Suppressed Alcohol Intake Research Articles

Association between preference for sweets and excessive alcohol intake: a review of animal and human studies.

This report reviews a series of studies demonstrating a relationship between the consumption of sweets and alcohol consumption. There is consistent evidence linking the consumption of sweets to alcohol intake in both animals and humans, and there are indications that this relationship may be at least partially genetic in nature. Alcohol-preferring rats have a tendency to consume sucrose and saccharin solutions far beyond the limits of their normal fluid intake and this has been proposed to be a model of the clinical phenomenon known as loss of control. Furthermore, rats and mice, genetically bred to prefer alcohol, tend to choose more concentrated sweet solutions, compared to animals which do not prefer alcohol. Similar tendencies to prefer ultra-sweet solutions have been noted in studies of alcoholic subjects, with most alcoholics preferring sweeter sucrose solutions than do controls. Evidence also exists that those alcoholics who prefer sweeter solutions may represent a familial form of alcoholism. Finally, consumption of sweets and/or sweet solutions may significantly suppress alcohol intake in both animals and in alcoholics. Carbohydrate structure and sweet taste may contribute to this effect through different physiological mechanisms involving serotonergic, opioid, and dopaminergic functions. The possibility that there is concordance between sweet liking and alcohol consumption and/or alcoholism has theoretical, biological, and diagnostic/practical implications.

The Chinese herbal medicine NPI‐028 suppresses alcohol intake in alcohol‐preferring rats and monkeys without inducing taste aversion

The Chinese herbal medicine NPI‐028 suppresses alcohol intake in alcohol‐preferring rats and monkeys without inducing taste aversion

Selective Inhibition of Alcohol Intake in Diverse Alcohol‐Preferring Rat Strains by the 5‐HT2A Antagonists Amperozide and FG 5974

The present studies sought to elucidate the role of 5-HT2A receptor antagonists in suppressing alcohol intake by comparing the effects of amperozide and FG 5974 on alcohol, food, and water intake in strains of alcohol-preferring rats: P, Alko Alcohol (AA), and Fawn-Hooded (FH). Both amperozide and FG 5974 have 5-HT2A receptor antagonist properties, but FG 5974 also shows presynaptic 5-HT1A receptor agonist activity. After establishment of stable baselines for intake measures in a two-bottle continuous access paradigm, rats (n = 10) were injected with 1 of 5 doses (0, 2.5, 5.0, and 10.0 mg/kg, sc) of amperozide or FG 5974 at weekly intervals. Amperozide dose-dependently reduced alcohol intake, total fluid intake, and alcohol preference in all three strains under continuous access conditions, whereas FG 5974 was less effective. Food intake was also suppressed by amperozide at higher doses, whereas it was increased by FG 5974. Amperozide also dose-dependently reduced alcohol intake when it was available for only 1 hr/day, but FG 5974 tended to increase it. After oral administration, amperozide was also more effective than FG 5974 in reducing alcohol intake. Despite these differences in efficacy in suppressing alcohol intake, both compounds produced taste aversion to a novel saccharin solution. These complex findings suggest that biochemical properties other than 5-HT2A receptor antagonism (e.g., 5-HT1A receptor agonism) may be involved in the effects of amperozide and FG 5974 on alcohol intake and other consummatory behaviors.

Selective Inhibition of Alcohol Intake in Diverse Alcohol-Preferring Rat Strains by the 5-HT2A Antagonists Amperozide and FG 5974

The present studies sought to elucidate the role of 5-HT2A receptor antagonists in suppressing alcohol intake by comparing the effects of amperozide and FG 5974 on alcohol, food, and water intake in strains of alcohol-preferring rats: P, Alko Alcohol (AA), and Fawn-Hooded (FH). Both amperozide and FG 5974 have 5-HT2A receptor antagonist properties, but FG 5974 also shows presynaptic 5-HT1A receptor agonist activity. After establishment of stable baselines for intake measures in a two-bottle continuous access paradigm, rats (n= 10) were injected with 1 of 5 doses (0, 1.0, 2.5, 5.0, and 10.0 mg/kg, sc) of amperozide or FG 5974 at weekly intervals. Amperozide dose-dependently reduced alcohol intake, total fluid intake, and alcohol preference in all three strains under continuous access conditions, whereas FG 5974 was less effective. Food intake was also suppressed by amperozide at higher doses, whereas it was increased by FG 5974. Amperozide also dose-dependently reduced alcohol intake when it was available for only 1 hr/day, but FG 5974 tended to increase it. After oral administration, amperozide was also more effective than FG 5974 in reducing alcohol intake. Despite these differences in efficacy in suppressing alcohol intake, both compounds produced taste aversion to a novel saccharin solution. These complex findings suggest that biochemical properties other than 5-HT2A receptor antagonism (e.g., 5-HT1A receptor agonism) may be involved in the effects of amperozide and FG 5974 on alcohol intake and other consummatory behaviors.

Attenuation of Alcohol Consumption by a Novel Nontoxic Ibogaine Analogue (18-Methoxycoronaridine) in Alcohol-Preferring Rats

We previously reported that single administration of ibogaine, an indol alkaloid with antiaddictive properties, dose dependently reduced alcohol intake in three strains of alcohol-preferring rats. The present study examined the effect of different doses of a newly developed nontoxic ibogaine analogue, 18-methoxycoronaridine (18-MC), on alcohol intake. Selectively bred alcohol-preferring rats received a single intraperitoneal injection of vehicle or 5, 20 and 40 mg/kg of 18-MC at 9:30 AM, and their consumption of alcohol, water and food was measured for 24 h. Our results demonstrate that a single injection of 18-MC significantly and dose dependently attenuated alcohol consumption and preference and commensurately increased water intake. Only the highest dose of 18-MC significantly decreased food intake. Although the true mechanism of action of 18-MC in suppressing alcohol intake is not yet fully understood, it may, like ibogaine, exert its attenuating effects on alcohol consumption by modulating neurotransmitters believed to be involved in the regulation of alcohol intake.

Thyrotropin Releasing Hormone Analog TA‐0910 Suppresses Alcohol Intake in Alcohol Drinking African Green Monkeys

In previous studies, we found that single injections of the thyrotropin-releasing hormone analog TA-0910 dose-dependently reduced alcohol intake and preference in alcohol-preferring (P) and Fawn-Hooded (FH) rats over a 24-hr period of continuous access to alcohol and water. However, several consecutive daily injections of TA-0910 resulted in the development of tolerance to these effects. In the present study, we found that in a 5-hr limited-access schedule in which monkeys could select an aqueous alcohol solution (7.5% v/v) or tap water, single doses of TA-0910 (0.0625, 0.125, 0.25, 0.5, and 0.75 mg/kg), similar to those found effective in P and FH rats, reduced consumption of alcohol. In this protocol, tolerance to the attenuating effects of TA-0910 on alcohol intake was not evident after five consecutive once-daily doses of 0.5 mg/kg. Furthermore, it was shown that a single dose of 0.75 mg/kg TA-0910 did not significantly influence 24-hr water intake when water was the only available fluid, but did reduce the intake of a preferred solution of saccharin. These findings suggest that activation of brain thyrotropin-releasing hormone systems reduces alcohol intake in primates and that tolerance to this effect is not evident within 5 days under a limited access schedule.

Thyrotropin Releasing Hormone Analog TA-0910 Suppresses Alcohol Intake in Alcohol Drinking African Green Monkeys

In previous studies, we found that single injections of the thyrotropin-releasing hormone analog TA-0910 dose-dependently reduced alcohol intake and preference in alcohol-preferring (P) and Fawn-Hooded (FH) rats over a 24-hr period of continuous access to alcohol and water. However, several consecutive daily injections of TA-0910 resulted in the development of tolerance to these effects. In the present study, we found that in a 5-hr limited-access schedule in which monkeys could select an aqueous alcohol solution (7.5% v/v) or tap water, single doses of TA-0910 (0.0625, 0.125, 0.25, 0.5, and 0.75 mg/kg), similar to those found effective in P and FH rats, reduced consumption of alcohol. In this protocol, tolerance to the attenuating effects of TA-0910 on alcohol intake was not evident after five consecutive once-daily doses of 0.5 mg/kg. Furthermore, it was shown that a single dose of 0.75 mg/kg TA-0910 did not significantly influence 24-hr water intake when water was the only available fluid, but did reduce the intake of a preferred solution of saccharin. These findings suggest that activation of brain thyrotropin-releasing hormone systems reduces alcohol intake in primates and that tolerance to this effect is not evident within 5 days under a limited access schedule.

Suppression of alcohol intake after administration of the Chinese herbal medicine, NPI-028, and its derivatives.

The Chinese herbal medicine, NPI-028, has been used for centuries in China to counteract alcohol intoxication. The present study used a number of different experimental conditions to determine whether NPI-028 and its derivatives might selectively influence alcohol intake in rodents that naturally exhibit high alcohol intakes. It was determined that intraperitoneal (i.p.) injections of NPI-028 (0.5, 0.75, and 1.0 g/kg) suppressed alcohol intake by up to 30% in both alcohol-preferring P and Fawn-Hooded (FH) rats during a continuous access schedule. These injections did not significantly affect food or water intakes, nor did the highest dose of NPI-028 (1 g/kg) alter blood ethanol levels after an i.p. injection of 2.5 g/kg of ethanol. In P rats, it was found that NPI-028 was orally active with the dose of 1.5 g/kg having a greater effect on ethanol intake than the 1.0 g/kg dose; once again, food and water intakes were not significantly altered. In FH rats maintained on a limited access schedule (1 hr/day), alcohol intake was completely abolished by 1.5 g/kg of NPI-028. Chronic i.p. administration of NPI-028 (0.75 g/kg) for four consecutive days in FH rats maintained on a continuous access schedule did not lead to any diminution of its alcohol-suppressant effects. Thus, NPI-028 has significant effects on alcohol intake without much effect on water and food intake, and tolerance does not readily develop to these effects. The i.p. administration of a partially purified extract (NPI-031) of NPI-028, obtained by countercurrent chromatography, also dose-dependently suppressed ethanol intake in FH rats, but the highest dose 200 mg/kg) also significantly decreased food intake. Finally, the i.p. administration of puerarin (NPI-31G), an isoflavone isolated from NPI-031 by countercurrent chromatography, significantly reduced ethanol intake in FH rats without affecting food or water intake. Therefore, NPI-028 and one of its pure components, NPI-031G, selectively reduced ethanol intake in alcohol-preferring rats.

Suppression of alcohol preference in high alcohol drinking rats: Efficacy of amperozide versus naltrexone

The selectively bred high alcohol drinking (HAD) line of rat is considered as a potential model of one type of alcoholism. The purpose of the present experiments was to compare the efficacy of two drugs on the volitional drinking of the HAD rats: the 5-HT2A receptor antagonist, amperozide, and a nonselective antagonist of opiate receptors, naltrexone. To determine the pattern of alcohol drinking of the HAD rats, a standard preference test was used in which water was offered with alcohol increased in concentrations from 3% to 30% over 11 days. The maximally preferred concentration of alcohol of each rat was offered for 4 days and ranged from 7% to 20% with a mean intake of 6.9 g/kg per day. Initially, 1.0 mg/kg amperozide, 2.5 mg/kg naltrexone, or the saline vehicle were injected twice daily for 4 days at 1600 and 2200 hours. Secondly, 2.0 mg/kg amperozide, 5.0 mg/kg naltrexone, or the saline vehicle were administered also for 4 days. After the drug sequences, alcohol preference tests continued for another 4 days. Whereas the saline vehicle was without effect on drinking, the administration of either drug caused a significant dose-dependent reduction in the daily intake of alcohol by the HAD rats in terms of absolute g/kg and proportion of alcohol to water consumed. A comparison of the drinking response to the higher doses of the two drugs showed that amperozide was more efficacious in suppressing alcohol intake than naltrexone. Niether amperozide nor naltrexone exerted any significant effects on food and water intakes or on body weight. These results support the concept of a functional link in the brain between the serotonergic and opioidergic systems postulated to underlie, in part, the aberrant drinking of alcohol. A marked dissociation between the temporal patterns of drinking after naltrexone and amperozide treatment suggests that the opiate receptors mediate the immediate reinforcing effects of alcohol, whereas the more vegetative phenomena underlying addictive properties of alcohol are regulated by 5-HT2A receptors postsynaptic to serotonergic neurons. Finally, the inhibitory actions of both drugs imply that multiple receptor mechanisms within the mesolimbic and other systems in the brain underpin the addictive liability to alcohol.

The delta 2-opioid receptor antagonist naltriben selectively attenuates alcohol intake in rats bred for alcohol preference

The relative importance of different opioid receptor types in mediating alcohol drinking behavior compared with the intake of other ingesta can be determined by characterizing the effects of selective opioid antagonists on the intake of various ingesta. Nonselective opioid receptor antagonists suppress the intake of many ingesta including alcohol, food, water, and sweets. Two distinct subtypes of delta-opioid receptors, delta 1 and delta 2, have recently been identified in rodent brain. We have previously reported that naltrindole (NTI), which blocks both delta 1 and delta 2 receptors, suppresses both alcohol and saccharin intake in rats selectively bred for high alcohol preference (P line). We now report that naltriben (NTB), an opioid antagonist that is selective for delta 2-opioid receptors, suppresses alcohol intake in rats of the P line and the effect appears to be both specific for alcohol and independent of alcohol palatability. NTB may reduce alcohol intake by attenuating the reinforcing pharmacological properties of alcohol.

The delta opioid receptor antagonist naltrindole attenuates both alcohol and saccharin intake in rats selectively bred for alcohol preference.

This study demonstrates that the selective delta receptor antagonists ICI 174864 and naltrindole (NTI) attenuate alcohol intake in a dose-dependent manner, without altering water intake, in rats selectively bred for alcohol preference. ICI 174864 had a very limited duration of action, as evidenced by the fact that suppression of alcohol intake lasted for only an hour following ICI 174864 administration. NTI, when administered in a dose of 10 mg/kg, suppressed alcohol intake by 28%. Increasing the dose of NTI to 15 mg/kg produced a 44% suppression of alcohol intake, but a further increase to 20 mg/kg did not produce greater suppression than was seen with a dose of 15 mg/kg (46% versus 44%, respectively). This suggests that NTI is maximally effective in suppressing alcohol intake at a dose of 15.0 mg/kg. NTI displayed a long duration of action, as evidenced by attenuation of alcohol drinking that lasted for at least 8 h following drug treatment. Administering the maximally effective dose of NTI (15 mg/kg) in two parts, separated by 4 h, served to prolong the duration of action of NTI and produced an attenuation of alcohol intake, but not water intake, that lasted for at least 28 h. The effect of NTI on alcohol intake was not specific for alcohol, as evidenced by the fact that NTI reduced the intake of saccharin solutions with and without alcohol.

Tomato juice, chocolate drink, and other fluids suppress volitional drinking of alcohol in the female syrian golden hamster

Although the hamster generally prefers alcohol at a level similar to that of the rat or mouse selectively bred to consume alcohol, the drinking hamster demonstrates neither physical dependence on alcohol nor elevated blood levels of alcohol, which are two typical criteria characterizing an animal model of alcoholism. The present investigation was designed to determine whether a third criterion of an animal model (i.e., consumption of high levels of alcohol in the presence of a palatable fluid, fulfilled by the P rat) would be met by the female Syrian golden hamster (Mesocricetus auratus). A standard 3-bottle preference test was undertaken in 6 female hamsters over an 11 day period, in which water was presented in one tube and, in a second tube, a v/v solution of alcohol which was increased in concentration from 3% to 50% on each day as follows: 3%, 5%, 7%, 9%, 12%, 15%, 20%, 25%, 30%, 40%, and 50%. Then each hamster was offered its individually determined, maximally preferred concentration of alcohol for 4-8 days, which was 20%, 25%, or 30% alcohol. The mean absolute intake of alcohol during this period was 17.9 +/- 1.1 g/kg per day, whereas the mean proportion of alcohol to total fluid was 0.68 +/- 0.05. Then over a 4-day interval, a solution of tomato juice, peach juice, mango juice, dextrose and a chocolate beverage (Ensure Plus), all made isocaloric to the alcohol solutions with dextrose, was placed in the third tube simultaneously with water and the individually preferred concentration of alcohol.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of nitric oxide synthesis attenuates alcohol consumption in two strains of alcohol-preferring rats

The effect of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on voluntary alcohol consumption was examined in two different strains of alcohol-preferring rats, in a continuous-access, two-bottle-choice paradigm. Compared with the vehicle, intraperitoneal injections of L-NAME significantly and dose-dependently (10, 30, and 60 mg/kg) suppressed alcohol intake and preference in both alcohol-preferring (P) and Fawn-Hooded (FH) rats. The effect of the highest dose of L-NAME was nonspecific; it caused general decreases in consumption of alcohol, water, and food. Repeated injection of L-NAME (30 mg/kg) for 4 consecutive days significantly attenuated alcohol intake, but tolerance developed after 3 days of treatment. A single administration of a high dose of L-NAME (60 mg/kg) did not influence the blood alcohol concentrations, which suggests a possible central effect. Furthermore, a moderate dose of 30 mg/kg L-NAME, which selectively inhibited alcohol intake, did not exert a significant effect on telemetrically measured heart rate, core body temperature, and gross motor activity of alcohol naive Fawn-Hooded rats. These results suggest an involvement of nitric oxide in alcohol drinking behavior. Although the true mechanism(s) of action is not yet clear, it can be speculated that L-NAME may exert its action indirectly by modulating neurotransmitters proposed to be involved in alcohol drinking and/or by influencing other neuronal factors, such as neuronal Ca2+ channels, which have been shown to be involved in alcohol drinking behavior.

Further evidence that 5-HT 4 receptor antagonists suppress alcohol intake in rats

Further evidence that 5-HT 4 receptor antagonists suppress alcohol intake in rats

Selective agonists at NK3 tachykinin receptors inhibit alcohol intake in Sardinian alcohol-preferring rats

The present study evaluated the effect of tachykinin agonists, selective for different neurokinin (NK) receptors, on alcohol intake in genetically selected, Sardinian alcohol-preferring rats. Tachykinins were given by intracerebroventricular injection just before access to fluids. In rats offered both water and 8% ethanol 2 h/day, the NK3 selective agonists [Asp5.6,MePhe8]substance P(5-11), Suc[Asp6,MePhe8]substance P(6-11), and [MePhe7]neurokinin B markedly suppressed alcohol intake. The NK1 selective agonist [Sar9,Met(O2)11]substance P and the NK2 selective agonist GR 64349 did not At doses that inhibited alcohol intake, the NK3 agonists did not modify water intake; total fluid intake was significantly reduced only following 500 ng/rat of [Asp5.6,MePhe8]substance P(5-11). When rats were given a longer access to fluids (8% alcohol for 2 h, but water for 4 h), again, NK3 agonists suppressed alcohol intake, but not total fluid intake. Moreover, NK3 agonists did not modify solid food intake in food-deprived rats, nor water intake in water-deprived rats, when alcohol was not available. These findings indicate that NK3 agonists inhibit alcohol intake in Sardinian alcohol-preferring rats and that their effect is behaviorally selective. They also suggest that central NK3 receptors may be involved in alcohol intake control in rats.

Bradykinin suppresses alcohol intake and plays a role in the suppression produced by an ACE inhibitor

The possible role of the endogenous kinins in the control of alcohol intake was assessed in two experiments. In Experiment 1, naive rats, maintained on ad lib food and water, were given daily 40-min access to a 6% (w/v) alcohol solution and water. Daily intraperitoneal (IP) injections of captopril (20 mg/kg) significantly reduced alcohol intake, while pretreatment with subcutaneous (SC) injections of the bradykinin antagonist [D-Phe7]-bradykinin (100-300 micrograms/kg) attenuated the suppressive effect of captopril on alcohol intake. The saline vehicle or the bradykinin antagonist alone did not alter alcohol intake. In Experiment 2, bradykinin was administered daily at 100, 200, and 400 micrograms/kg doses SC either alone or in combination with captopril 10 mg/kg IP. Neither bradykinin nor captopril by themselves changed alcohol or water intake. Bradykinin combined with captopril stimulated water intake and reduced alcohol intake by up to 70%. This effect was not due to drug-induced changes in the pharmacokinetics of alcohol. The angiotensin II receptor antagonist [Sar1,Thr8]-angiotensin II at 250 and 500 micrograms/kg SC attenuated the stimulation of water intake but not the reduction in alcohol intake. It is suggested that by inhibiting kininase II, ACE inhibitors extend the duration of action of bradykinin and thereby unmask a potent inhibition of alcohol intake mediated by kinins--an effect that is dissociable from the accompanying stimulation of water intake. Taken together, these results point to an involvement of the kinin system in the regulation of alcohol intake and in particular to a role of bradykinin in the suppressive effect of ACE inhibitors on alcohol intake.

Captopril and hydrochlorothiazide (Capozide) combine to enhance the reduction in voluntary alcohol intake in rats.

The effect of Capozide, the combination of captopril with a hydrochlorothiazide diuretic, on voluntary alcohol intake was assessed in two experiments. In experiment 1 naive rats who were maintained on ad libitum food and water were given daily 40-min access to a 6% (w/v) alcohol solution and water. Daily intraperitoneal injections of captopril (10 mg/kg) reduced alcohol intake, but the combination of captopril (5 and 10 mg/kg) and hydrochlorothiazide (2.5, 5, and 10 mg/kg) enhanced the reduction in intake. In experiment 2, captopril alone, hydrochlorothiazide alone, and the combination of captopril and hydrochlorothiazide were again administered daily in the limited access procedure. Captopril (10 mg/kg) again reduced alcohol intake as did all three doses of hydrochlorothiazide (2.5, 5, and 10 mg/kg). Compared with the individual effects of captopril and hydrochlorothiazide, Capozide exerted a supra-additive reduction in alcohol intake. These effects were not due to drug-induced changes in the pharmacokinetics of alcohol. Taken together these results demonstrate an enhanced potency of Capozide in suppressing alcohol intake and invite their testing in a population of hypertensive alcoholics and alcohol abusers.

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. Compared to sham-operated controls, rats with AP lesions consumed significantly more of a palatable 3% alcohol solution, and equal amounts of a less palatable 6% alcohol solution, but the lesion did not alter the ability of ANG II to reduce alcohol intake. These findings indicate that while the AP plays no role in the suppressive effect of ANG II on alcohol consumption, it can modulate alcohol consumption through its responsiveness to orosensory stimuli.

The tachykinin NH 2-senktide inhibits alcohol intake in alcohol-preferring rats

The present study evaluated the effect of the intracerebroventricular injection of the tachykinins, substance P, neurokinin A and [Asp5.6,MePhe8]substance P(5-11) (also referred to as NH2-senktide), on the alcohol intake of genetically selected, alcohol-preferring rats. Animals were offered both water and 8% ethanol 2 h/day; tachykinins were administered just before access to fluids. Neurokinin A and substance P did not modify alcohol intake at doses up to 1000 and 2000 ng/rat, respectively. On the other hand, NH2-senktide potently suppressed alcohol intake at doses of 31.2-500 ng/rat. At the same doses, however, it did not significantly affect water intake. This finding suggests that its effect on alcohol intake might be rather selective and not due to general impairment of the behavior. Activation of tachykinin NK-3 receptors, for which NH2-senktide is a highly selective agonist, produces angiotensin II release in the brain; however, the effect of NH2-senktide on alcohol intake is probably not mediated by angiotensin II, as suggested by the fact that it is not modified by captopril pretreatment.

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.