Suppressed Alcohol Intake Research Articles

Unequal interactions between alcohol and nicotine co-consumption: suppression and enhancement of concurrent drug intake.

Alcohol and nicotine addiction are prevalent conditions that co-occur. Despite the prevalence of co-use, factors that influence the suppression and enhancement of concurrent alcohol and nicotine intake are largely unknown. Our goals were to assess how nicotine abstinence and availability influenced concurrent alcohol consumption and to determine the impact of quinine adulteration of alcohol on aversion-resistant alcohol consumption and concurrent nicotine consumption. Male and female C57BL/6J mice voluntarily consumed unsweetened alcohol, nicotine, and water in a chronic 3-bottle choice procedure. In experiment 1, nicotine access was removed for 1week and re-introduced the following week, while the alcohol and water bottles remained available at all times. In experiment 2, quinine (100-1000μM) was added to the 20% alcohol bottle, while the nicotine and water bottles remained unaltered. In experiment 1, we found that alcohol consumption and preference were unaffected by the presence or absence of nicotine access in both male and female mice. In experiment 2a, we found that quinine temporarily suppressed alcohol intake and enhanced concurrent nicotine, but not water, preference in both male and female mice. In experiment 2b, chronic quinine suppression of alcohol intake increased nicotine consumption and preference in female mice without affecting water preference, whereas it increased water and nicotine preference in male mice. Quinine suppression of alcohol consumption enhanced the preference for concurrent nicotine preference in male and female mice, suggesting that mice compensate for the quinine adulteration of alcohol by increasing their nicotine preference.

Revisiting baclofen in the treatment of alcoholism: just a question of enantiomer?

The benefit-risk balance of the GABA (α-aminobutyric acid)-B receptor agonist baclofen in the treatment of alcohol addiction is still controversial not only because the efficacy has not been clearly demonstrated but also because of the recent safety concern. Most of the preclinical and clinical studies used the racemic baclofen [RS(±)-baclofen], however, recent data showed that the effect of baclofen on alcohol intake may be enantiomer dependent. Here we used the gold standard animal model of alcohol dependence with the aim of analyzing the effects of the RS-baclofen and its enantiomers, R-baclofen and S-baclofen, on different alcohol-related behaviors. We showed that: – R-Bac was more effective than RS-Bac in suppressing alcohol intake, while S-Bac failed to affect alcohol consumption. – The effects of R-Bac and RS-Bac (1.5 and 2 mg/kg, respectively) on alcohol intake were not explained by any motor impairment. – Some animals (around 27%) were less sensitive to the effects of R-Bac (1.5 mg/kg). Also, there was a negative correlation between the efficacy of this dose and the motivation for alcohol. – R-Bac (1 mg/kg, IP) suppressed intake for both nondependent and dependent animals. However, the sensitivity to this dose was reduced in dependent rats. In conclusion, our results suggest that R-Bac could be a potentially more effective medication than RS-Bac in the treatment of alcohol dependence, and actually our studies are focused on the individual variability in sensitivity to blaclofen.

The Hormone FGF21 Stimulates Water Drinking in Response to Ketogenic Diet and Alcohol

Alcohol and ketogenic diets increase water consumption. Here, we show that the hormone FGF21 is required for this drinking response in mice. Circulating levels of FGF21 are increased by alcohol consumption in humans and by both alcohol and ketogenic diets in mice. Pharmacologic administration of FGF21 stimulates water drinking behavior in mice within 2hr. Concordantly, mice lacking FGF21 fail to increase water intake in response to either alcohol or a ketogenic diet. The effect of FGF21 on drinking is mediated in part by SIM1-positive neurons of the hypothalamus and is inhibited by β-adrenergic receptor antagonists. Given that FGF21 also is known to suppress alcohol intake in favor of pure water, this work identifies FGF21 as a fundamental neurotropic hormone that governs water balance in response to specific nutrient stresses that can cause dehydration.

Long-Term Alcohol Drinking Reduces the Efficacy of Forced Abstinence and Conditioned Taste Aversion in Crossed High-Alcohol-Preferring Mice.

Negative outcomes of alcoholism are progressively more severe as the duration of problem of alcohol use increases. Additionally, alcoholics demonstrate tendencies to neglect negative consequences associated with drinking and/or to choose to drink in the immediate presence of warning factors against drinking. The recently derived crossed high-alcohol-preferring (cHAP) mice, which volitionally drink to heavier intoxication (as assessed by blood ethanol [EtOH] concentration) than other alcohol-preferring populations, as well as spontaneously escalating their intake, may be a candidate to explore mechanisms underlying long-term excessive drinking. Here, we hypothesized that an extended drinking history would reduce the ability of 2 manipulations (forced abstinence [FA] and conditioned taste aversion [CTA]) to attenuate drinking. Experiment 1 examined differences between groups drinking for either 14 or 35days, half of each subjected to 7days of FA and half not, to characterize the potential changes in postabstinence drinking resulting from an extended drinking history. Experiment 2 used a CTA procedure to assess stimulus specificity of the ability of an aversive flavorant to decrease alcohol consumption. Experiment 3 used this taste aversion procedure to assess differences among groups drinking for 1, 14, or 35days in their propensity to overcome this aversion when the flavorant was mixed with either EtOH or water. Experiment 1 demonstrated that although FA decreased alcohol consumption in mice with a 14-day drinking history, it failed to do so in mice drinking alcohol for 35days. Experiment 2 showed that the addition of a flavorant only suppressed alcohol drinking if an aversion to the flavorant was previously established. Experiment 3 demonstrated that an extended drinking history expedited extinction of suppressed alcohol intake caused by a conditioned aversive flavor. These data show that a history of long-term drinking in cHAP mice attenuates the efficacy of interventions that normally reduce drinking. Analogous to alcoholics who may encounter difficulties in limiting their intake, cHAP mice with long drinking histories are relatively insensitive to both abstinence and signals of harmful consequences. We propose that the cHAP line may be a valid model for adaptations that occur following the extended heavy alcohol drinking.

R(+)-Baclofen, but Not S(-)-Baclofen, Alters Alcohol Self-Administration in Alcohol-Preferring Rats.

Racemic baclofen [(±)-baclofen] has repeatedly been reported to suppress several ­alcohol-motivated behaviors, including alcohol drinking and alcohol ­self-administration, in rats and mice. Recent data suggested that baclofen may have bidirectional, stereospecific effects, with the more active enantiomer, R(+)-baclofen, suppressing alcohol intake and the less active enantiomer, S(−)-baclofen, stimulating alcohol intake in mice. The present study was designed to investigate whether this enantioselectivity of baclofen effects may also extend to the reinforcing properties of alcohol in rats. To this end, selectively bred Sardinian alcohol-preferring (sP) rats were initially trained to lever respond on a fixed ratio 4 (FR4) schedule of reinforcement for alcohol (15%, v/v) in daily 30-min sessions. Once responding had stabilized, rats were tested with vehicle, (±)-baclofen (3 mg/kg), R(+)-baclofen (0.75, 1.5, and 3 mg/kg), and S(−)-baclofen (6, 12, and 24 mg/kg) under the FR4 schedule of reinforcement. Treatment with 3 mg/kg (±)-baclofen reduced the number of lever responses for alcohol and estimated amount of self-administered alcohol by approximately 60% in comparison to vehicle treatment. R(+)-baclofen was approximately twice as active as (±)-baclofen: treatment with 1.5 mg/kg R(+)-baclofen decreased both variables to an extent similar to that of the decreasing effect of 3 mg/kg (±)-baclofen. Conversely, treatment with all doses of S(−)-baclofen failed to affect alcohol self administration. These results (a) confirm that non-sedative doses of (±)-baclofen effectively suppressed the reinforcing properties of alcohol in sP rats and (b) apparently do not extend to operant alcohol self-administration in sP rats the capability of S(−)-baclofen to stimulate alcohol drinking in mice.

Corticostriatal BDNF and alcohol addiction

Growth factors, long studied for their involvement in neuronal development and plasticity, also regulate responses to drugs of abuse, including alcohol. This review details the intricate interaction between the Brain-Derived Neurotrophic Factor (BDNF) and alcohol, and provides evidence to suggest that corticostriatal BDNF signaling acts to keep alcohol drinking in moderation. Specifically, we describe studies in rodent models suggesting that moderate consumption of alcohol increases BDNF levels in the dorsal striatum, which in turn act to suppress alcohol intake by activating a Mitogen-Activated Protein Kinase (MAPK)-dependent genomic mechanism. We further provide data to suggest that alcohol intake levels escalate when the endogenous corticostriatal BDNF pathway becomes dysregulated. Finally, we summarize recent studies suggesting that specific microRNAs targeting BDNF mRNA in the medial prefrontal cortex (mPFC) regulate the breakdown of the protective corticostriatal BDNF pathway.This article is part of a Special Issue entitled SI:Addiction circuits.

A Pharmacogenetic Determinant of Mu-Opioid Receptor Antagonist Effects on Alcohol Reward and Consumption: Evidence from Humanized Mice

BackgroundIt has been proposed that therapeutic responses to naltrexone in alcoholism are moderated by variation at the mu-opioid receptor gene locus (OPRM1). This remains controversial because human results vary and no prospectively genotyped studies have been reported. We generated humanized mice carrying the respective human OPRM1 A118G alleles. Here, we used this model system to examine the role of OPRM1 A118G variation for opioid antagonist effects on alcohol responses. MethodsEffects of naltrexone on alcohol reward were examined using intracranial self-stimulation. Effects of naltrexone or nalmefene on alcohol intake were examined in continuous access home cage two-bottle free-choice drinking and operant alcohol self-administration paradigms. ResultsAlcohol lowered brain stimulation reward thresholds in 118GG mice in a manner characteristic of rewarding drugs, and this effect was blocked by naltrexone. Brain stimulation reward thresholds were unchanged by alcohol or naltrexone in 118AA mice. In the home cage, increased alcohol intake emerged in 118GG mice with increasing alcohol concentrations and was 33% higher at 17% alcohol. At this concentration, naltrexone selectively suppressed alcohol intake in 118GG animals to a level virtually identical to that of 118AA mice. No effect of naltrexone was found in the latter group. Similarly, both naltrexone and nalmefene were more effective in suppressing operant alcohol self-administration in 118GG mice. ConclusionsIn a model that allows close experimental control, OPRM1 A118G variation robustly moderates effects of opioid antagonism on alcohol reward and consumption. These findings strongly support a personalized medicine approach to alcoholism treatment that takes into account OPRM1 genotype.

Acamprosate-responsive brain sites for suppression of ethanol intake and preference

Acamprosate suppresses alcohol intake and craving in recovering alcoholics; however, the central sites of its action are unclear. To approach this question, brain regions responsive to acamprosate were mapped using acamprosate microimplants targeted to brain reward and circadian areas implicated in alcohol dependence. mPer2 mutant mice with nonfunctional mPer2, a circadian clock gene that gates endogenous timekeeping, were included, owing to their high levels of ethanol intake and preference. Male wild-type (WT) and mPer2 mutant mice received free-choice (15%) ethanol/water for 3 wk. The ethanol was withdrawn for 3 wk and then reintroduced to facilitate relapse. Four days before ethanol reintroduction, mice received bilateral blank or acamprosate-containing microimplants releasing ∼50 ng/day into reward [ventral tegmental (VTA), peduculopontine tegmentum (PPT), and nucleus accumbens (NA)] and circadian [intergeniculate leaflet (IGL) and suprachiasmatic nucleus (SCN)] areas. The hippocampus was also targeted. Circadian locomotor activity was measured throughout. Ethanol intake and preference were greater in mPer2 mutants than in wild-type (WT) mice (27 g·kg(-1)·day(-1) vs. 13 g·kg(-1)·day(-1) and 70% vs. 50%, respectively; both, P < 0.05). In WTs, acamprosate in all areas, except hippocampus, suppressed ethanol intake and preference (by 40-60%) during ethanol reintroduction. In mPer2 mutants, acamprosate in the VTA, PPT, and SCN suppressed ethanol intake and preference by 20-30%. These data are evidence that acamprosate's suppression of ethanol intake and preference are manifest through actions within major reward and circadian sites.

Role of caloric homeostasis and reward in alcohol intake in Syrian golden hamsters

The Syrian golden hamster drinks alcohol readily, but only achieves moderate blood alcohol levels, and does not go through withdrawal from alcohol. Because the hamster is a model of caloric homeostasis, both caloric content and reward value may contribute to the hamster's alcohol consumption. The current study examines alcohol consumption in the hamster when a caloric or non-caloric sweet solution is concurrently available and caloric intake in the hamster before, during, and after exposure to either: alcohol, sucrose or saccharin. In Experiments 1 and 2, hamsters were given access to alcohol (15% v/v) and water; once alcohol consumption steadied, a bottle containing an ascending concentration of sucrose (99–614 mM) or saccharin (2–10 mM), or water was added. In Experiment 3, hamsters were given access to alcohol (15% v/v), sucrose (614 mM), saccharin (4 mM), or a second water bottle for 14 days. After the second bottle was removed, measurements continued for 14 days. Sucrose exposure suppressed alcohol consumption at concentrations lower in calories than the alcohol solution. Saccharin exposure failed to suppress alcohol consumption. Exposure to sucrose and alcohol but not saccharin decreased food intake. Decreased alcohol consumption in response to a caloric sweetener and decreased food intake during alcohol exposure support that alcohol consumption by the hamster is mediated by caloric content. However, suppression of alcohol intake by a sucrose solution of lower caloric content and the equivalent intake of individual alcohol, sucrose and saccharin solutions support a role for reward value in alcohol consumption.

Neurokinin-1 receptors (NK1R:s), alcohol consumption, and alcohol reward in mice

Reduced voluntary alcohol consumption was recently found in neurokinin-1 receptor (NK1R)-deficient (KO) mice. It remains unknown whether this reflects developmental effects or direct regulation of alcohol consumption by NK1R:s, and whether the reduced consumption reflects motivational effects. The objective of this study is to obtain an expanded preclinical validation of NK1R antagonism as a candidate therapeutic mechanism in alcohol use disorders. The NK1R antagonist L-703,606 and NK1R KO mice were used in models that assess alcohol-related behaviors. L-703,606 (3-10 mg/kg i.p.) dose-dependently suppressed alcohol intake in WT C57BL/6 mice under two-bottle free choice conditions but was ineffective in NK1R KO:s, demonstrating the receptor specificity of the effect. Alcohol reward, measured as conditioned place preference for alcohol, was reduced by NK1R receptor deletion in a gene dose-dependent manner. In a model where escalation of intake is induced by repeated cycles of deprivation and access, escalation was seen in WT mice, but not in KO mice. Among behavioral phenotypes previously reported for NK1R mice on a mixed background, an analgesic-like phenotype was maintained on the C57BL/6 background used here, while KO:s and WT:s did not differ in anxiety- and depression-related behaviors. Acute blockade of NK1R:s mimics the effects of NKR1 gene deletion on alcohol consumption, supporting a direct rather than developmental role of the receptor in regulation of alcohol intake. Inactivation of NK1R:s critically modulates alcohol reward and escalation, two key characteristics of addiction. These data provide critical support for NK1R antagonism as a candidate mechanism for treatment of alcoholism.

Requirement of central ghrelin signaling for alcohol reward

The stomach-derived hormone ghrelin interacts with key CNS circuits regulating energy balance and body weight. Here we provide evidence that the central ghrelin signaling system is required for alcohol reward. Central ghrelin administration (to brain ventricles or to tegmental areas involved in reward) increased alcohol intake in a 2-bottle (alcohol/water) free choice limited access paradigm in mice. By contrast, central or peripheral administration of ghrelin receptor (GHS-R1A) antagonists suppressed alcohol intake in this model. Alcohol-induced locomotor stimulation, accumbal dopamine release and conditioned place preference were abolished in models of suppressed central ghrelin signaling: GHS-R1A knockout mice and mice treated with 2 different GHS-R1A antagonists. Thus, central ghrelin signaling, via GHS-R1A, not only stimulates the reward system, but is also required for stimulation of that system by alcohol. Our data suggest that central ghrelin signaling constitutes a potential target for treatment of alcohol-related disorders.

Opioid maintenance therapy suppresses alcohol intake in heroin addicts with alcohol dependence: Preliminary results of an open randomized study

An open randomized study lasting 12 months was performed to evaluate the efficacy of methadone or buprenorphine to suppress alcohol use in two hundred and eighteen heroin addicts with alcohol dependence. Daily maintenance doses of methadone were 80, 120, 160, and 200 mg/day, while doses of buprenorphine were 8, 16, 24, and 32 mg/day. As expected, both treatments were able to reduce both heroin use and addiction severity (measured with ASI interview). However, although both medications were able to suppress alcohol use, the highest dose of buprenorphine was better than the highest dose of methadone, in reducing alcohol craving, ethanol intake (measured as daily number of drinks), and the ASI subscale of alcohol use. The mechanism underlying the effects of the opioid maintenance therapy on the reduction of alcohol intake is still unclear. The results of the present study may represent the first clinical evidence of the potential effective use of the highest doses of buprenorphine for the suppression of ethanol intake in heroin addicts with alcohol dependence.

Neuropeptide Y behavioral effects in alcohol‐preferring rats

Neuropeptide Y (NPY) has anxiolytic and orexigenic behavioral effects, and is involved in the regulation of alcohol drinking. Intracerebroventricular (ICV) administration of NPY suppresses alcohol intake in alcohol-preferring (P) rats, selectively bred for high voluntary oral alcohol intake. Previous findings indicate that endogenous NPY activity may be altered by chronic exposure to alcohol and alcohol withdrawal. The present experiments examine whether the behavioral effects of exogenously administered NPY are also altered by different histories of alcohol exposure. Female P rats had continuous access to 15% (v/v) alcohol and water for 6 weeks. This was followed by two or three 4-week alcohol access cycles, each consisting of 2 weeks with forced alcohol abstinence and 2 weeks with alcohol available. Following ICV cannulae implantation during the final period of alcohol abstinence, separate groups were infused with NPY (2.5, 5.0, 10.0 μg) or aCSF. Alcohol intake, food intake, and anxiety (light-enhanced acoustic startle response) were measured. Continuous access controls were treated similarly except that access to alcohol was not interrupted by periods of forced abstinence. NPY dose-dependently suppressed alcohol intake, increased food intake, and reduced anxiety. However, these effects were greater and/or longer in groups that underwent alcohol abstinence periods relative to continuous access controls. These results suggest that chronic drinking with periods of forced alcohol abstinence may produce a global dysregulation of NPY systems that enhances sensitivity to the behavioral effects of NPY. Supported by NIH grants AA12857, AA07611, and AA10722.

NEUROPEPTIDE Y IN ANXIETY AND ALCOHOLISM

Neuropeptide Y (NPY) has been established by us and others across a wide range of animal models as a potent endogenous anti-stress /anti-anxiety signal. Overexpression of NPY renders subjects insensitive to stress, providing a proof of principle for potentiation of NPY transmission as a novel candidate treatment in anxiety disorders and depression. More recent work suggests an involvement of NPY in regulation of alcohol intake and in alcohol dependence. Seminal work by Thiele et al demonstrated an inverse correlation between NPY expression and alcohol self-administration in NPY KO:s and transgenics, respectively. NPY selectively suppresses alcohol intake in states of pathologically elevated consumption following a history of dependence or due to genetic selection for high preference, but not basal intake which occurs in genetically non-selected animals for non-pharmacological properties of alcohol. We have targeted the presynaptic Y2 autoreceptor to potentiate endogenous NPY drive. Icv administration of the selective Y2 antagonist BIIE0246 dose dependently suppressed EtOH self-administration. Following a history of dependence, doses of the compound that are subthreshold in animals without such a history were active. Similar effects to those seen with the Y2 antagonist were obtained using antisense oligonucleotides to transiently suppress Y2 receptor expression. The relevance of these findings has been examined through a genetic study in humans. A 4-marker haplotype of the preproNPY gene was reconstructed, and a variant gain-of-function allele identified. The frequency of this allele was significantly lower in alcoholics than in normals, indicating a protective influence of the variant allele. This association was further strengthened using the intermediate phenotype of late onset, anxious subtype of alcohol dependence. This data strengthen the rationale for potentiation of NPY transmission as a protective mechanism in alcoholism.

Alterations in alcohol consumption, withdrawal seizures, and monoamine transmission in rats treated with phentermine and 5-hydroxy-L-tryptophan

We have previously shown that coadministration of the dopamine (DA) agonist phentermine plus the serotonergic agonist fenfluramine suppresses alcohol intake and withdrawal seizures in rats. In the present study, phentermine and the serotonin (5-HT) precursor, 5-hydroxy-L-tryptophan (5-HTP), were administered alone, or in combination, to rats fed on a 6% alcohol-containing diet or an isocaloric control diet. Following a 9-h withdrawal period from the alcohol-containing diet, phentermine enhanced the effects of 5-HTP on both reduction of alcohol withdrawal seizures as well as changes in striatal serotonin. Food intake was monitored for 24 h after drug treatment, and neurochemical measures were examined at various time points. Phentermine alone reduced food intake in all diet conditions, but this anorectic effect was followed by hyperphagia in control rats. Phentermine plus 5-HTP reduced the consumption of the alcohol-containing diet, while its effects on consumption of control diets were mixed. In vivo microdialysis in rat nucleus accumbens revealed that phentermine increased extracellular DA, whereas 5-HTP caused marked elevations in extracellular 5-HT. Coadministration of phentermine and 5-HTP evoked simultaneous elevations in extracellular DA and 5-HT that mirrored the effects of each drug alone. Collectively, these findings show that coadministered phentermine plus 5-HTP is effective in reducing alcohol intake and suppressing alcohol withdrawal seizures. These therapeutic actions may be related to elevations in synaptic DA and 5-HT in critical brain regions.

Effects of purified puerarin on voluntary alcohol intake and alcohol withdrawal symptoms in P rats receiving free access to water and alcohol.

Alcohol preferring (P) rats, given "free choice" of water, exhibited daily intake of 60-75 g of water/kg of body weight. When given "free choice" of water and 15% ethanol, P rats consumed 7-13 g of alcohol/kg. Their water intake decreased proportionally to the alcohol intake, but total fluid intake did not differ significantly. Alcohol withdrawal after 50 days of alcohol drinking caused withdrawal symptoms such as hypersensitivity, poor coordination, and tremors. A daily 50 mg/kg dose of puerarin (PU) caused approximately 50% suppression in alcohol intake, but did not affect body weight and food and total fluid intake in P rats receiving "free choice" of water and 15% ethanol. Alcohol ingestion gradually returned to the control level despite consistent PU intake. However, alcohol intake following alcohol withdrawal was suppressed in PU-fed P rats. PU suppressed the severity of alcohol withdrawal symptoms. Thus, withdrawal symptoms do not occur in PU-fed rats even though their alcohol ingestion is comparable to that in control P rats. Brain, plasma, and liver samples were analyzed for the presence of kudzu root isoflavones, which are mostly PU (>90% of total isoflavones) and a trace amount of daidzin. Liver samples obtained from PU-fed P rats contained 20-30 microg/g of PU. An important observation was that plasma or brain samples obtained from PU-fed or alcohol + PU-fed rats did not contain PU. This study indicated that PU feeding transiently suppressed alcohol intake and abolished withdrawal symptoms at a time when alcohol intake had returned to the control level. The absence of PU in plasma and brain indicates the possibility that some nonspecific mechanism may be involved in the anti-alcoholism effects of PU in P rats.

Reduction of alcohol drinking and upregulation of opioid receptors by oral naltrexone in AA rats

Rats of the high-drinking AA line were given 1 mg/kg naltrexone (NTX) or vehicle orally with a stress-free procedure just before 1 h of access to 10% ethanol daily for 8 days and again, 8 h later on the first 7 days. Forebrain homogenate binding studies using 0.03–6.00 nM [ 3H] naloxone were conducted from 1 to 4 days following treatment. NTX significantly suppressed alcohol intake, with the effect becoming progressively greater over days and continuing during the post-treatment period. Saturation binding studies in brain homogenate revealed that NTX had increased the B max for opioid receptors by 93%, 74%, 49%, and 28%, respectively, from post-treatment days 1 to 4 without altering K d. B max was negatively correlated ( r=−0.510, p=0.008) with alcohol intake during the preceding hour, but in control rats, it was positively correlated with changes in alcohol intake over time ( r=+0.790, p=0.020). These results are consistent with the hypothesis that opioid receptors mediate reinforcement from alcohol and that NTX reduces subsequent alcohol drinking by extinction. Opioid receptor upregulation can develop simultaneously with suppression of drinking and may partially counteract the clinical benefits from NTX in the treatment of alcoholism.

Inhibition of alcohol uptake in C57Bl/6 mice by splenocytes extracorporeally stimulated with vasopressin.

Experiments on C57Bl/6 mice kept under conditions of free choice between alcohol and water for 4 and 12 months showed that adoptive transfer of splenocytes extracorporeally stimulated with arginine vasopressin suppressed alcohol intake.

Suppression of Alcohol Intake by Chronic Naloxone Treatment in P Rats

Suppression of Alcohol Intake by Chronic Naloxone Treatment in P Rats

Attenuation of alcohol intake by extract of Hypericum perforatum (St. John's Wort) in two different strains of alcohol-preferring rats.

Extract of the common plant Hypericum perforatum L. (St John's Wort, SJW) has been used successfully for the treatment of mild to moderate depression since ancient times and has recently been studied clinically. Depression and alcoholism have some neurochemical similarities, such as low brain serotonin activities. Thus, we hypothesized that SJW extract, which contains 0.22% hypericin and 4.05% hyperforin, also may be effective in suppressing alcohol intake. To test this hypothesis, the effects of SJW extract on voluntary alcohol intake were studied in two different genetic animal models of human alcoholism: fawn-hooded (FH) and high-alcohol drinking (HAD) rats. FH and HAD rats received a single oral administration (5 ml/kg) of either vehicle or one of the five doses (100, 200, 400, 600, and 800 mg/kg) of SJW extract. The oral administration of SJW extract significantly (P < 0.0001) reduced alcohol intake in both FH and HAD rats. In a third study, FH rats did not develop tolerance to the suppressant effects of SJW on alcohol intake and preference following oral administration of (400 mg/kg) of the extract for 15 consecutive days. These promising findings suggest that SJW extract should be evaluated clinically as a potential therapeutic agent in the treatment of alcoholism.