Ethanol Consumption In Rats Research Articles

Chronic ethanol consumption in rats produces residual increases in anxiety 4 months after withdrawal

The present study investigated the long-term effects of ethanol consumption in rats. Subjects were maintained on either an ethanol (alcohol) (2.7–6.7%, v/v) or an isocaloric liquid control diet for 26 consecutive days ( M = 13.7 g/kg/day). Testing for working memory was conducted in a Morris water maze (2 trials/day for 8 days) and commenced after either a short (19 days) or long (120 days) abstinence period. This was followed by assessment of 72 h retention of passive avoidance. Animals were killed either 41 (short abstinence) or 152 days (long abstinence) post-ethanol and their brains stained with cresyl violet. Assessments of dorsal-ventral and medial-lateral cortical vertices were measured in sections derived from eight coronal planes extending +4.20 to −4.16 mm from Bregma. Results indicated that subjects in the ethanol/long abstinence group exhibited increased state anxiety due to their propensity to be thigmotaxtic (i.e., wall-hugging) in the water maze. Unfortunately, such a swim pattern precluded assessment of working memory in our subjects. No evidence of ethanol-induced memory decrements were observed on retention of passive avoidance. There was some evidence that animals in the ethanol/long abstinent group suffered cortical thinning and slight compression of the CA1 layer within the hippocampus, although age might have contributed to the former effect. It was concluded that chronic ethanol consumption increases anxiety even after an extended period of withdrawal and may conspire with age to affect cortical integrity.

Overexpression of neuropeptide Y in the central nucleus of the amygdala decreases ethanol self-administration in "anxious" rats.

Neuropeptide Y (NPY) has been implicated in a variety of behaviors including those associated with anxiety and ethanol administration. The current experiment investigated the predictive role of anxiety-like behaviors in ethanol self-administration and the relationship of NPY in the central nucleus of the amygdala (CeA) with anxiety and ethanol self-administration. Rats were divided into anxious and nonanxious groups based on behavior in the elevated plus maze. Following elevated plus maze testing, rats were allowed to consume increasing concentrations of ethanol (2, 4, and 6%) in a 2-bottle choice procedure over a period of 31 days. anxious rats showed an increased preference for 4% ethanol and 6% ethanol compared with non-anxious rats. Following 20-day access to 6% ethanol, rats underwent gene transfer surgery with replication-defective recombinant herpes simplex 1 vectors encoding prepro-NPY, an antisense NPY RNA, or LacZ (control) into the CeA. In anxious rats, bilateral injections into the CeA with the NPY-antisense vector increased 6% ethanol preference, while the vector encoding NPY decreased 6% ethanol preference. Herpes simplex viral-mediated alterations in CeA NPY expression did not alter ethanol preference in nonanxious rats. These results suggest that virally mediated alterations in NPY levels in the CeA differentially affect ethanol consumption in rats with low and high basal levels of anxiety.

4-hydroxynonenal detoxification by mitochondrial glutathione S-transferase is compromised by short-term ethanol consumption in rats.

4-Hydroxynonenal (HNE), a toxic lipid peroxidation product, has been implicated in mitochondrial damage in rat liver by ethanol consumption. The present study assessed the effects of short-term in vivo ethanol exposure on HNE detoxification by mitochondrial glutathione S-transferase (GST). Male Sprague Dawley rats were administered 5 doses of ethanol (4 g/kg) at 12 hr intervals by gavage. Pair-fed rats that received isocaloric dextrose instead of ethanol served as controls. Mitochondrial and submitochondrial fractions were prepared from the livers. Mitochondrial contents of HNE and HNE-glutathione conjugate were measured by high-performance liquid chromatography. GST isoforms were identified by Western blots in submitochondrial fractions. Whereas there was an 80% increase in mitochondrial HNE content after ethanol consumption, there was a 42% decrease in the content of HNE-glutathione conjugate, compared with controls (p< 0.05). After ethanol exposure, the GST activities toward HNE in intact mitochondria and in the membranous fraction were decreased by 37% and 45% (p< 0.05), respectively, whereas that in the aqueous fraction was unchanged. Kinetic analysis of HNE conjugation by the membrane-associated GST showed that ethanol decreased the V(max) nearly by half (p< 0.05), whereas it did not affect the K(m). HNE conjugation by the aqueous GST demonstrated a higher K(m) than that of the membrane-associated GST, although its kinetics were not significantly altered by ethanol. Immunochemical analysis with Western blots demonstrated that both the membranous and the aqueous fractions of mitochondria contain GST-alpha and GST-mu isoforms, whereas GST-pi was absent. HNE detoxification by mitochondrial GST is compromised by short-term ethanol consumption, which may contribute to elevated mitochondrial HNE content and hence its toxicity in the ethanol-exposed liver.

A single injection of the kappa opioid antagonist norbinaltorphimine increases ethanol consumption in rats

A single injection of the kappa opioid antagonist norbinaltorphimine increases ethanol consumption in rats

A single injection of the kappa opioid antagonist norbinaltorphimine increases ethanol consumption in rats

Kappa opioid receptor (KOR) agonists interfere with the reinforcing effects of drugs of abuse. KOR agonists decrease heroin, cocaine, and ethanol self-administration, and block heroin and cocaine conditioned place preference (CPP) in rats. However, KOR agonists also produce emesis and dysphoria, making it difficult to determine if their effects on self-administration are due to an action on reward mechanisms or are secondary to the drug's direct aversive effects. Assuming that endogenous KOR ligands modulate circuits involved in drug and alcohol reward, selective KOR antagonists can be used to clarify these issues. If KOR antagonists increase drug self-administration then it is likely that endogenous KOR agonists directly modulate drug intake. To determine the effects of nor-BNI, the highly selective KOR antagonist, on ethanol consumption and CPP. Thirty-eight male Lewis rats were given free access to ethanol until stable self-administration was achieved. Animals were then administered a single injection of nor-BNI (10 mg kg(-1)) while ethanol intake was monitored. A single injection of nor-BNI induces a long-lasting increase in ethanol consumption, but does not induce a CPP. A high/low split revealed that this effect was primarily due to an increase in drinking in nor-BNI-treated high drinkers, which drank significantly more than saline-treated high drinkers and also drank significantly more when compared to their own pretreatment baseline. Blocking the KOR system increases ethanol self-administration, suggesting that the decrease in self-administration seen with KOR agonists is due to a direct modulation of reward circuitry.

Polymorphisms in the mitochondrial aldehyde dehydrogenase gene (Aldh2) determine peak blood acetaldehyde levels and voluntary ethanol consumption in rats

Dependence on alcohol, a most widely used drug, has a heritability of 50-60%. Wistar-derived rats selectively bred as low-alcohol consumers for many generations present an allele (Aldh2(2)) of mitochondrial aldehyde dehydrogenase that does not exist in high-alcohol consumers, which mostly carry the Aldh2(1) allele. The enzyme coded by Aldh2(2) has a four- to five-fold lower affinity for NAD than that coded by Aldh2(1). The present study was designed to determine whether these polymorphisms account for differences in voluntary ethanol intake and to investigate the biological mechanisms involved. Low-drinker F0 Aldh2(2)/Aldh2(2) rats were crossed with high-drinker F0 Aldh2(1)/Aldh2(1) rats to obtain an F1 generation, which was intercrossed to obtain an F2 generation that segregates the Aldh2 alleles from other genes that may have been coselected in the breeding for each phenotype. Data show that, with a mixed genetic background, F2 Aldh2(1)/Aldh2(1) rats voluntarily consume 65% more alcohol (P<0.01) than F2 Aldh2(2)/Aldh2(2) rats. A major phenotypic difference was a five-fold higher (P<0.0025) peak blood acetaldehyde level following ethanol administration in the lower drinker F2 Aldh2(2)/Aldh2(2) compared to the higher drinker F2 Aldh2(1)/Aldh2(1) animals, despite the existence of identical steady-state levels of blood acetaldehyde in animals of both genotypes. Polymorphisms in Aldh2 play an important role in: (i) determining peak blood acetaldehyde levels and (ii) modulating voluntary ethanol consumption. We postulate that the markedly higher peak of blood acetaldehyde generated in Aldh2(2)/Aldh2(2)(2) animals is aversive, leading to a reduced alcohol intake in Aldh2(2)/Aldh2(2) versus that in Aldh2(1)/Aldh2(1) animals.

The selective dopamine D3 receptor antagonist SB-277011-A attenuates ethanol consumption in ethanol preferring (P) and non-preferring (NP) rats

The mesolimbic dopamine (DA) system plays an important role in mediating addiction to alcohol and other drugs of abuse. Recent evidence points toward the role of the DA D3 receptor (D3R) in drug-induced reward, drug-taking, as well as cue-, drug-, and stress-triggered relapse to drug-seeking behavior. Accordingly, the present study examined the effects of acute selective antagonism of the D3R on ethanol consumption in alcohol Preferring (P) and Non-Preferring (NP) rats. We employed the two-bottle choice paradigm to monitor ethanol consumption in these rats before and after treatment with 3, 10, and 30 mg/kg (i.p.) of the selective D3R antagonist SB-277011-A. Results indicated a significant attenuation in ethanol preference, intake and lick responses in P rats treated with 10 and 30 mg/kg SB-277011-A. A similar, though not as robust effect was observed in ethanol consumption in the NP rats when treated with 30 mg/kg SB-277011-A. Finally, the acute administration of SB-277011-A did not produce extrapyramidal side effects, as indicated by stable lick response–volume ratios and lick response time distributions. These results further support the notion that the D3R is important in mediating the addictive properties of alcohol and suggest that selective blockade of the D3R may constitute a new and useful target for prospective pharmacotherapeutic approaches to alcoholism.

Complex I regulates mutant mitochondrial aldehyde dehydrogenase activity and voluntary ethanol consumption in rats

Animals selectively bred for a desirable trait retain wanted genes but exclude genes that may counteract the expression of the former. The possible interactions between selected and excluded genes cannot be readily studied in transgenic or knockout animals but may be addressed by crossing animals bred for opposite traits and studying the F2 offspring. Ninety-seven percent of Wistar-derived rats selectively bred for their voluntary low-alcohol consumption display a mutated nuclear allele of aldehyde dehydrogenase Aldh22 that encodes an enzyme with a low affinity for NAD+, whereas rats bred for high-alcohol consumption do not present the Aldh22 allele. This enzyme is inserted into mitochondria, where NADH-ubiquinone oxidoreductase (complex I) regenerates NAD+. The possible influence of complex I on ALDH2 activity and voluntary ethanol intake was investigated. Homozygous Aldh22/Aldh22 rats derived from a line of high-drinker F0 females (and low-drinker F0 males) showed a markedly higher ethanol consumption (3.9=/-0.5 g x kg(-1) x day(-1)) than homozygous animals derived from a line of low-drinker F0 females (and high-drinker F0 males) (1.8+/-0.4 g x kg(-1) x day(-1)). Mitochondria of F2 rats derived from high alcohol-consuming females were more active in oxidizing substrates that generate NADH for complex I than were mitochondria derived from low alcohol-consuming females, leading in the former to higher rates of acetaldehyde metabolism and to a reduced aversion to ethanol. This is the first demonstration that maternally derived genes can either allow or counteract the phenotypic expression of a mutated gene in the context of alcohol abuse or alcoholism

The effect of baclofen alone and in combination with naltrexone on ethanol consumption in the rat

Naltrexone has been evaluated in preclinical animal models of ethanol consumption and found to be effective in most reports. In clinical use, naltrexone has not proved to be as efficacious in preventing relapse. While naltrexone targets opioid receptors, many other neurotransmitter systems are targeted by ethanol and, to a greater or lesser extent, contribute to modulating ethanol's reinforcing effects. There has been indication that drugs active at the gamma amino butyric acid B (GABA B) receptors can affect the self-administration of many drugs with abuse potential. The experiments reported here evaluated the effect of three doses of baclofen (2.5, 5.0, or 7.5 mg/kg), a GABA B agonist, administered alone or in combination with a single dose of naltrexone (1.0 mg/kg). In Experiment 1, both naltrexone and baclofen, at the two higher doses tested, significantly reduced ethanol consumption in Wistar rats using a limited access procedure on Drug Days 1 and 2. When combined on Drug Days 3 and 4, baclofen/naltrexone was significantly more effective in reducing ethanol consumption than did either drug alone. Neither drug, alone or in combination, had an effect on water consumption. In Experiment 2, both baclofen and naltrexone again significantly reduced ethanol consumption, with no evidence that chronic administration across Drug Days 3 and 4 further reduced consumption compared with Drug Days 1 and 2. The clinical use of multiple pharmacotherapeutic agents in combination may allow for the use of lower doses of individual components, thereby reducing the negative side effects that contribute to lower compliance and higher relapse.

Residual behavioral and neuroanatomical effects of short-term chronic ethanol consumption in rats

The residual effects of short-term chronic ethanol consumption were investigated in rats maintained on an ethanol liquid diet for 26 consecutive days (mean intake=16.1 g/kg/day). Animals were assessed for spontaneous motor activity (12 days post-ethanol), spatial working memory (17 days post-ethanol), spatial reference memory (184 days post-ethanol), and retention of passive avoidance (201 days post-ethanol). Measurements of brain weights and cortical thickness vertices within the dorsomedial and ventrolateral cortex of eight coronal planes were determined 260 days post-ethanol. Two-dimensional cell profile densities within six coronal planes and within CA1 region of the hippocampus were also obtained, along with the total volumetric measurement of the hippocampus proper. Results indicated between group differences when subjects were assessed on working memory with ethanol-treated animals exhibiting longer escape latencies in a Morris water maze, an effect partially attributed to the perseverance of ethanol-treated animals in exhibiting thigmotaxicity. No other ethanol-related behavioral impairment was noted. Neuroanatomically, ethanol-treated rats had thinner cortical mantles (6.3% and 6.6% reductions) within the frontoparietal cortex and had lower two-dimensional cell profile densities within the most caudal cortical region studied. Interestingly, control animals with thicker cortical mantles tended to perform better on the working memory task, whereas the opposite was true for ethanol-treated subjects. These data led to the conclusion that chronic ethanol consumption of a relatively short duration produces working memory impairments, albeit mild, that are partially related to an inability to abandon ineffectual behavioral strategies, and also produces neuroanatomical alterations within the cortex.

The effects of chronic ethanol consumption and ethanol withdrawal on serum cholinesterase activity in rats.

The effect of chronic ethanol consumption and ethanol withdrawal on serum cholinesterase (ChE) activity was investigated in female Wistar rats. Ethanol was administered by a modified liquid diet with 4.8% (v/v) ethanol for 3 days followed by 25 days on a liquid diet in which the ethanol concentration was increased to 7.2%. Control rats were pair-fed with an isocaloric liquid diet not containing ethanol. The blood ethanol concentration and serum ChE activity were measured at the end of the 4.8% ethanol consumption period; after 7, 14 and 35 days of ethanol (7.2%) consumption, and at 24 and 72 h after ethanol withdrawal following ethanol consumption of 35 days. Daily ethanol consumption of the rats ranged from 11.5 to 14.9 g/kg. Serum ChE activity was found significantly increased from the 3rd day of ethanol (4.8%) consumption. Serum ChE activities of the rats receiving 7.2% ethanol also increased significantly compared with rats ingesting 4.8% ethanol. Blood ethanol levels were measured as 121 and 0.88 mg/dl on the 35th day of ethanol (7.2%) consumption (just before ethanol withdrawal) and after 24 h of ethanol withdrawal, respectively. Increased serum ChE activity (1968 U/l) was still observed (1942 U/l) after 24 h of ethanol withdrawal. ChE activity returned to control levels (501 U/l) after 72 h of ethanol withdrawal. Audiogenic seizures indicating development of physical dependence on ethanol were also observed after 8 h of ethanol withdrawal in another individual group of ethanol-fed rats. Our results show that serum ChE activity is increased by chronic ethanol consumption in rats and that this increase is affected by ethanol concentration and duration of ethanol ingestion.

Sex differences in L-type calcium current after chronic ethanol consumption in rats

Chronic ethanol consumption elicits a progressive cardiac contractile dysfunction, and studies in rats suggest that this alcoholic heart muscle disease is more pronounced in males than females. Cellular changes associated with the ethanol-induced cardiotoxicity remain largely undefined; however, it is possible that L-type Ca 2+ channel current ( I Ca,L) is affected. Using whole-cell patch-clamp techniques, this study examined I Ca,L in adult ventricular myocytes isolated from male and female P-rats that had consumed drinking water (controls) or a 25% ethanol/water mixture for 14 months. The peak amplitude and maximum conductance of I Ca,L were 32 and 26% greater, respectively, in cardiomyocytes isolated from ethanol-consuming compared to control male rats. In contrast, no differences in the amplitude or conductance of I Ca,L were observed when comparing myocytes isolated from control and ethanol-consuming females. Ethanol treatment had no significant effects on the kinetics I Ca,L inactivation or on steady-state activation and inactivation in either gender. In conclusion, male but not female cardiomyocytes respond to chronic ethanol consumption with an increased I Ca,L that may represent a compensatory response to the depressed contractility.

A re-evaluation of the role of tetrahydropapaveroline in ethanol consumption in rats

The role of tetrahydropapaveroline (THP), a condensation product of a dopaldehyde with dopamine, in the regulation of alcohol consumption was investigated. In the first experiment, rats received intraventricular injections of either racemic THP hydrobromide (0.65 or 1.3 μg/μl), R-(+)-THP (0.66 or 1.4 μg/μl), or an equal volume of vehicle. The lower doses of both (±)-THP and (+)-THP significantly increased volitional alcohol intake. For the racemic compound, the increase was significant at 7–13% concentrations. The R-(+)-enantiomer increased consumption at 4–11 and 15–20% concentrations of ethanol. The higher doses of both compounds did not significantly alter alcohol preference. A second experiment evaluated the chronic effect of THP delivered subcutaneously via osmotic minipump. Animals receiving THP (0.1, 0.5, 1.0, 2.0, and 4.0 mg/ml) did not differ in their alcohol intake, compared to vehicle-treated controls. Whether or not endogenously formed THP participates in the etiology of alcohol addiction remains unclear. Nonetheless, there are few known compounds that induce a preference for unsweetened alcohol solutions over water in laboratory animals.

Cardiac structure and function after short-term ethanol consumption in rats

Using an animal model of alcoholism, we investigated whether 4 months of ethanol consumption was associated with a preclinical stage of alcoholic cardiomyopathy (ACM), as well as activation of the renin-angiotensin system and natriuretic peptides (NPs). In other forms of cardiovascular disease, the latter peptide systems have been used as markers of left ventricular (LV) remodeling and dysfunction. Rats were fed either a liquid ethanol or control diet, and serial blood samples were collected at baseline, as well as at 2 and 4 months, for plasma renin activity (PRA), angiotensin II (ANG II), atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) levels. Serial echocardiography (echo) was performed at the same time points, and isolated heart studies were performed to assess ex vivo contractility at 4 months. In both groups at 4 months, there were significant and similar increases in end-diastolic and end-systolic echo dimensions and LV mass. At 4 months, however, a significant decrease was found in the relative wall thickness in the ethanol-fed group compared with findings for the control group. In both groups at 4 months, significant and similar time-dependent decreases were shown in BNP and ANP levels compared with baseline values. No differences were found in NP gene expression or tissue levels. In both groups at 4 months, significant and similar increases were found in ANG II levels compared with baseline values. Over time, in both groups, PRA levels were unchanged. In this study, the only cardiac structural feature characteristic of a preclinical ACM was a decrease in relative wall thickness.

4‐Hydroxynonenal Detoxification by Mitochondrial Glutathione S‐Transferase Is Compromised by Short‐Term Ethanol Consumption in Rats

Background 4‐Hydroxynonenal (HNE), a toxic lipid peroxidation product, has been implicated in mitochondrial damage in rat liver by ethanol consumption. The present study assessed the effects of short‐term in vivo ethanol exposure on HNE detoxification by mitochondrial glutathione S‐transferase (GST).Methods Male Sprague Dawley® rats were administered 5 doses of ethanol (4 g/kg) at 12 hr intervals by gavage. Pair‐fed rats that received isocaloric dextrose instead of ethanol served as controls. Mitochondrial and submitochondrial fractions were prepared from the livers. Mitochondrial contents of HNE and HNE‐glutathione conjugate were measured by high‐performance liquid chromatography. GST isoforms were identified by Western blots in submitochondrial fractions.Results Whereas there was an 80% increase in mitochondrial HNE content after ethanol consumption, there was a 42% decrease in the content of HNE‐glutathione conjugate, compared with controls (p &lt; 0.05). After ethanol exposure, the GST activities toward HNE in intact mitochondria and in the membranous fraction were decreased by 37% and 45% (p &lt; 0.05), respectively, whereas that in the aqueous fraction was unchanged. Kinetic analysis of HNE conjugation by the membrane‐associated GST showed that ethanol decreased the Vmax nearly by half (p &lt; 0.05), whereas it did not affect the Km. HNE conjugation by the aqueous GST demonstrated a higher Km than that of the membrane‐associated GST, although its kinetics were not significantly altered by ethanol. Immunochemical analysis with Western blots demonstrated that both the membranous and the aqueous fractions of mitochondria contain GST‐α and GST‐μ isoforms, whereas GST‐π was absent.Conclusions HNE detoxification by mitochondrial GST is compromised by short‐term ethanol consumption, which may contribute to elevated mitochondrial HNE content and hence its toxicity in the ethanol‐exposed liver.

4-Hydroxynonenal Detoxification by Mitochondrial Glutathione S-Transferase Is Compromised by Short-Term Ethanol Consumption in Rats

Background 4-Hydroxynonenal (HNE), a toxic lipid peroxidation product, has been implicated in mitochondrial damage in rat liver by ethanol consumption. The present study assessed the effects of short-term in vivo ethanol exposure on HNE detoxification by mitochondrial glutathione S-transferase (GST). Methods Male Sprague Dawley® rats were administered 5 doses of ethanol (4 g/kg) at 12 hr intervals by gavage. Pair-fed rats that received isocaloric dextrose instead of ethanol served as controls. Mitochondrial and submitochondrial fractions were prepared from the livers. Mitochondrial contents of HNE and HNE-glutathione conjugate were measured by high-performance liquid chromatography. GST isoforms were identified by Western blots in submitochondrial fractions. Results Whereas there was an 80% increase in mitochondrial HNE content after ethanol consumption, there was a 42% decrease in the content of HNE-glutathione conjugate, compared with controls (p < 0.05). After ethanol exposure, the GST activities toward HNE in intact mitochondria and in the membranous fraction were decreased by 37% and 45% (p < 0.05), respectively, whereas that in the aqueous fraction was unchanged. Kinetic analysis of HNE conjugation by the membrane-associated GST showed that ethanol decreased the Vmax nearly by half (p < 0.05), whereas it did not affect the Km. HNE conjugation by the aqueous GST demonstrated a higher Km than that of the membrane-associated GST, although its kinetics were not significantly altered by ethanol. Immunochemical analysis with Western blots demonstrated that both the membranous and the aqueous fractions of mitochondria contain GST-α and GST-μ isoforms, whereas GST-π was absent. Conclusions HNE detoxification by mitochondrial GST is compromised by short-term ethanol consumption, which may contribute to elevated mitochondrial HNE content and hence its toxicity in the ethanol-exposed liver.

A comparison of the effects of 6-β naltrexol and naltrexone on the consumption of ethanol or sucrose using a limited-access procedure in rats

We recently reported that 6-β naltrexol, the major metabolite of naltrexone in humans, reduced ethanol consumption in rats. Two new experiments were designed to compare 6-β naltrexol and naltrexone across three dose levels on an ethanol or sucrose baseline using a limited-access procedure in Wistar rats. The results of Experiment 1 showed that both 6-β naltrexol and naltrexone reduced ethanol consumption across a range of doses. An in vivo assay showed that naltrexone was approximately 25 times more potent than 6-β naltrexol at comparable ED 50 doses. In addition, there was no indication of systematic development of tolerance to the effect of either drug across the 4 days of drug administration. In Experiment 2, both 6-β naltrexol and naltrexone reduced the consumption of a sucrose solution using a limited-access procedure. The implications of these data for the development of pharmacotherapeutic agents capable of reducing drinking in recovering alcoholics are discussed.

Aversion to acetaldehyde: differences in low-alcohol-drinking (UChA) and high-alcohol-drinking (UChB) rats

We have previously found the existence of a relation between activity of the brain mitochondrial aldehyde dehydrogenase (ALDH2) and consumption of ethanol in rats of the low-alcohol-drinking (UChA) and the high-alcohol-drinking (UChB) strains. The aim of the present study was to determine whether UChA and UChB rats also differed in sensitivity to the aversive effects of acetaldehyde (AcH). Aversion to AcH was studied by using a conditioned taste aversion (CTA) paradigm. Ethanol naive UChA and UChB rats were administered AcH intraperitoneally (50, 100, or 150 mg/kg) or saline and exposed to a banana-flavored solution during five conditioning trials. A strong dose-dependent CTA to AcH was found in UChA rats, whereas UChB rats did not show a CTA to any dose of AcH. At equal doses of AcH, cerebral venous blood AcH levels in UChA rats were consistently higher than in UChB rats, a finding that may reflect the previously observed differences in the activity of ALDH2 between these strains. However, this observation is unlikely to explain fully the differences observed because aversion to AcH was developed in the UChA strain at blood levels of AcH that did not produce any aversion in the UChB strain. These results support the suggestion that, for the first time, differences in central or systemic effects of AcH per se may play a major role in determining the aversion to AcH in drinker and nondrinker animals.

Interaction of morphine and naltrexone on oral ethanol self-administration in rhesus monkeys.

Opioid antagonists, such as naltrexone (NTX), reduce ethanol consumption and opioid agonists increase or decrease ethanol consumption in rats depending upon the dose. If the opioid antagonist and agonist effects on ethanol consumption are mediated by mu-opioid receptors, then NTX doses that reduce ethanol consumption should be similar to the doses necessary to antagonize the effects of opioid agonists on ethanol consumption. The purpose of these experiments was: (1) to determine whether morphine increases ethanol consumption in rhesus monkeys as it does in rodents; (2) to determine if the mu-receptor mediates the effects of morphine on ethanol consumption by conducting a pK(B) analysis using NTX; and (3) to determine if the mu-receptor also mediates the NTX-induced decreases in ethanol consumption by making comparisons between the NTX doses that affect ethanol consumption and the NTX doses that block the effects of morphine on ethanol consumption. Three male rhesus monkeys responded for 2% ethanol and water for 2 h/day on a fixed-ratio 4 schedule of reinforcement. Morphine doses as low as 0.0032mg/kg failed to increase ethanol fluid deliveries, whereas higher doses produced a dose-related decrease in ethanol fluid deliveries. Although 0.01 mg/kg NTX alone had no effect on ethanol fluid deliveries, it reduced the suppressant effects of morphine with a mu-receptor pK(B) of 8.21 (8.08-8.34). When given alone, 0.1 mg/kg NTX decreased ethanol fluid deliveries but failed to reverse the suppression caused by 1 mg/kg morphine. Therefore, monkeys may differ from rats in their response to morphine when ethanol consumption is the dependent variable. Furthermore, because the NTX dose that reduced the effects of morphine on responding for ethanol was smaller than the NTX doses that suppressed ethanol-reinforced responding when given alone, NTX may exert these two effects through different mechanisms.

Differences in sensitivity to the aversive effects of ethanol in low-alcohol drinking (UChA) and high-alcohol drinking (UChB) rats

A conditioned taste aversion paradigm was used to determine whether aversion to the pharmacological effects of ethanol, apart from orosensory cues, can contribute to differences in voluntary ethanol consumption in rats of the low-alcohol drinking (UChA) and the high-alcohol drinking (UChB) strains. “Alcohol-naive” UChA and UChB rats were injected intraperitoneally with ethanol (0.5, 1.0, 1.5, or 2.0 g/kg) or saline, paired with consumption of a banana-flavored solution during five conditioning trials. Repeated pairings of banana-flavored solution and ethanol at a dose of 1.5 g/kg produced aversion to the banana-flavored solution in UChA rats, but not in UChB rats, at comparable blood ethanol levels. In addition, the highest dose of ethanol tested (2.0 g/kg) produced stronger aversion to the banana-flavored solution in UChA rats, compared with findings in UChB rats. From these results it is suggested that rats of the UChA strain find the postingestional effects of high-dose ethanol more aversive than do UChB rats. Differences in voluntary ethanol consumption seem to be associated with differences in sensitivity to the aversive effects of ethanol.