Antidipsogenic Effect Research Articles

Potent Action of Leumorphin on Consummatory Behaviors in Rats: Comparison with Other Opioid Peptides

Leumorphin is a 29-amino-acid peptide derived from preproenkephalin B. Intracerebroventricular (i.c.v.) injection of leumorphin through an implanted cannula into the lateral ventricle of rats dose-dependently inhibited water intake induced by water deprivation, angiotensin II (AII) and carbachol. This effect was partially reversed by intraperitoneal injection of naloxone, an opiate antagonist. Naloxone alone rather attenuated water intake. The antidipsogenic effect of leumorphin was very potent: 0.6 pmol of the peptide significantly inhibited AII-induced drinking. Dynorphin 1-17 was almost as potent as leumorphin in inhibiting drinking, whereas alpha-neo-endorphin and leucine-enkephalin (Leu-enkephalin) were far less effective. Leumorphin given i.c.v. dose-dependently enhanced eating and this effect was abolished by naloxone. Dynorphin was as potent as leumorphin in inducing feeding, whereas alpha-neo-endorphin and Leu-enkephalin had no significant activity when 6 nmol was used. General activity measured by an Automex was enhanced by i.c.v. injection of leumorphin but required larger amounts of the peptide than did drinking behavior. The very potent and specific effects of leumorphin and dynorphin on drinking behavior suggest that the antidipsogenic activity of these peptides is of physiological significance like their effect on feeding.

Inhibition of spontaneous or angiotensin II-stimulated water intake by atrial natriuretic factor

A family of peptides, known as atrial natriuretic factors (ANF), have been isolated from atrial muscle tissue and reported to have profound effects on water and salt metabolism. ANF have also been reported to be present in the brain. The primary actions of these peptides lead to a reduction in plasma and extracellular fluid volume by eliciting natriuresis and diuresis, and by opposing the action of other peptidergic systems such as the vasopressin and angiotensin systems that promote water retention and enhance drinking behavior. This study was designed to determine if, in addition to its peripheral actions, ANF would also affect water ingestion, a mechanism that would be consistent with its general actions as a factor regulating extracellular fluid volume. Intraventricular (IVT) administration of an ANF, atriopeptin III (APIII), to intact male rats resulted in a significant inhibition of water intake in animals which were conditioned to drink during a one hour period. The inhibitory effects of APIII were immediate and most effective during the first 15 minute period, when maximal drinking occurred. Most remarkably, APIII given IVT also inhibited the potent dipsogenic action of angiotensin II (AH) on both water and a 2% NaCl solution intake. The results strongly suggest that ANF may have a significant role in central regulation of fluid intake and that its antidipsogenic effects may be mediated, at least in part, by an inhibitory effect on the central action of AII.

Effect of intracerebroventricularly administered octopamines and synephrines on angiotensin II-induced water intake in rats

Recent studies from this laboratory showed that l-m-synephrine (phenylephrine), a metabolite of l-m-octapamine, inhibited the drinking response of rats to peripherally administered angiotensin II. The objective of this investigation was to determine whether the isomers of both octapamine and synephrine could inhibit angiotensin II-induced dipsogenesis in the rat. Of the isomers tested, only d, l-m-octopamine and l-m-synephrine blocked the dipsogenic response to administration of angiotensin II (200 μg/kg, SC). The antidipsogenic effect of both d, l-m-octopamine and l-m-synephrine could be blocked by concurrent administration of yohimbine (300 μg/kg, IP), an α 2-adrenoceptor antagonist. The results indicate that m-octopamine and m-synephrine exert their antidipsogenic effect via α 2-adrenoceptors. These studies add to a growing body of data suggesting that activation of α 2-adrenoceptors inhibits, while blockade of these receptors enhances, angiotensin II-induced drinking.

A role for presynaptic α 2-adrenoceptors in angiotensin II-induced drinking in rats

Studies from this laboratory have shown that either central or peripheral administration of clonidine, the α 2-adrenoceptor agonist, can attenuate a variety of dipsogenic stimuli in rats. Further, yohimbine and tolazoline, α 2-adrenoceptor antagonists, augment the drinking response to both peripherally administered isoproterenol and angiotensin II. Studies reported here establish a dose-inhibition relationship between the dose of clonidine administered (2 to 32 μg/kg) intracerebroventricularly (IVT) and inhibition of the drinking response to peripherally administered angiotensin II (200 μg/kg, SC). DI 50 was approximately 4 μg/kg. Yohimbine (300 μg/kg, SC) reversed the antidipsogenic effect of centrally administered clonidine (32 μg/kg, IVT) on angiotensin II-induced (200 μg/kg, SC) water intake. Phenylephrine, an α 2-adrenoceptor agonist, administered IVT (40 and 80 μg/kg) also inhibited angiotensin II-induced drinking in a dose-related fashion. The antidipsogenic effect of phenylephrine (80 μg/kg) was blocked by administration of yohimbine (300 μg/kg, SC). Thus, this effect of phenylephrine most likely occurs by way of α 2-adrenoceptors. These results support a role for the pre-synaptic α 2-adrenoceptor in the mediation of drinking in rats. Activation of α 2-adrenoceptors is accompanied by reduced water intake while inhibition of these receptors enhances water intake.

Drinking: a final Common Pathway?

Administration of either naloxone, an opioid antagonist (1 mg/kg i.p.), or clonidine, an alpha 2 adrenoceptor agonist (12 micrograms/kg i.p.), attenuated the dipsogenic responses of female rats to both angiotensin II (200 micrograms/kg s.c.) and isoproterenol (25 micrograms/kg s.c.). The effect of simultaneous administration of naloxone and clonidine at these submaximal doses was an additive attenuation of both angiotensin II- and isoproterenol-induced water intakes. The absence of a significant interaction between naloxone and clonidine to inhibit drinking suggests that they act by a similar mechanism. Yohimbine, an alpha 2 adrenoceptor antagonist (300 micrograms/kg i.p.), administered in combination with naloxone, reversed the antidipsogenic effect on angiotensin II-induced drinking. These results provide further support for a role for alpha 2-adrenoceptors in laboratory-induced drinking in rats, and suggest the possibility that the antidipsogenic effect of naloxone is related to alpha 2 adrenergic mechanisms. A model to support these observations is presented in which two separate pathways for the induction of drinking (osmoreceptor- and angiotensin II-induced) converge on a final common pathway. Since both naloxone and clonidine inhibit responses to stimulation of both pathways for drinking, these results suggest that their actions are likely to be at some point as yet undetermined on the final common pathway.

Naloxone-induced hypodipsia: A CNS mapping study

Opiate antagonists have been shown to reliably attenuate drinking behavior. Recent research points to a central site of action for this antidipsogenic effect. To pursue this issue of site specificity, naloxone, a specific opiate antagonist, was delivered into a number of discrete subcortical areas in 23 hour water-deprived rats. Water intake was measured at 5, 15, 30 and 60 minutes post drug injection. Compared to saline control injections, naloxone reliably depressed water intake, in a dose-related manner, in lateral hypothalamus, preoptic area and zona incerta. Previous research has repeatedly implicated these areas in drinking behavior. Placements which were not generally effective included lateral ventricle, nucleus accumbens, substantia nigra and cortex/corpus callosum. Latency to drink was never affected by any dose of naloxone injected into any site, suggesting an opioid influence on mechanisms involved in termination and/or maintenance rather than on initiation of drinking.

Antidipsogenic action of naloxone under different water deprivation conditions

1. 1. Naloxone (1mg/kg s.c.), in the light phase of the daily light-dark cycles during the 30 and 60 min of the test, shows an antidipsogenic effect of the same intensity in chronically water-deprived rats which drink more (+ 176% and + 162%) than the acutely water-deprived animals. 2. 2. In chronically water-deprived rats, the time interval from the drug introduction (5,30,60 and 90 min) is not critical for the intensity of the antidipsogenic action of naloxone. 3. 3. When water intake is controlled by a 20% variable ratio schedule that does not allow the animals to satisfy, during the session, more than 50% of their thirst, the time interval from the introduction of naloxone is critical. 4. 4. When the rats can drink freely for 30 min in their home-cage after they satisfied their thirst partially by means of bar-pressing, naloxone, paradoxically shows a weaker and not significant antidipsogenic action. 5. 5. The results and the usefulness of the behavioural test are briefly discussed .

A study on behavioural alterations induced by intracerebroventricular administration of bombesin to rats

Summary The intracerebroventricular (i.c.v.) injection of bombesin to rats, besides inhibiting water and food intake, produced intense grooming, alteration of explorative behaviour and of spontaneous motor activity, but neither neurological nor autonomic modifications. Experimental data suggest that the antidipsogenic effect of bombesin is specific and cannot be considered a mere consequence of other specific or aspecific behavioural alterations.

Flavor enhances the antidipsogenic effect of naloxone

Naloxone suppressed ingestion of tap water following a 15 hour deprivation at doses of 20, 10 and 5 mg/kg. Addition of saccharine (0.2%), saline (0.8%), sucrose (2%) and HCl (0.1 M) to tap water resulted in an increased sensitivity to naloxone-induced suppression of water intake following the 15 hour deprivation. The volume of quinine solution (0.1%) consumed was not altered by administration of naloxone. We suggest that naloxone suppresses drinking behavior due to alterations in taste perception.

Antidipsogenic effect of clonidine on angiotensin II-, hypertonic saline-, pilocarpine- and dehydration-induced water intakes

The dipsogenic responses of female rats to administration of angiotensin II (150 μg/kg b.w., IP), pilocarpine (3 mg/kg/IP), hypertonic saline (1 M NaCl solution, 1% b.w.), and a 24 hour dehydration were attenuated by acute IP administration of graded doses of the central and peripheral α 2-adrenergic agonist, clonidine. For all treatments except dehydration, clonidine inhibited significantly the dipsogenic response at the lowest dose used (6 μg/kg, IP). The first significant effect on dehydration-induced drinking required approximately a 4 fold higher dose (25 μg/kg, IP). Attenuation of the response to these dipsogenic stimuli by clonidine, suggests that its ability to stimulate α-adrenergic receptors centrally may play an important role in its dipsogenic inhibitory activity.

Flavour modulates the antidipsogenic effect of substance P

Substance P reduces water intake in a dose-dependent manner. In this report we show that the antidipsogenic effect of substance P is markedly reduced when sucrose (2%), saccharine (0.2%) or quinine (0.1%) are added to the water. Addition of saline (0.8%) has no effect on the antidipsogenic effect of substance P. These findings indicate that flavour modulates the antidipsogenic effect of parenterally administered substance P.

Opiate antagonists: central sites of action in suppressing water intake of the rat

The pure opiate antagonists, naloxone and naltrexone (0.1–10 mg/kg), dose-dependently suppressed water intake of 24 h water-deprived rats upon subcutaneous administration; their quaternary derivatives, methyl-naloxone and methyl-naltrexone, which are impermeable to the blood-brain barrier, failed to affect drinking. Upon intracerebroventricular administration, both quaternary analogs attenuated drinking at a dose of only 10 μg. These results demonstrate that the antidipsogenic effects of opiate antagonists are primarily mediated at sites within the central nervous system.

Suppression of drinking by naloxone in rats homo- and heterozygous for diabetes insipidus

The effects of the opiate antagonist, naloxone, alone and in combination with morphine, were examined on drinking induced by water deprivation in homo- and heterozygous Brattleboro rats manifesting an inherited diabetes insipidus. Both naloxone and a structurally-related congener, naltrexone (0.01–10 mg/kg), attenuated water consumption in adose-related fashion of 1 hr water-deprived homozygotes, which exhibit a complete absence of vasopressin. Drinking was also reduced by the two drugs in 24 hr water-deprived heterozygotes, which have detectable levels of vasopressin. Morphine pretreatment enhanced the antidipsogenic effects of naloxone in a dose- and time-dependent manner. The administration of 10 mg/kg of morphine 3 hr before testing, which itself did not affect drinking, maximally potentiated the suppressant effects of naloxone on drinking in homozygotes. This potentiating effect of morphine persisted for at least 48 hr. These results indicate that vasopressin is not essential for the antidipsogenic effects of the narcotic antagonists. The polydipsic Brattleboro rat may provide a convenient animal model for studies of the effects of opiate agonists and antagonists on drinking behavior.

Cerebral prostaglandin biosynthesis and angiotensin-induced drinking in rats.

Prostaglandin E2 (PGE2) suppressed drinking induced by angiotensin II (A II) when both were injected into the cerebral ventricles of the rat. This antidipsogenic effect of PGE2 was correlated with its known pyrexic actions. Intracerebroventricular injection of arachidonic acid (AA), the precursor of PGE2, also suppressed A II-induced drinking. This antidipsogenic effect of AA was similarly correlated with pyrexia and was dependent upon the conversion of the precursor to a prostaglandin within the brain. These observations are consistent with the hypothesis that newly synthesized cerebral PGEs, in response to elevated A II levels, contribute to the cessation of drinking by opposing the dipsogenic action of A II. However, blockade of cerebral prostaglandin biosynthesis by central injection of indomethacin did not enhance drinking elicited by A II even at doses that completely eliminated the antidipsogenic and pyrexic actions of AA. Collectively, the results suggest that exogenous PGEs or AA may inhibit A II-induced drinking by elevating body temperature or some other pharmacological action and that endogenously synthesized PGEs of cerebral origin do not play an important role in the normal termination of drinking induced by centrally administered A II.

Antidipsogenic effect of clonidine on isoproterenol-induced water intake

Acute administration of the β-adrenergic agonist, isoproterenol (25–50μg/kg body weight, subcutaneous), induced drinking and an antidiuresis in rats during the first hour after treatment. Clonidine, administered at doses of 12·5 to 200μg/kg b.w., intraperitoneal, simultaneously with isoproterenol (25 μg/kg), attenuated the drink in a dose-dependent fashion. However, the antidiuresis induced by isoproterenol could be attenuated only by a very high dose of Clonidine (200μg/kgb.w.). When administered alone, Clonidine increased both urine and urinary sodium outputs in a dose-related fashion. Since Clonidine is reported to inhibit release of both antidiuretic hormone and renin, the increased urine output, increased urinary sodium excretion and reduction of the drinking response to isoproterenol are not unexpected findings. However, it appears likely that these effects may be secondary to its central a-adrenergic stimulatory action.

Modifications of drinking behaviour and of arterial blood pressure induced by tachykinins in rats and pigeons.

Intracerebroventricular injections of the naturally occurring tachykinins eledoisin, physalaemin and substance P elicit a powerful antidipsogenic effect in the rat, while in the pigeon they potently stimulate water intake. The aim of this paper was to study in conscious rats and pigeons the vascular effect of these peptides and to compare this effect to the one elicited on water intake. The results of these experiments demonstrate that there is no direct relationship between the two effects. Our findings suggest that the effect of these peptides on water intake might be specific on CNS and not related to their vascular activity.

Water intake inhibition and vasopressin release induced by eledoisin and leu-enkephalin in rats of the brattleboro and wistar strain

Summary The antidipsogenic effect and the vasopressin releasing effect of ELS and LEN were studied in WSTR, HEBR and HOBR rats. The results of these experiments suggest for these substances a common or similar mechanism of action. Conversely, they suggest that their antidipsogenic effect is independent from the neuro-hypophyseal control of water conservation.

Drinking behaviour induced by intracerebroventricular administration of enkephalins to rats

INTRACRANIAL administration of substance P to rats inhibits drinking induced by water deprivation, sodium-chloride load, and intracerebroventricular (i.c.) injection of angiotensin II or carbachol1. It has been suggested that substance P is a neurotransmitter used in primary afferent fibres terminating in the spinal cord2–4, but recent findings suggest also that, at least in mice, substance P may release endogenous opioids and thus produce analgesia5. If cerebral effects of substance P are, at least in part, due to the release of endogenous opioids, these substances might also possess an antidipsogenic effect. We describe here experiments in which we observed that enkephalins administered into the lateral ventricles of rats inhibited drinking induced by water deprivation or by i.c. injection of angiotensin II. We thus provide evidence that enkephalins have a potent and reproducible antidipsogenic effect in the rat.

Effects of eledoisin, physalaemin and some related peptides on water intake and arterial blood pressure in conscious rats

Summary The hypotensive and antidipsogenic effects of eledoisin, physalaemin and some synthetic eledoisin- or physalaemin-like peptides were studied in conscious rats, respectively after intravenous or intracerebroventricular administration. The effects of the peptides were compared to the hypotensive or anti-dipsogenic activities of eledoisin considered equal to 100. Eledoisin and its C-terminal nonapeptide proved to be the most active antidipsogens. Conversely, physalaemin and physalaemin-like substances were poor inhibitors of water intake, but potently lowered arterial blood pressure. Apparently, there was no relationship between hypotensive and antidipsogenic effects of the substances tested.

Antidipsogenic effect of intracranial injections of substance P in rats.

1. The effect on water intake of intracranial injections of Substance P was studied in the rat. 2. Substance P strongly inhibited drinking elicited by Angiotensin II, Carbachol water deprivation or sodium chloride load, in that order. 3. The peptide was particularly effective when water intake was induced by injections of Angiotensin II into the preoptic area. In these experiments, drinking was inhibited by doses of Substance P as low as 1 ng. 4. The results suggest that in the rat Substance P may play a role in the brain in the regulation of water intake, acting as a thirst inhibitor.