The amino acid composition of angiotensin alters its ability to reduce alcohol consumption in rats.

The voluntary consumption of alcohol has been shown to be reduced by a variety of manipulations which enhance activity in the renin-angiotensin system, including the administration of the bovine form of angiotensin II-[Val5]-ANG II. The present study investigated the relationship between the amino acid composition of angiotensin II and its ability to reduce alcohol intake by administering a number of different forms or fragments of the parent peptide. [Ile5]-Angiotensin II ([Ile5]-ANG II), two endogenous fragments of angiotensin II [( Des-Asp1]-ANG II and [Des-Phe8]-ANG II) were administered subcutaneously in rats across a range of doses.

Systemic angiotensin II does not act at the area postrema to suppress alcohol intake.

The area postrema (AP), a circumventricular organ located in the dorsal medulla, is involved in the coordination of visceral and taste sensory stimuli in the control of ingestive behaviors. This area lacks a blood-brain barrier and is rich in angiotensin receptors. Because systemically administered angiotensin II reduces voluntary alcohol intake, we examined the effect of AP lesions on alcohol intake and on the ability of ANG II reduces alcohol intake.

Regulation of alcohol consumption by the renin-angiotensin system: a review of recent findings and a possible mechanism of action.

The renin-angiotensin system has traditionally been associated with the regulation of fluid and electrolyte balance. In this review we summarize the data which ascribes a completely new function to this system, i.e.

Vasopressin does not mediate the inhibition of ethanol drinking by the renin-angiotensin system.

Manipulations which are known to enhance activity in the renin-angiotensin system (RAS) have been found to reduce the voluntary consumption of ethanol in rats. Since angiotensin II is a potent stimulus for the release of vasopressin (VP), it is possible that the RAS modulates ethanol (ETOH) consumption through a mechanism involving VP. The present investigation examined the effect of peripheral injections of arginine-VP (AVP) and desglycinamide-AVP (DGAVP) on ETOH consumption in rats given daily one-hour access to ETOH.

Prostaglandin E2 reduces voluntary ethanol consumption in the rat.

A number of prior studies have suggested that the prostaglandins may mediate some of the physiological effects of ethanol, and while it has been suggested that PGE2 may be involved in regulating ethanol consumption, evidence for this has been inconclusive. In the present study, rats injected with PGE2 at doses of 50, 100 and 200 micrograms/kg consumed significantly less alcohol than vehicle-treated controls. Doses of PGE2 which were highly effective in reducing ethanol intake produced only marginal changes in the consumption of water and glucose solution.

The role of the gastric and hepatic vagus in voluntary alcohol intake.

The present study investigated a possible role for neural signals sent from the liver and stomach to the brain in the regulation of alcohol intake. Experiment 1 showed that gastric vagotomy (GVX) reduced the intake of 3% alcohol and 6% alcohol, while water intake was increased. This effect was not due to an alteration in pharmacokinetics, although an alteration in taste function could not be ruled out.

Cholecystokinin octapeptide reduces ethanol intake in food- and water-sated rats.

The putative satiety peptide cholecystokinin octapeptide (CCK-8) has been shown to reduce ethanol intake induced by prior fluid deprivation. Since fluid-deprived animals tend to reduce their food intake and consequently become hungry, the ability of CCK-8 to reduce ethanol intake might be limited to conditions where the motivation for food and fluid are accentuated. The present study assessed this possibility by examining the effect of peripheral injections of CCK-8 on voluntary ethanol intake fostered by the limited access procedure which uses food- and water-sated rats.

Angiotensin converting enzyme inhibitors reduce alcohol consumption: some possible mechanisms and important conditions for its therapeutic use.

Alcoholism is a prevalent problem of contemporary society, yet there are virtually no clinically effective drugs for the management of this disorder. A previous study demonstrating the ability of angiotensin-converting enzyme (ACE) inhibitors to attenuate voluntary alcohol intake in rats prompted the suggestion that these drugs, currently marketed for the treatment of hypertension, may also be useful in dealing with human alcohol abuse. The present experiments explored in more detail the effect and possible mechanisms of action of this class of drug on alcohol consumption in rats.

Systemic angiotensin II acts at the subfornical organ to suppress voluntary alcohol consumption.

The subfornical organ plays a role in a number of the effects of blood-borne angiotensin II (ANG II) including the increase in water drinking and blood pressure and the release of vasopressin from the pituitary. Recently it has been shown that systemically administered ANG II also reduces voluntary alcohol intake. The present study assessed the role of the SFO in alcohol consumption by examining the effects of SFO lesions on voluntary alcohol intake and on the suppression of voluntary alcohol intake by ANG II.

The beta adrenergic agonist isoproterenol suppress voluntary alcohol intake in rats.

The effects of isoproterenol on alcohol consumption were examined to investigate whether beta adrenergic stimulation can reduce voluntary alcohol intake. Two and one-half, 5 and 10 micrograms/kg isoproterenol administered subcutaneously (SC) just prior to alcohol availability produced a dose-dependent reduction in alcohol intake and elevation in water intake. Blood alcohol levels measured subsequent to a SC injection of 5 micrograms/kg isoproterenol or vehicle followed by an intraperitoneal injection of 2.

Angiotensin II-induced suppression of alcohol intake and its reversal by the angiotensin antagonist Sar-1 Thr-8 angiotensin II.

The effects of three doses of angiotensin II (AII) on alcohol consumption using the limited access procedure were studied. Fifty and 100 micrograms/kg AII administered subcutaneously (SC) did not alter alcohol intake while 200 micrograms/kg suppressed alcohol intake. These findings confirm previous work and show that AII begins to be effective in reducing alcohol intake in the range of 200 micrograms/kg.

Area postrema and alcohol: effects of area postrema lesions on ethanol self-administration, pharmacokinetics, and ethanol-induced conditioned taste aversion.

An investigation was carried out to test the hypothesis that the area postrema (AP) may detect ethanol as a blood-borne toxin and thereby mediate aversive postingestinal effects of the drug. These aversive effects in turn may impose an upper limit on the amount of drug that can be consumed. In Experiment 1 rats had continuous access to water and a 4% ethanol solution.

Ethanol as a reinforcer for rats: factors of facilitation and constraint.

This review examines some particular approaches that have been used to investigate factors that facilitate or constrain the self-administration of ethanol by rats. A technique for increasing ethanol self-administration in rats, the prandial drinking method, was examined and the effect of body-weight reduction on drug intake was discussed. Emphasis was placed on how ethanol intake may be controlled by processes in addition to the direct pharmacological actions of the drug in the CNS.

Attenuation of alcohol intake by a serotonin uptake inhibitor: evidence for mediation through the renin-angiotensin system.

Although the serotonin uptake inhibitors have been shown to reduce alcohol intake in both animals and man, the mechanism of this effect is unclear. It is known that enhanced serotonergic activity can stimulate activity in the renin-angiotensin system and that elevated activity in the renin-angiotensin system can reduce voluntary alcohol intake. Therefore, serotonin uptake inhibitors such as fluoxetine might exert their effect on alcohol intake, in part, through the renin-angiotensin system.

Voluntary alcohol intake is attenuated in two-kidney, one-clip, but not in one-kidney, one-clip Goldblatt hypertensive rats.

Voluntary alcohol intake was examined in two models of renovascular hypertension known to differ in their effects on the renin-angiotensin system. In experiment 1, Two-Kidney, One-Clip (renin-dependent) hypertensive rats (T-K,O-C) or their sham operated controls were offered limited access to alcohol for 1 hr each day. Over a four week period the T-K,O-C rats drank significantly less 3% and 6% (w/v) alcohol solution than the sham operated controls.

Angiotensin II reduces voluntary alcohol intake in the rat.

The voluntary intake of alcohol has been shown to be attenuated by a variety of manipulations which increase activity in the renin-angiotensin system. In the present study we examined the effects of peripheral injections of the peptide angiotensin II on alcohol drinking. The peptide produced a dose-dependent decrease in alcohol intake with 20 micrograms/kg having little effect, 200 micrograms/kg reducing intake by approximately 50% and 1 mg/kg virtually abolishing all alcohol drinking.

Angiotensin converting enzyme inhibitors: animal experiments suggest a new pharmacological treatment for alcohol abuse in humans.

The prevalence of heavy alcohol consumption is a major problem of increasing proportions throughout the world. Although alcohol sensitizing drugs and more recently serotonin uptake inhibitors are drug interventions with some following, their long term beneficial consequences have yet to be demonstrated. In recent years, we have demonstrated that manipulating activity in the renin-angiotensin system will dramatically alter voluntary alcohol consumption in rats.

Renal artery stenosis: an example of how the periphery can modulate voluntary alcohol drinking.

Voluntary alcohol drinking, using a free-access procedure, was studied in rats three weeks after unilateral renal artery stenosis was produced by applying a 0.20 mm solid silver clip to the left renal artery (Two-Kidney, One-Clip, Hypertension). The group of animals with the arterial clip drank significantly less alcohol and more water than a sham-operated group.

Voluntary alcohol intake in the hypertension prone Dahl rat.

Previous work in our laboratory has shown that alterations in the sodium content of the diet which alter salt appetite, can modify ethanol self-selection and intoxication. The present experiment investigates the relationship between the intakes of sodium and ethanol on the one hand and the development of hypertension, by measuring voluntary ethanol consumption and blood pressure in two rat lines, the salt sensitive (SS) and salt resistant (SR) Dahl rats, specially bred to show differential sensitivity to dietary sodium supplements. All rats were given 24 hr access to 6% (v/v) ethanol and water and first offered a control diet (0.

Diet and diuretics in the reduction of voluntary alcohol drinking in rats.

Three rats were trained and given extensive experience with an operant-conditioning model of alcohol self-administration which produces pharmacologically significant drug intake. In this model, lever presses on a fixed ratio (FR) schedule of reinforcement allowed the animal brief access to an 8% (w/v) alcohol solution. Drug intake was then assessed when the animals were given a low-sodium diet and a low-sodium diet in combination with injections of the salt-losing diuretic furosemide (Lasix).

Modification of ethanol-induced motor impairment by diet, diuretic, mineralocorticoid, or prostaglandin synthetase inhibitor.

Ethanol-induced motor impairment in rats was measured following a number of different dietary or drug treatments. A low sodium diet combined with injections of the diuretic furosemide, but not a low sodium diet alone, increased motor impairment while a high sodium diet decreased impairment. Blood ethanol measurements indicated that both effects were probably mediated by changes in blood ethanol levels.

Dietary salt and doca-salt treatments modify ethanol self-selection in rats.

The effect of a salt supplemented diet on the voluntary intake of ethanol in male Wistar rats was examined in two experiments. In Experiment 1, the addition of 3% sodium chloride to the diet selectively increased the intake of moderately concentrated ethanol solutions (3 and 6%) while leaving the choice of a 12% solution unaffected. The choice and intake of water in the two former groups declined.

Responding under a fixed interval schedule of intravenous ethanol presentation in the rat.

Specific behavioural procedures have been developed which lead animals to give themselves electric shock. The present study investigated the possibility that the same set of procedures would lead to intravenous (i.v.