R.B. Stewart

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. This decrease was not due to a peptide induced motor deficit, or state of sickness, and could also not be accounted for by the increased water intake, or by a change in pharmacokinetics and taste function. These data provide direct evidence that angiotensin II can modulate voluntary alcohol drinking. The possibility that the level of angiotensin II serves as a satiety signal in alcohol drinking is discussed.

An investigation of the interaction between the reinforcing properties of food and ethanol using the place preference paradigm

Abstract 1. 1. For three groups of rats, intraperitoneal injections of either 250, 500, or 1000 mg/kg ethanol were paired with a distinctive environment and later a choice was offered between that environment and one that had previously been associated with saline injections. 2. 2. For a second set of three groups of animals the identical procedure was followed except that food was available in both the environment paired with ethanol and the one paired with saline. 3. 3. The rats showed no preference or aversion for the environment paired with the 250 mg/kg dose either when the drug was given alone or when combined with the availability of food. No preference or aversion for the 500 mg/kg dose was indicated when the drug was given alone, but the same dose combined with food was preferred to food plus saline. The 1000 mg/kg dose was found to be aversive when given by itself, yet the same dose was neither aversive nor preferred when combined with the availability of food. 4. 4. These findings suggest that ethanol can interact with food, a positive reinforcer, in ways that cannot be predicted from the effect of the drug when presented alone.

Conditioned place aversion mediated by self-administered ethanol in the rat: a consideration of blood ethanol levels

A previous experiment has shown that rats will avoid environmental cues that have been associated with a history of ethanol self-administration. One possible explanation for this conditioned place aversion may be related to the temporal parameters of that experiment. During the initial segment of each 90-min conditioning/drinking trial (when most of the drinking occurred) the blood ethanol levels (BELs) were low and may well have produced positive effects at that time. However, as the drug continued to be absorbed and BELs increased during the remainder of the 90-min trial, the final (and conditioned) drug effects may have been aversive. In the present experiment the trial length was shortened to a 15-min period so that only low BELs would be temporally paired with the conditioning environment. A conditioned preference for that environment was predicted. Twelve rats were trained to self-administer ethanol in one environment and had water available in a different environment. Eight control animals had only water in both environments. BELs were measured and found to be low (16.8 to 57.6 mg%) and rising during the conditioning trials. However, when given a choice between the two environments, the rats avoided the environment in which they formerly consumed ethanol. No change in preference was noted for the control animals. This result was in accordance with previous findings but did not support the hypothesis that low, excitatory BELs would mediate a conditioned place preference in the rat.

Some determinants of the motivational properties of ethanol in the rat: Concurrent administration of food or social stimuli

The hypothesis was examined that the interaction of ethanol with the conditions under which it is administered may determine whether either preference or aversion for the drug develops. In Experiment 1, eight groups of food-deprived rats received injections of ethanol (175–1,400 mg/kg) in one environment and were later offered a choice between that environment and a different one previously associated with saline injections. Another eight groups were treated identically, except that food was available in both the saline and ethanol-paired environments. The groups given the drug without food showed no preference or aversion at low doses (175–700 mg/kg), but showed aversion at higher doses (1,000 and 1,400 mg/kg). When food was available, there was an increased preference for the environment paired with the 500 mg/kg doses. In Experiment 2, placing two rats together increased each rats preference for the environment associated with the other animal. However, rats pretreated with 500 mg/kg ethanol before being placed together showed a reduced preference for the environment associated with the drug and the other animal. Controls never paired with another rat showed no preference or aversion at the same ethanol dose. Thus, ethanol may interact with conditions such as the presence of food or another animal to determine final effects that are unique to those conditions.

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 (0.5% Na) followed by a 4% and then an 8% sodium supplemented diet. While on the control diet there were significant between strain differences in ethanol consumption, suggesting that the SS animals came genetically prepared to consume more ethanol. Blood pressure measured at regular intervals indicated significant changes only in the SS rats even though both lines as well as a group of Wistar rats, added for purposes of comparison, all increased their ethanol intake to the salt supplemented diets. A second experiment suggested that the initial difference in consumption between the SS and SR lines may be related to central nervous system sensitivity since differences were found in salt appetite but not in taste sensitivity or in the absorption, distribution or metabolism of the drug. These findings demonstrate that the Dahl SS rat is predisposed to consume more ethanol than the SR rat even before exposure to the hypertension-inducing diet, and that this predisposition is probably central in origin.(ABSTRACT TRUNCATED AT 250 WORDS)

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. In a second experiment four different groups of rats were offered the 3% salt supplemented diet in combination with daily injections of the synthetic salt-retaining mineralocorticoid desoxycorticosterone acetate (0.5, 1.5, and 6.0 mg/day). Ethanol intake again tended to increase in the 3 and 6% groups but in contrast to the results of Experiment 1 water intake also increased significantly. When desoxycorticosterone was administered without the salt supplemented diet, ethanol intake was significantly depressed while water intake increased. These findings indicate that a salt supplemented diet can significantly and selectively enhance the intake of moderately concentrated ethanol solutions and that while the addition of desoxycorticosterone injections to this diet has its effect primarily on water intake, these injections alone can also suppress ethanol intake indirectly by shifting the animals choice toward water and away from ethanol.

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. The present experiment assesses this possibility by examining the effect of the angiotensin converting enzyme inhibitor, enalapril, on the fluoxetine-induced decrease in alcohol intake. Four groups of rats were offered limited access to alcohol for 1 hr each day. When intake stabilized each group was injected with 2.5, 5.0 or 10.0 mg/kg of fluoxetine or the saline vehicle 1 hr prior to the access to alcohol. Fluoxetine produced a dose-dependent decrease in alcohol intake. Following this, all groups received injections of 1 mg/kg of the angiotensin converting enzyme inhibitor, enalapril, 40 min prior to the fluoxetine. Enalapril had no effect on alcohol intake in the saline group, but reversed the suppression in alcohol intake produced by the 2.5 mg/kg and 5.0 mg/kg doses of fluoxetine and partially reversed the effect of the 10.0 mg/kg dose. These findings indicate that the fluoxetine-induced reduction in alcohol intake may, in part, be mediated through the renin-angiotensin system.

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. In the second part of the study, the AII antagonist Sar-1 Thr-8 AII (500 micrograms/kg SC) was given immediately prior to the administration of either saline or 200 micrograms/kg AII. In the control group treated with saline, the antagonist had no effect of its own on intake but completely blocked the suppressive effect of the 200 micrograms/kg dose AII on alcohol consumption. These findings indicate that the reduction in alcohol intake produced by AII is mediated by events occurring at the receptor level.

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. Whereas the lesion did not alter alcohol consumption per se, it did significantly attenuate the ability of ANG II to reduce alcohol intake. This effect was not due to a lesion-induced change in the pharmacokinetics of alcohol and was observed only in those animals whose lesions produced a functional deficit, i.e., abolishing the increase in water drinking produced by ANG II. These results indicate that the SFO mediates the effect of systemically administered ANG II on alcohol intake but does not otherwise affect the regulation of alcohol consumption.

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. In experiment 2, One-Kidney, One-Clip (renin-independent) hypertensive rats or their sham operated controls were offered alcohol on a similar limited access basis. Over a four week period, the O-K,O-C rats did not show a reduction in the intake of either a 3% or 6% alcohol solution compared to the sham operated controls. These results provide further documentation for the role of the renin-angiotensin system in modulating alcohol intake. The process by which this system might influence alcohol intake is outlined.