Regulation Of Alcohol Consumption Research Articles

PPAR-α L162V and PGC-1 G482S gene polymorphisms, but not PPAR-γ P12A, are associated with alcohol consumption in a Spanish Mediterranean population

Background Peroxisome Proliferator-Activated Receptors (PPARs) and its co-activators are regulatory elements of the cellular lipid homeostasis and have been associated with feeding behavior modulation. Animal models suggest that these genes may be involved in alcohol consumption regulation. However, no studies in humans exist. Our aim is to estimate the possible association between polymorphisms in the PPAR-α, PPAR-γ and PPAR-γ co-activator 1A ( PGC-1A) genes and alcohol consumption in humans. Methods We have conducted a cross-sectional study between the PPAR-α L162V, PPAR-γ P12A and PGC-1A G482S polymorphisms, and alcohol consumption in a general Mediterranean Spanish population (303 men and 443 women). Results We have found an association between the L162V polymorphism and alcohol consumption in which, carriers of the V allele were more prevalent among alcohol consumers (19.4% vs. 9.8%; OR 2.69; 95% CI: 1.31–5.54, p = 0.007). The G482S polymorphism showed a significantly higher frequency in the group of high alcohol drinkers than in non-high alcohol drinkers (33.4% vs. 20.6%; OR 2.28; 95% CI: 1.07–4.88, p = 0.034). Mean alcohol consumption was higher as the number of G alleles increased (GG 8.6 ± 12.8 g/day, GS 6.6 ± 9.2 g/day, SS 5.6 ± 7.8 g/day, p = 0.003). These results remained statistically significant after covariate adjustment. Conclusions PPAR-α L162V and PGC-1A G482S polymorphisms are associated with alcohol consumption in the Mediterranean population.

Strain Differences in Alcohol‐Induced Neurochemical Plasticity: A Role for Accumbens Glutamate in Alcohol Intake

Repeated alcohol administration alters nucleus accumbens (NAC) basal glutamate content and sensitizes the capacity of alcohol to increase NAC extracellular glutamate levels. However, the relevance of alcohol-induced changes in NAC glutamate for alcohol drinking behavior is under-investigated. To examine the relationship between genetic variance in alcohol consumption and alcohol-induced neuroadaptations within the NAC, in vivo microdialysis was conducted in the alcohol-preferring C57BL/6J (B6) and alcohol-avoiding DBA2/J (D2) mouse strains on injections 1 and 8 of repeated alcohol treatment (8 x 2 g/kg, IP). To confirm an active role for NAC glutamate in regulating alcohol drinking behavior, the glutamate reuptake inhibitor dl-threo-beta-benzyloxyaspartic acid (TBOA) (300 microM) and the Group 2 metabotropic glutamate autoreceptor agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) (50 microM) were infused into the NAC of B6 and D2 mice prior to alcohol consumption in a 4 bottle-choice test. While strain differences were not apparent for NAC basal levels of dopamine, serotonin or gamma-amino butyric acid (GABA), repeated alcohol treatment elevated NAC basal glutamate content only in B6 mice. Strain differences in both the acute and the sensitized neurochemical responses to 2 g/kg alcohol were observed for all neurotransmitters examined. While the alcohol-induced rise in NAC dopamine and glutamate levels sensitized in B6 mice, a sensitization was not observed in D2 animals. Moreover, B6 mice exhibited a sensitized serotonin and GABA response to alcohol followed repeated treatment, whereas neither tolerance nor sensitization was observed in D2 animals. An intra-NAC APDC infusion reduced alcohol intake in both B6 and D2 mice by approximately 50%. In contrast, TBOA infusion elevated alcohol intake selectively in B6 mice. These data indicate an active role for NAC glutamate in regulating alcohol consumption in mice and support the hypothesis that predisposition to high alcohol intake involves genetic factors that facilitate alcohol-induced adaptations in glutamate release within the NAC.

Urocortin 1 microinjection into the mouse lateral septum regulates the acquisition and expression of alcohol consumption

Previous studies using genetic and lesion approaches have shown that the neuropeptide urocortin 1 (Ucn1) is involved in regulating alcohol consumption. Ucn1 is a corticotropin releasing factor (CRF) –like peptide that binds CRF1 and CRF2 receptors. Perioculomotor urocortin-containing neurons (pIIIu), also known as the non-preganglionic Edinger-Westphal nucleus, are the major source of Ucn1 in the brain and are known to innervate the lateral septum. Thus, the present study tested whether Ucn1 could regulate alcohol consumption through the lateral septum. In a series of experiments Ucn1 or CRF was bilaterally injected at various doses into the lateral septum of male C57BL/6J mice. Consumption of 20% volume/volume ethanol or water was tested immediately after the injections using a modification of a 2-h limited access sweetener-free “drinking-in-the-dark” procedure. Ucn1 significantly suppressed ethanol consumption when administered prior to the third ethanol drinking session (the expression phase of ethanol drinking) at doses as low as 6 pmol. Ethanol intake was differentially sensitive to Ucn1, as equivalent doses of this peptide did not suppress water consumption. In contrast, CRF suppressed both ethanol and water intake at 40 and 60 pmol, but not at lower doses. Repeated administration of Ucn1 during the acquisition of alcohol consumption showed that 40 pmol (but not 2 or 0.1 pmol) significantly attenuated ethanol intake. Repeated administration of Ucn1 also resulted in a decrease of ethanol intake in sham-injected animals, a finding suggesting that the suppressive effect of Ucn1 on ethanol intake can be conditioned. Taken together, these studies confirm the importance of lateral septum innervation by Ucn1 in the regulation of alcohol consumption.

Alcoholism and Neuropeptides: An Update

As with other addictions, human alcoholism is characterised as a chronically relapsing condition. Consequently, the "holy grail" from a therapeutic viewpoint is the development of clinically effective, safe drugs that promote high compliance rates and prevent relapse. Here we discuss the potential of therapeutics targeting neuropeptide systems implicated in aberrant alcohol-seeking behaviour. Clearly, much of the data so far available comes from pre-clinical studies; however, one of the first effective therapeutic strategies for alcoholism (still in use today) was the use of non-selective opioid receptor antagonists, such as naltrexone (Revia). In addition to opioid receptors, other neuropeptide receptors including those for corticotrophin releasing factor (CRF), neuropeptide Y and nociceptin may represent valid therapeutic targets to regulate alcohol consumption and the affective consequences of alcohol withdrawal.

BIG News in Alcohol Addiction: New Findings on Growth Factor Pathways BDNF, Insulin, and GDNF

In recent years, it has become clear that growth factors are not only critical for the development of the central nervous system (CNS) but may also be important contributors to other neuronal functions in the adult brain. This symposium, presented at the 2005 RSA meeting, discussed evidence to support the hypothesis that alterations in growth factor pathways produce dramatic changes in the effects of alcohol on the CNS. The 4 speakers showed that the behavioral effects of alcohol in the adult are regulated by 3 growth factors, insulin, glial cell line-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF). Dr. Wolf from the Heberlein laboratory presented findings obtained from genetic manipulations in Drosophila melanogaster, demonstrating that the insulin pathway controls sensitivity to the intoxicating effects of alcohol. Marian Logrip from the Ron and Janak laboratories presented evidence obtained in rodents that low concentrations of alcohol increase the expression of BDNF in the brain to regulate alcohol consumption. Dr. Pandey showed that amygdalar BDNF regulates alcohol's anxiolytic effects and preference. Finally, Dr. Janak presented evidence that increases in the expression of GDNF in the midbrain reduce alcohol self-administration in rats.

Meta‐analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence

The neurotransmitter serotonin (5-HT) has been shown to regulate alcohol consumption in both animals and humans. Since activity of the 5-HT transporter protein (5-HTT) regulates 5-HT levels, the gene encoding this protein may contribute to the risk of alcohol dependence (AD). Studies of the association to AD of a functional insertion-deletion polymorphism in the 5-HTT-linked promoter region (5-HTTLPR) have yielded inconsistent results. We conducted a meta-analysis of data from 17 published studies (including 3,489 alcoholics and 2,325 controls) investigating the association between 5-HTTLPR alleles and AD. The frequency of the short (S) allele at 5-HTTLPR was significantly associated with AD [odds ratio (OR) = 1.18, 95% CI = 1.03-1.33). Moreover, a greater association with the S allele was seen among individuals with AD complicated by either a co-morbid psychiatric condition or an early-onset or more severe AD subtype [OR = 1.34 (95% CI = 1.11-1.63)]. Allelic variation at 5-HTTLPR contributes to risk for AD, with the greatest effect observed among individuals with a co-occurring clinical feature.

The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption

Period (Per) genes are involved in regulation of the circadian clock and are thought to modulate several brain functions. We demonstrate that Per2(Brdm1) mutant mice, which have a deletion in the PAS domain of the Per2 protein, show alterations in the glutamatergic system. Lowered expression of the glutamate transporter Eaat1 is observed in these animals, leading to reduced uptake of glutamate by astrocytes. As a consequence, glutamate levels increase in the extracellular space of Per2(Brdm1) mutant mouse brains. This is accompanied by increased alcohol intake in these animals. In humans, variations of the PER2 gene are associated with regulation of alcohol consumption. Acamprosate, a drug used to prevent craving and relapse in alcoholic patients is thought to act by dampening a hyper-glutamatergic state. This drug reduced augmented glutamate levels and normalized increased alcohol consumption in Per2(Brdm1) mutant mice. Collectively, these data establish glutamate as a link between dysfunction of the circadian clock gene Per2 and enhanced alcohol intake.

Increased GABA Release in the Central Amygdala of Ethanol-Dependent Rats

The central nucleus of amygdala (CeA) is important in regulating alcohol consumption and plays a major role in the anxiogenic response to ethanol withdrawal. We showed previously that acute ethanol augments GABA(A) receptor-mediated IPSPs and IPSCs, possibly by a presynaptic mechanism. Here, we have examined the interaction of acute ethanol with the GABAergic system in chronic ethanol-treated (CET) rats using an in vitro CeA slice preparation and in vivo brain microdialysis. We found that in CeA slices from CET rats, the baseline evoked IPSP and IPSC amplitudes were increased, and paired-pulse facilitation ratios were lower than in naive rats, suggesting an increased GABAergic transmission after chronic ethanol treatment. Interestingly, acute ethanol (5-66 mm) significantly enhanced IPSPs and IPSCs equally in CET and naive rats, indicating a lack of tolerance for this effect of acute ethanol. Analysis of miniature IPSC frequency suggests that the increased GABAergic transmission by both acute and chronic ethanol arises from a presynaptic mechanism involving enhanced vesicular release of GABA. These data are supported by microdialysis studies showing that CET rats presented a fourfold increase in baseline GABA dialysate content compared with naive rats. In vivo administration of ethanol (0.1, 0.3, and 1.0 m) produced a dose-dependent increase in GABA release in the CeA dialysate in both CET and naive rats. These combined findings suggest that acute and chronic ethanol increases GABA release in CeA and support previous reports that the behavioral actions of ethanol are mediated, in part, by increased GABAergic transmission in the CeA.

The Edinger-Westphal–Lateral Septum Urocortin Pathway and Its Relationship to Alcohol Consumption

Identifying and characterizing brain regions regulating alcohol consumption is beneficial for understanding the mechanisms of alcoholism. To this aim, we first identified brain regions changing in expression of the inducible transcription factor c-Fos in the alcohol-preferring C57BL/6J (B6) and alcohol-avoiding DBA/2J (D2) mice after ethanol consumption. Drinking a 5% ethanol/10% sucrose solution in a 30 min limited access procedure led to induction of c-Fos immunoreactivity in urocortin (Ucn)-positive cells of the Edinger-Westphal nucleus (EW), suppression of c-Fos immunoreactivity in the dorsal portion of the lateral septum (LS) of both strains of mice, and strain-specific suppression in the intermediate portion of the LS and the CA3 hippocampal region. Because the EW sends Ucn projections to the LS, and B6 and D2 mice differ dramatically in EW Ucn expression, we further analyzed the Ucn EW-LS pathway using several genetic approaches. We find that D2 mice have higher numbers of Ucn-immunoreactive processes than B6 mice in the LS and that consumption of ethanol/sucrose in the F2 offspring of a B6D2 intercross positively correlates with Ucn immunoreactivity in the EW and negatively correlates with Ucn immunoreactivity in the LS. In agreement with these findings, we find that alcohol-avoiding male B6.D2 Alcp1 line 2.2 congenic mice have lower Ucn immunoreactivity in the EW than male B6.B6 mice. Finally, we also find that HAP mice, selectively bred for high alcohol preference, have higher Ucn immunoreactivity in EW, than LAP mice, selectively bred for low alcohol preference. Taken together, these studies provide substantial evidence for involvement of the EW-LS Ucn pathway in alcohol consumption.

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.

Measuring public opinion on alcohol policy: A factor analytic study of a US probability sample

Public opinion has been one factor affecting change in policies designed to reduce underage alcohol use. Extant research, however, has been criticized for using single survey items of unknown reliability to define adult attitudes on alcohol policy issues. The present investigation addresses a critical gap in the literature by deriving scales on public attitudes, knowledge, and concerns pertinent to alcohol policies designed to reduce underage drinking using a US probability sample survey of 7021 adults. Five attitudinal scales were derived from exploratory and confirmatory factor analyses addressing policies to: (1) regulate alcohol marketing, (2) regulate alcohol consumption in public places, (3) regulate alcohol distribution, (4) increase alcohol taxes, and (5) regulate youth access. The scales exhibited acceptable psychometric properties and were largely consistent with a rational framework which guided the survey construction.

Conditional Rescue of Protein Kinase C ε Regulates Ethanol Preference and Hypnotic Sensitivity in Adult Mice

Conventional gene targeting is a powerful tool to study the influence of specific genes on behavior. However, conclusions relevant for adult animals are limited by consequences of gene loss during development. Mice lacking protein kinase C epsilon (PKCepsilon) consume less alcohol and show greater acute sensitivity to alcohol than do wild-type mice. There are no selective inhibitors of PKCepsilon that can be administered systemically and cross the blood-brain barrier to test whether these phenotypes result from loss of PKCepsilon during development or in adulthood. Here we used conditional expression of PKCepsilon in the basal forebrain, amygdala, and cerebellum to rescue wild-type responses to alcohol in adult PKCepsilon(-/-) mice. Subsequent suppression of transgenic PKCepsilon restored PKCepsilon(-/-) behaviors. These findings establish that PKCepsilon signaling in the adult brain regulates alcohol consumption and sensitivity. If this extends to humans, then PKCepsilon inhibitors might prove useful as novel therapeutics for alcoholism.

Intake of saccharin, salt, and ethanol solutions is increased by infusion of a mu opioid agonist into the nucleus accumbens.

Endogenous opioids have been implicated in the hedonic evaluation of food and palatability. Opioids may also be involved in alcohol intake, as there is a positive correlation between alcohol drinking and preference for sweets and fats. Our previous studies have shown that mu opioid stimulation of the nucleus accumbens preferentially augments intake of palatable food containing sucrose and fat. The first goal of the present study was to further explore the nature of the involvement of mu opioids within the nucleus accumbens in ingestive behavior by investigating the importance of orosensory reward in opioid-mediated feeding, using non-caloric tasty substances (saccharin and salt). Second, we investigated whether mu opioid receptors within the nucleus accumbens also regulate alcohol consumption. The mu agonist, D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO; 0, 0.025 and 0.25 microg/0.5 microl per side), was microinfused into the nucleus accumbens, and intake of 0.6% saline, 0.15% sodium saccharin, water, and 6% ethanol was measured. Microinfusion of DAMGO into the nucleus accumbens increased the drinking of salt and saccharin solutions in non-deprived rats. However, water intake was not increased by this treatment in water-deprived rats. Mu opioid stimulation of the nucleus accumbens also augmented ethanol intake in rats not deprived of fluid, while leaving water intake unchanged when water was concurrently available. These results provide evidence to suggest that the mu opioid system within the ventral striatum regulates ingestive behavior via a mechanism related to the hedonic assessment of taste. In addition, the nucleus accumbens may be a key brain area where ethanol interacts with endogenous opioid systems, and thus may be a common neural substrate for both food palatability and alcohol drinking.

Differential Expression of NPY and Its Receptors in Alcohol‐Preferring AA and Alcohol‐Avoiding ANA Rats

Central neuropeptide Y (NPY) is known to control feeding and stress responses. Recently, it has been suggested that NPY also has a role in regulation of alcohol consumption. NPY and NPY receptor expression in genetically selected alcohol-preferring (AA), alcohol-nonpreferring (ANA), and Wistar rats were investigated. Expression was assessed using in situ hybridization histochemistry with riboprobes specific for preproNPY, Y1, and Y2 receptors. Effects of central NPY administration on ethanol self-administration were also examined in AA, ANA, and Wistar rats by using oral operant self-administration. NPY mRNA expression was higher in ANA than in both AA and Wistar rats in the hippocampal CA region and dentate gyrus, whereas AA and Wistar did not differ from each other. No differences in NPY expression were found in the other regions analyzed: cingulate cortex, medial nucleus of the amygdala, arcuate, and paraventricular nuclei of the hypothalamus. Y1 receptor mRNA expression did not differ between the three lines. Y2 expression was higher in the dentate gyrus of both AA and ANA rats than in Wistar subjects. In the medial amygdala, Y2 mRNA was reduced in the AA line, compared to both ANA and Wistar rats. NPY injected intracerebroventricularly (1.5-3.0 nmol) did not affect operant ethanol self-administration in any of the three lines examined. The NPY system seems to differ in several respects between rat lines with different levels of alcohol preference. Differences observed within the hippocampus could be related to behavioral traits other than alcohol intake but it is also possible that elevated hippocampal expression of NPY in the ANA rats contributes to the low alcohol intake of this line. Aberrant NPY expression and/function within the amygdala complex could contribute to alcohol preference and constitute an anatomic substrate of the effects of NPY expression on alcohol intake observed previously in genetically modified animals.

Identification and confirmation of quantitative trait loci regulating alcohol consumption in congenic strains of mice.

C57BL/6 inbred mice prefer alcohol whereas DBA/2 mice avoid it. We describe the construction of congenic strains of mice in which DBA/2 alleles for alcohol avoidance were placed on a C57BL/6 background using phenotypic selection. Mice were primed to drink 10% v/v ethanol in water for 2 days before a two-bottle choice paradigm. N2 males who demonstrated an alcohol-avoidance phenotype were backcrossed to B6 females to construct 15 independent lines. Eight of these lines were lost due to failure to breed or absence of males with an alcohol-avoidance phenotype. The remaining sublines were split to form a total of 21 sublines. In the N7 and N9 generations, a genome scan located provisional quantitative trait loci (QTLs) on chromosomes 1, 2, 3, 6, and 9. Progeny testing confirmed QTLs on chromosomes 1 and 2. The QTL on chromosome 2 overlaps the 95% confidence interval of Alcp1 whereas that on chromosome 1 is new and has been called Alcp5. Marker-assisted selection was used in the N9 and subsequent generations to maintain the congenic lines and produce congenic strains.

Increased impulsivity after injected alcohol predicts later alcohol consumption in rats: evidence for "loss-of-control drinking" and marked individual differences.

A delay-of-reward paradigm was used to assess impulsivity in rats. Previous research with this paradigm has found that normally occurring impulsivity scores predict magnitude of voluntary alcohol intake. The authors' primary findings were (a) injected alcohol produced a dose-dependent increase in impulsivity, (b) varying the intervals between alcohol and testing yielded orderly effects, (c) there were extreme individual differences in impulsive reactivity to alcohol, (d) these individual differences did not reflect differences in alcohol pharmacokinetics, (e) subject selection procedures ensured that differences in impulsive reactivity to alcohol were independent of significant variations in baseline impulsivity scores, and (f) individual differences in impulsive reactivity to injected alcohol strongly predicted magnitude of voluntary alcohol intake. The findings are discussed in terms of evidence for a dysfunctional alcohol-induced positive feedback loop ("loss-of-control drinking"), alcohol disinhibition, and the relationship between impulse control and the regulation of alcohol consumption.

S.13.03 Pharmacology of the human CRF 1, CRF 2 α and CRF 2 β receptors and CRF binding protein

Previous studies using genetic and lesion approaches have shown that the neuropeptide urocortin 1 (Ucn1) is involved in regulating alcohol consumption. Ucn1 is a corticotropin releasing factor (CRF) –like peptide that binds CRF1 and CRF2 receptors. Perioculomotor urocortin-containing neurons (pIIIu), also known as the non-preganglionic Edinger-Westphal nucleus, are the major source of Ucn1 in the brain and are known to innervate the lateral septum. Thus, the present study tested whether Ucn1 could regulate alcohol consumption through the lateral septum. In a series of experiments Ucn1 or CRF was bilaterally injected at various doses into the lateral septum of male C57BL/6J mice. Consumption of 20% volume/volume ethanol or water was tested immediately after the injections using a modification of a 2-h limited access sweetener-free “drinking-in-the-dark” procedure. Ucn1 significantly suppressed ethanol consumption when administered prior to the third ethanol drinking session (the expression phase of ethanol drinking) at doses as low as 6 pmol. Ethanol intake was differentially sensitive to Ucn1, as equivalent doses of this peptide did not suppress water consumption. In contrast, CRF suppressed both ethanol and water intake at 40 and 60 pmol, but not at lower doses. Repeated administration of Ucn1 during the acquisition of alcohol consumption showed that 40 pmol (but not 2 or 0.1 pmol) significantly attenuated ethanol intake. Repeated administration of Ucn1 also resulted in a decrease of ethanol intake in sham-injected animals, a finding suggesting that the suppressive effect of Ucn1 on ethanol intake can be conditioned. Taken together, these studies confirm the importance of lateral septum innervation by Ucn1 in the regulation of alcohol consumption.

The regulation of alcohol consumption in rats: The role of alcohol-metabolizing enzymes—Catalase and aldehyde dehydrogenase

Aldehyde dehydrogenase (ALDH) and catalase enzymatic activities in brain were assayed and compared to measures of alcohol consumption in two groups of animals screened and maintained on free-choice alcohol access under different conditions. In the first group of Long-Evans rats screened and maintained in home cages, mean alcohol intake was 3.49 g/kg/day with a range of 1.69–5.33 g/kg/day. When alcohol intake (g/kg), total ALDH, low K m ALDH, and catalase activities were entered in a multiple regression, a significant correlation of r = 0.51 ( p < 0.05) was obtained. In the second group of rats consisting of Long-Evans, P, and NP rats screened using a drinkometer procedure, a multiple correlation between ALDH and catalase enzyme activities and alcohol intake of r = 0.42 ( p < 0.05) was obtained. There was a strong relationship between the frequency of alcohol drinking bouts and the activities of catalase and ALDH ( r = 0.68, p < 0.0001). The P rats had significantly higher catalase activities than either the NP or Long-Evans rats. The results of the present study confirmed earlier reports on the role of alcohol-metabolizing enzymes in the regulation of alcohol intake. The results also highlighted the fact that the activity of these alcohol-metabolizing enzymes may play a mediating role in patterns of alcohol intake displayed by animals selected for high and low alcohol drinking and also unselected animals.

USE OF SEROTONIN (5-HT) AND OPIATE-BASED DRUGS IN THE PHARMACOTHERAPY OF ALCOHOL DEPENDENCE: AN OVERVIEW OF THE PRECLINICAL DATA

Numerous neurotransmitter systems [e.g. dopamine, gamma-aminobutyric acid (GABA), the endogenous opioids, and serotonin (5-hydroxytryptamine, 5-HT)] are involved in the regulation of alcohol consumption. Because 5-HT reuptake inhibitors and opioid antagonists modify the activity of neurotransmitters, it has been hypothesized that they may also mediate the desire to drink alcohol by acting on specific receptors in the brain. Animal studies have shown that concomitant administration of 5-HT and opioid antagonists reduces alcohol consumption; therefore, the combined use of several pharmacotherapies may be the most effective treatment for alcohol dependence.

Neuropeptidergic Control of Ethanol Intake

AbstractNeural peptides found in brain and gut tissues modulate the intake of ethanol by animals and humans. Experiments show that injections of sulfated cholecystokinin octapeptide, tetradecapeptide bombesin, angiotensin, and the opioid receptor blockers, naloxone and naltrexone, potently reduce oral consumption of ethanol solutions. Vasoactive intestinal peptide, neuropeptide Y, and galanin increase ethanol intake, and increases in blood levels of the opioid peptide beta endorphin are associated with relapse in alcoholics. Specific neuropeptide receptor blockers increase ethanol intake and prevent injected cholecystokinin and bombesin from inhibiting ethanol intake. Recently, naltrexone (Revia®) has been approved by the FDA for wider clinical use in the treatment of alcoholism. These findings support the hypothesis of neuropeptidergic regulation of alcohol consumption and innovative therapies for alcoholism.