With increasing salivation rate produced by parasympathetic nerve stimulation, K concentration fell to a plateau level of about 30 mM whilst Na concentration fell rapidly to reach the low value of 3 mM, then began to rise again at the higher flow rates.3. Ligation of the submandibular duct produced a reversal of the ion concentrations in spontaneous saliva. By 4 days K concentration was lower and that of Na higher than control values until by 2 weeks the effect was maximal with mean concentrations of 25 mM for K and 153 mM for Na.4. Ouabain increased the spontaneous salivation rate and ethacrynic acid slowed or prevented it altogether. On the basis of the known sites of action of these drugs it is postulated that two pumps are involved in the regulation of spontaneous salivation. There appears to be basal activity of an acinar mechanism pumping NaCl into the lumen, taking water with it. This pump is activated directly or indirectly by the intracellular Na concentration which itself is controlled by an Na-K exchange pump.5. Excitation of the sympathetic trunk produced a small, though definite, increase in salivation rate. There was evidence that myoepithelial cells might also be involved in the sympathetic response and that they were activated by alpha receptor stimulation. Salivation evoked by sympathetic nerve stimulation would seem to be a response to beta receptor stimulation, but the possibility that activation of both alpha and beta receptors was required could not be excluded entirely.
Substance P (3 micrograms/kg), neurokinin A (20 micrograms/kg), neurokinin B (6 micrograms/kg) and acetylcholine (875 micrograms/kg) all produced salivation upon i.v. infusion in the anesthetized rat. Against single equivalent agonist doses, atropine (135 micrograms/kg i.v.) blocked both acetylcholine- and neurokinin B-, but not substance P- or neurokinin A-induced salivation. [D-Pro2,D-Trp7,9]-substance P (1 mg/kg i.v.), a putative substance P antagonist, reduced responses to mammalian neurokinins but caused a 2-fold potentiation of acetylcholine-induced salivation. [D-Pro2,D-Trp6,8,Nle10]-Neurokinin B (1 mg/kg i.v.), a novel putative neurokinin B antagonist, significantly reduced substance P- and neurokinin B- but not acetylcholine- or neurokinin A-induced salivation. The three agonists (at doses that produced salivation) and [D-Pro2,D-Trp6,8,Nle10]-neurokinin B (1 mg/kg i.v.) lowered blood pressure in anesthetized rats by 35 to 40%. [D-Pro2,D-Trp7,9]-Substance P (1 mg/kg i.v.) had no significant effect on blood pressure. Hydralazine at 0.60 mg/kg (i.v.), a dose which lowered blood pressure by 47%, did not reduce substance P-induced salivation. Thus, blockade of neurokinin-induced salivation by [D-Pro2,D-Trp6,8,Nle10]-neurokinin B was probably not due to hypotension. Based on the differential effects of the three antagonists on neurokinin- and acetylcholine-induced salivation, we hypothesize the existence of three distinct neurokinin receptors in rat salivary gland, and suggest that neurokinin B receptors reside presynaptically.
The sialogogic effect of SNI-2011, a novel muscarinic receptor agonist, (+/-)-cis-2-methylspilo [1,3-oxathiolane-5,3'-quinuclidine] hydrochloride, hemihydrate, was compared with that of pilocarpine hydrochloride in a dose range in which the two muscarinic agonists exhibited approximately similar efficacy in eliciting salivation. Pilocarpine (0.66-2.0 mg/kg, i.d.) induced a marked but short-lasting salivation in rats, whereas the salivation induced by SNI-2011 (20-60 mg/kg, i.d.) lasted 1.4- to 1.8-fold longer. In dogs, the sialogogic effect of SNI-2011(1-3 mg/kg, i.v.) also lasted about 2-fold longer than that of pilocarpine (0.1-0.3 mg/kg, i.v.). The plasma SNI-2011 level that caused salivation at a rate of 0.4 ml/min was about 100 ng/ml and higher rates of salivation (over 0.4 ml/min) induced by 1 mg/kg SNI-2011 lasted for about 90 min in dogs. The plasma pilocarpine level that caused salivation at a rate of 0.4 ml/min was about 25 ng/ml and the higher rate of salivation (over 0.4 ml/min) induced by 0.1 mg/kg pilocarpine lasted only for 20 min in dogs. Effective plasma levels of SNI-2011 persisted longer than those of pilocarpine. These results indicate that SNI-2011 may be useful in the treatment of xerostomia because of its long-lasting sialogogic action.
Methyldopate (methyldopa (ethyl ester)), carbidopa, clonidine, and ST-91 were evaluated for their effects on conditioned salivation in unanesthetized dogs. Clonidine produced dose-dependent inhibition of salivation 20 min after an intravenous injection. At equivalent and larger doses, ST-91, a clonidine analog which does not penetrate the blood-brain barrier, was ineffective in inhibiting conditioned salivation, suggesting that central rather than peripheral mechanisms are involved in clonidine-induced inhibition of salivation. Methyldopate also produced a dose-dependent inhibition of salivation in dogs. The mechanism involved in methyldopa-induced inhibition of salivation may involve both central and peripheral mechanisms because carbidopa, an inhibitor (like methyldopa) of peripheral aromatic decarboxylase (EC 4.1.1.28), significantly inhibited salivation.
The dose-effect of oxotremorine upon the onset, duration and magnitude of tremor and salivation was studied in both mice and rats. The threshold doses of oxotremorine (SC) for eliciting tremor were above 50 micrograms/kg in mice and above 150 micrograms/kg in rats and the threshold doses for eliciting salivation were above 75 micrograms/kg in mice and above 200 micrograms/kg in rats. Alaproclate, a nontricyclic 5-HT uptake inhibitor, when injected 30 min prior to the administration of the cholinergic agonist, produced a dose-dependent enhancement of tremor and salivation in both rats and mice. Alaproclate itself did not produce these effects in the absence of a muscarinic cholinergic stimulant such as oxotremorine, arecoline or the acetylcholine esterase inhibitor physostigmine. Both salivation and tremor could be fully blocked by atropine at any dose of the cholinergic stimulant and of alaproclate used. The potentiating effects of alaproclate on salivation and tremor could also be blocked by two serotonin receptor antagonists, metitepine and danitracen, but not by metergoline or cinanserin. Other compounds which inhibit the uptake of 5-HT such as fluoxetine, citalopram, norzimeldine, zimeldine and the non-tricyclic antidepressant, iprindol, did not enhance the cholinergic agonist induced tremor or salivation under the same conditions as did alaproclate. It is suggested that alaproclate exerts the potentiating effect at a hitherto undefined serotonergic receptor site.
In the present study, the authors tested whether an increase in salivation is associated with an increase in subjectively experienced hunger. After conditioning, subjects showed a significant increase in salivation flow. Hunger levels, however, were significantly decreased after conditioning. No correlation was found between salivation flow and hunger levels. It is argued that salivation responses and subjectively experienced hunger are loosely coupled systems. Salivation flow reflects the learning history of a subject which may sometimes be paralleled by a biological state which is called hunger, whereas, at other times, hunger may be absent. The authors conclude that conditioning of preparatory responses such as salivation depends on the probability relationship between exposure to cues (CSs) and food intake (US), as well as the intensity of the US.
The mechanism of the clonidine induced reduction in submaxillary salivation evoked by electrical stimulation of the chorda tympani was investigated in anaesthetised cats. This effect of clonidine was found to be dose and frequency dependent. In addition to clonidine, tramazoline, also a preferential presynaptic alpha-adrenoceptor agonist, produced a reduction in electricallly evoked salivation. Methoxamine, noradrenaline and naphazoline, which are less potent presynaptic alpha-receptor agonists, caused increases in salivation. Phentolamine only partially antagonized the decrease in salivation produced by clonidine whereas it was virtually abolished by yohimbine. Clonidine increased salivation evoked by intra-arterial injections of carbachol. These findings suggest that clonidine reduces peripheral parasympathetically evoked submaxillary salivation by activation of presynaptic alpha-adrenoceptors which inhibit cholinergic transmission.
This study assessed the influence of introducing a new food after repeated presentations of one food on food consumption, hedonics, and salivation. Male subjects were provided repeated 150-calorie courses of pizza or cheeseburger until satiety. Hedonics and salivation were measured before each course. Subject were then provided an additional 450 calorie course of the same or the new food. During the development of satiety, subjects showed reliable increases in fullness and decreases in hunger and hedonics. Salivation briefly increased to maximal salivation, followed by reliable decreases. No differences in pattern of change for fullness, hunger, hedonics or salivation were noted across foods. Presentation of the new food resulted in significantly greater caloric consumption than another serving of the same food (130 vs. 44.5 kcal), an increase in hedonics and salivation relative to presentation of the same food, with no influence on hunger or fullness. These results suggest that after satiety develops, response recovery for subjective, physiological, and behavioral components of eating can be observed when new, palatable foods are presented.
Two experiments were done to study inhibition of cue-dependent salivation and craving responses. Experiment 1 suggests that total prevention of tasting during cue exposure inhibits salivation responses to chocolate cues. On the other hand, salivation was triggered by chocolate cues after tasting a very small amount of chocolate, indicating a very robust and rapid learning of conditioned salivation responses. However, prevention of tasting during cue exposure did not affect craving, suggesting that this method cannot decrease craving or that craving is affected at different rate than salivation. Experiment 2 tested the hypothesis that tasting irrelevant food during repeated exposure to chocolate cues would inhibit anticipatory salivation and craving responses to these cues. No support for this hypothesis was observed.