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The nucleus accumbens (NAc) participates in the control of both motivation and addiction. To test the possibility that opioids in the NAc can cause rats to select ethanol in preference to food, Sprague-Dawley rats with ethanol, food, and water available, were injected with two doses each of morphine, the mu-receptor agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-Enkephalin (DAMGO), the delta-receptor agonist D-Ala-Gly-Phe-Met-NH2 (DALA), the k-receptor agonist (+/-)-trans-U-50488 methanesulfonate (U-50,488H), or the opioid antagonist naloxone methiodide (m-naloxone). As an anatomical control for drug reflux, injections were also made 2mm above the NAc. The main result was that morphine in the NAc significantly increased ethanol and food intake, whereas m-naloxone reduced ethanol intake without affecting food or water intake. Of the selective receptor agonists, DALA in the NAc increased ethanol intake in preference to food. This is in contrast to DAMGO, which stimulated food but not ethanol intake, and the k-agonist U-50,488H, which had no effect on intake. When injected in the anatomical control site 2mm dorsal to the NAc, the opioids had no effects on ethanol intake. These results demonstrate that ethanol intake produced by morphine in the NAc is driven in large part by the delta-receptor. In light of other studies showing ethanol intake to increase enkephalin expression in the NAc, the present finding of enkephalin-induced ethanol intake suggests the existence of a positive feedback loop that fosters alcohol abuse. Naltrexone therapy for alcohol abuse may then act, in part, in the NAc by blocking this opioid-triggered cycle of alcohol intake.

Studies in both humans and animals suggest a positive relationship between the intake of ethanol and intake of fat, which may contribute to alcohol abuse. This relationship may be mediated, in part, by hypothalamic orexigenic peptides such as orexin (OX), which stimulate both consumption of ethanol and fat, and circulating triglycerides (TGs), which stimulate these peptides and promote consummatory behavior. The present study investigated this vicious cycle between ethanol and fat, to further characterize its relation to TGs and to test the effects of lowering TG levels. In Experiment 1, the behavioral relationship between fat intake and ethanol was confirmed. Adult male Sprague-Dawley rats, chronically injected intraperitoneally with ethanol (1g/kg) and tested in terms of their preference for a high-fat diet (HFD) compared with low-fat diet (LFD), showed a significant increase in their fat preference, compared with rats injected with saline, in measures of 2h and 24h intake. Experiment 2 tested the relationship of circulating TGs in this positive association between ethanol and fat, in rats chronically consuming 9% ethanol versus water and given acute meal tests (25kcal) of a HFD versus LFD. Levels of TGs were elevated in response to both chronic drinking of ethanol versus water and acute eating of a high-fat versus low-fat meal. Most importantly, ethanol and a HFD showed an interaction effect, whereby their combination produced a considerably larger increase in TG levels (+172%) compared to ethanol with a LFD (+111%). In Experiment 3, a direct manipulation of TG levels was found to affect ethanol intake. After intragastric administration of gemfibrozil (50mg/kg) compared with vehicle, TG levels were lowered by 37%, and ethanol intake was significantly reduced. In Experiment 4, the TG-lowering drug gemfibrozil also caused a significant reduction in the expression of the orexigenic peptide, OX, in the perifornical lateral hypothalamus. These results support the existence of a vicious cycle between ethanol and fat, whereby each nutrient stimulates intake of the other. Within this vicious cycle, ethanol and fat act synergistically to increase TG levels, which in turn stimulate peptides that promote further consumption, and these phenomena are reversed by gemfibrozil, which lowers TG levels.

Background: The question is which hypothalamic systems for food intake might play a role in ethanol intake and contribute to alcohol abuse. The peptide orexin was found to exhibit similar properties to galanin in its relation to dietary fat and may therefore be similar to galanin in having a stimulatory effect on alcohol intake., Methods: Rats were trained to drink 10% ethanol, implanted with brain cannulas, and then injected in the paraventricular nucleus (PVN), lateral hypothalamus (LH), or nucleus accumbens (NAc) with galanin, orexin-A, and for comparison, ghrelin. Ethanol, food, and water intake were measured at 1, 2, and 4 hours postinjection., Results: In the PVN, both orexin and galanin significantly increased ethanol intake, whereas ghrelin increased food intake. In the LH, orexin again induced ethanol intake, while ghrelin increased eating. In the NAc, orexin failed to influence ethanol intake but did stimulate food intake., Conclusions: In ethanol-drinking rats, injection of orexin or galanin into the appropriate locus in the hypothalamus induced significant ethanol intake instead of food intake. Ghrelin, as a positive control, failed to influence ethanol intake at the same hypothalamic sites. In the NAc, as an anatomical control, orexin augmented eating but not ethanol intake. Thus orexin and galanin in the hypothalamus selectively stimulated ethanol intake at sites where other studies have shown that both ethanol and fat increase expression of the endogenous peptides. Thus, a neural circuit that evolved with the capability to augment food intake is apparently co-opted by ethanol and may serve as a potential positive feedback circuit for alcohol abuse.

Background: Recent evidence has demonstrated that ethanol intake can stimulate the expression and production of the feeding-stimulatory peptide, galanin (GAL), in the hypothalamic paraventricular nucleus (PVN), and that PVN injection of this peptide, in turn, can increase the consumption of ethanol. To test the hypothesis that other feeding-related systems are involved in ethanol intake, this study examined the effect of ethanol on the hypothalamic opioid peptides, enkephalin (ENK), and dynorphin (DYN)., Method: Adult, male Sprague-Dawley rats were trained to voluntarily drink increasing concentrations of ethanol, up to 9% v/v, on a 12-hour access schedule or were given a single injection of ethanol (10% v/v) versus saline vehicle. The effect of ethanol on GAL, ENK, and DYN mRNA was measured using real-time quantitative polymerase chain reaction and radiolabeled in situ hybridization, while radioimmunoassay was used to measure peptide levels. In addition to blood alcohol, circulating levels of triglycerides (TG), leptin, and insulin were also measured., Results: The data demonstrated that: (1) rats voluntarily drinking 9% v/v ethanol (approximately 2.0 g/kg/d) show a significant increase in GAL, ENK, and DYN mRNA in the PVN compared with water-drinking rats; (2) voluntary consumption of ethanol also increases peptide levels of ENK and DYN in the PVN; (3) acute injection of 10% ethanol (1.0 g/kg of 10% v/v) similarly increases the expression of GAL, ENK, and DYN in the PVN; and (4) ethanol consumption and injection, while having little effect on leptin and insulin, consistently increase circulating levels of TG as well as alcohol, both of which are strongly, positively correlated with peptide expression in the PVN., Conclusions: These findings, together with published studies, suggest a possible role for hypothalamic opioid peptides in the drinking of ethanol. Based on evidence that dietary fat and lipid injections stimulate the PVN peptides and injection of the opiates and GAL increase ethanol intake, it is proposed that both TG and alcohol in the circulation, which are elevated by the ingestion or injection of ethanol, are involved in stimulating these peptides in the PVN, which in turn promote further consumption of ethanol.

Background: The neuropeptide galanin increases food intake. Chronic ethanol (EtOH) increases the expression of galanin in the hypothalamus. The research presented here examines the effects of microinjection of galanin in the third ventricle on voluntary alcohol intake., Methods: Male Sprague Dawley rats with a cannula in the third ventricle were given access to increasing concentrations of EtOH for 12 hr/day until all acquired a preference for 7% EtOH over water in a two-bottle choice. Rats then received a microinjection of galanin (0, 1, and 3 nmol) alone or in combination with the galanin antagonist M40 (1 nmol) and with M40 alone to determine the effects on EtOH and water intake. Tests were conducted during both the light and dark periods of a 12:12-hr light-dark cycle with food available ad libitum. As a control for galanin-induced calorie intake, both EtOH and food were measured in a subset of rats during the dark., Results: Microinjections of galanin (1.0 and 3.0 nmol) increased EtOH consumption during both periods of the light-dark cycle. Galanin's effect on ethanol intake during the light was large relative to the very low intake of food and water during this period. Rats increased their intake of EtOH but not food. Receptor specificity for galanin (3 nmol) was shown by the galanin antagonist M40, which blocked the increase in EtOH intake. M40 alone decreased EtOH intake slightly., Conclusions: These data show that galanin injected in the third ventricle increases EtOH consumption and that the effect can occur during both the light and the dark periods of the diurnal cycle in the presence of food and water. This suggests that galanin may play a role in augmenting voluntary alcohol intake and perhaps the development of alcohol dependence.

Findings of earlier studies support the idea of a possible relation between dietary fat and ethanol intake, but it is unclear whether acute exposure to fat can increase ethanol consumption directly. In the current series of experiments, we examined whether daily overeating of fat, a single high-fat meal, or the injection of fat can increase ethanol intake. In Experiment 1, adult Sprague-Dawley rats were maintained on a high-fat diet (50% fat) for 7 days and switched subsequently to a laboratory chow diet while being trained to drink 9% ethanol. Rats that had eaten the greatest amount of the high-fat diet subsequently drank the most ethanol. In Experiment 2, a 1-h meal of the high-fat diet (50% fat) produced a significant increase in 7% ethanol consumption in comparison with what occurred after consumption of an equicaloric, low-fat (10% fat) meal. In Experiment 3, the orosensory effect of fat was eliminated with an intraperitoneal injection of a fat emulsion, Intralipid (20% fat, 5.0 ml). The injection of Intralipid, in comparison with saline, increased the ingestion of 9% ethanol. This finding is in contrast to what occurred with injection of an equicaloric, 50% glucose solution, which suppressed ethanol intake. These findings provide new evidence to support a positive relation between dietary fat and the consumption of ethanol.

Rats show signs of dependence on sugar when it is available intermittently, including bingeing, withdrawal, and cross-sensitization with amphetamine. In the current study, we sought to determine whether sugar-dependent rats would show increased intake of unsweetened ethanol and, conversely, whether intermittent access to ethanol would augment sugar consumption. In Experiment 1, with intermittent versus ad libitum access to ethanol, Sprague-Dawley rats were given escalating concentrations of ethanol (1%, 2%, 4%, 7%, and 9%) over the course of 20 days. Rats in the intermittent ethanol access group, with 12-h daily access, consumed more 4%, 7%, and 9% ethanol during the first hour of access, and more 9% ethanol daily, than did rats in the ad libitum ethanol access group. In Experiment 2, with ethanol as a gateway to sugar intake, the rats from Experiment 1 were switched to 10% sucrose with 12-h daily access for 1 week. Rats in the intermittent ethanol access group consumed significantly more sugar than was consumed by rats in a control group with no prior ethanol experience. In Experiment 3, with sugar as a gateway to ethanol to determine whether sugar dependence leads to increased ethanol intake, four groups were maintained for 21 days according to the following designations: intermittent access to sugar and chow, ad libitum access to sugar and chow, intermittent access to chow, or ad libitum access to chow. Four days later, all groups were switched to intermittent ethanol access, as described in Experiment 1. The group with intermittent access to sugar and chow consumed the most 9% ethanol, supporting the suggestion that sugar dependence alters a rat's proclivity to drink ethanol. These results may relate to the co-morbidity between binge-eating disorders and alcohol intake and the tendency of people abstaining from alcohol to consume excessive amounts of sugar. In conclusion, bingeing on either ethanol or sugar fosters intake of the other.

Alcoholism can be viewed as a motivational disorder that results from alterations in brain systems for ingestive behavior. Therefore, it was hypothesized that alcohol intake might alter the expression of hypothalamic peptides that stimulate feeding. Earlier studies showed that hypothalamic injection of the feeding-stimulatory peptide, galanin (GAL), increases the release of dopamine (DA) in the nucleus accumbens (NAc), as does systemic alcohol, leading to a focus on GAL. Results of this study demonstrate the following: (1). Ethanol, injected daily (0.8 g/kg 10% v/v) for 7 days in male rats, markedly increased the expression of GAL but not of neuropeptide Y (NPY). This occurred in specific hypothalamic nuclei, namely the dorsomedial nucleus (DMN), paraventricular nucleus (PVN) and perifornical lateral hypothalamus (PLH). (2). Rats induced to drink ethanol ad libitum, by gradually increasing the concentration from 1% to 9% v/v without adding sugar or flavoring, exhibited a similar stimulation of GAL mRNA in the PVN and GAL immunoreactivity in the DMN and PVN. (3). Rats given increasing ethanol concentrations, with 12 h access starting 4 h into the dark cycle, had a mean blood alcohol concentration of 18 mg/dl and exhibited a similar increase in GAL expression in the DMN and PVN. (4) Withdrawal from the opioid effects of 9% ethanol, produced by injection of naloxone (3 mg/kg sc), reversed this ethanol effect by significantly reducing GAL expression in the DMN and PLH below baseline levels. These studies suggest a possible role for hypothalamic GAL in alcohol abuse.

Background The neurotransmitter dopamine ( DA), acting in various mesolimbic brain regions, is well known for its role in promoting motivated behaviors, including ethanol (EtOH) drinking. Indirect evidence, however, suggests that DA in the perifornical lateral hypothalamus ( PF/ LH) has differential effects on EtOH consumption, depending on whether it acts on the DA 1 ( D1) or DA 2 ( D2) receptor subtype, and that these effects are mediated in part by local peptide systems, such as orexin/hypocretin ( OX) and melanin-concentrating hormone ( MCH), known to stimulate the consumption of EtOH. Methods The present study in brain-cannulated Sprague- Dawley rats measured the effects of dopaminergic compounds in the PF/ LH on drinking behavior in animals trained to consume 7% EtOH and also on local peptide mRNA expression using digoxigenin-labeled in situ hybridization in EtOH-naïve animals. Results Experiments 1 and 2 showed that the D1 agonist SKF81297 (10.8 nmol/side) in the PF/ LH significantly increased food intake, while tending to increase EtOH intake, and the D1 antagonist SCH23390 significantly decreased EtOH intake without affecting food intake. In contrast, the D2 agonist quinelorane (6.2 nmol/side) in the PF/ LH significantly reduced EtOH consumption, while the D2 antagonist sulpiride increased it. Experiments 3 and 4 revealed differential effects of PF/ LH injection of the DA agonists on local OX mRNA, which was increased by the D1 agonist and decreased by the D2 agonist. These DA agonists had no impact on MCH expression. Conclusions These results support a stimulatory role of the PF/ LH D1 receptor in promoting the consumption of both EtOH and food, in contrast to a suppressive effect of the D2 receptor on EtOH drinking. They further suggest that these receptors affect consumption, in part, through local OX-expressing neurons. These findings provide new evidence for the function of PF/ LH DA receptor subtypes in controlling EtOH and food intake. [ABSTRACT FROM AUTHOR]

Background Glutamate ( GLUT) in the lateral hypothalamus ( LH) has been suggested to mediate reward behaviors and may promote the ingestion of drugs of abuse. This study tested the hypothesis that GLUT in the LH stimulates consumption of ethanol ( EtOH) and that this effect occurs, in part, via its interaction with local peptides, hypocretin/orexin ( OX), and melanin-concentrating hormone ( MCH). Methods In Experiments 1 and 2, male Sprague- Dawley rats, after being trained to drink 9% EtOH, were microinjected in the LH with N-methyl- d-aspartate ( NMDA) or its antagonist, D- AP5, or with alpha-amino-5-methyl-3-hydroxy-4-isoxazole propionic acid ( AMPA) or its antagonist, CNQX-ds. Consumption of EtOH, chow, and water was then measured. To provide an anatomical control, a separate set of rats was injected 2 mm dorsal to the LH. In Experiment 3, the effect of LH injection of NMDA and AMPA on the expression of OX and MCH was measured using radiolabeled in situ hybridization ( ISH) and also using digoxigenin-labeled ISH, to distinguish effects on OX and MCH cells in the LH and the nearby perifornical area ( PF) and zona incerta ( ZI). Results When injected into the LH, NMDA and AMPA both significantly increased EtOH intake while having no effect on chow or water intake. The GLUT receptor antagonists had the opposite effect, significantly reducing EtOH consumption. No effects were observed with injections 2 mm dorsal to the LH. In addition to these behavioral effects, LH injection of NMDA significantly stimulated expression of OX in both the LH and PF while reducing MCH in the ZI, whereas AMPA increased OX only in the LH and had no effect on MCH. Conclusions Glutamatergic inputs to the LH, acting through NMDA and AMPA receptors, appear to have a stimulatory effect on EtOH consumption, mediated in part by increased OX in LH and PF and reduced MCH in ZI. [ABSTRACT FROM AUTHOR]

Background: Specialized hypothalamic systems that increase food intake might also increase ethanol intake. To test this possibility, morphine and receptor-specific opioid agonists were microinjected in the paraventricular nucleus (PVN) of rats that had learned to drink ethanol. To cross-validate the results, naloxone methiodide (m-naloxone), an opioid antagonist, was microinjected with the expectation that it would have the opposite effect of morphine and the specific opioid agonists. Methods: Sprague–Dawley rats were trained, without sugar, to drink 4 or 7% ethanol and were then implanted with chronic brain cannulas aimed at the PVN. After recovery, those drinking 7% ethanol, with food and water available, were injected with 2 doses each of morphine or m-naloxone. To test for receptor specificity, 2 doses each of the μ-receptor agonist [d-Ala2, N-Me-Phe4,Gly5-ol]-Enkephalin (DAMGO), δ-receptor agonistd-Ala-Gly-Phe-Met-NH2 (DALA), or κ-receptor agonist U-50,488H were injected. DAMGO was also tested in rats drinking 4% ethanol without food or water available. As an anatomical control for drug reflux, injections were made 2 mm dorsal to the PVN. Results: A main result was a significant increase in ethanol intake induced by PVN injection of morphine. The opposite effect was produced by m-naloxone. The effects of morphine and m-naloxone were exclusively on intake of ethanol, even though food and water were freely available. In the analysis with specific receptor agonists, PVN injection of the δ-agonist DALA significantly increased 7% ethanol intake without affecting food or water intake. This is in contrast to the κ-agonist U-50,488H, which decreased ethanol intake, and the μ-agonist DAMGO, which had no effect on ethanol intake in the presence or absence of food and water. In the anatomical control location 2 mm dorsal to the PVN, no drug caused any significant changes in ethanol, food, or water intake, providing evidence that the active site was close to the cannula tip. Conclusions: The δ-opioid receptor agonist in the PVN increased ethanol intake in strong preference over food and water, while the κ-opioid agonist suppressed ethanol intake. Prior studies show that learning to drink ethanol stimulates PVN expression and production of the peptides enkephalin and dynorphin, which are endogenous agonists for the δ- and κ-receptors, respectively. These results suggest that enkephalin via the δ-opioid system can function locally within a positive feedback circuit to cause ethanol intake to escalate and ultimately contribute to the abuse of ethanol. This is in contrast to dynorphin via the κ-opioid system, which may act to counter this escalation. Naltrexone therapy for alcoholism may act, in part, by blocking the enkephalin-triggered positive feedback cycle. [ABSTRACT FROM AUTHOR]

Different alcohol drinking patterns, involving either small and frequent drinking bouts or large and long-lasting bouts, are found to differentially affect the risk for developing alcohol-related diseases, suggesting that they have different underlying mechanisms. Such mechanisms may involve orexigenic peptides known to stimulate alcohol intake through their actions in the hypothalamic paraventricular nucleus (PVN). These include orexin (OX), which is expressed in the perifornical lateral hypothalamus, and galanin (GAL) and enkephalin (ENK), which are expressed within as well as outside the PVN. To investigate the possibility that these peptides affect different aspects of consumption, a microstructural analysis of ethanol drinking behavior was performed in male, Sprague-Dawley rats trained to drink 7% ethanol and implanted with guide shafts aimed at the PVN. While housed in specialized cages containing computerized intake monitors (BioDAQ Laboratory Intake Monitoring System, Research Diets Inc., New Brunswick, NJ) that measure bouts of ethanol drinking, these rats were given PVN injections of OX (0.9 nmol), GAL (1.0 nmol), or the ENK analog D-Ala2-met-enkephalinamide (DALA) (14.2 nmol), as compared to saline vehicle. Results revealed clear differences between the effects of these peptides. While all 3 stimulated ethanol intake, they had distinct effects on patterns of drinking, with OX increasing the number of drinking bouts, GAL increasing the size of the drinking bouts, and DALA increasing both the size and duration of the bouts. In contrast, these peptides had little impact on water or food intake. These results support the idea that different peptides can increase ethanol consumption by promoting distinct aspects of the ethanol drinking response. The stimulatory effect of OX on drinking frequency may be related to its neuronally stimulatory properties, while the stimulatory effect of GAL and ENK on bout size and duration may reflect a suppressive effect of these neuronally inhibitory peptides on the satiety-controlling PVN. [ABSTRACT FROM AUTHOR]

Different alcohol drinking patterns, involving either small and frequent drinking bouts or large and longlasting bouts, are found to differentially affect the risk for developing alcohol-related diseases, suggesting that they have different underlying mechanisms. Such mechanisms may involve orexigenic peptides known to stimulate alcohol intake through their actions in the hypothalamic paraventricular nucleus (PVN). These include orexin (OX), which is expressed in the perifornical lateral hypothalamus, and galanin (GAL) and enkephalin (ENK), which are expressed within as well as outside the PVN. To investigate the possibility that these peptides affect different aspects of consumption, a microstructural analysis of ethanol drinking behavior was performed in male, Sprague-Dawley rats trained to drink 7% ethanol and implanted with guide shafts aimed at the PVN. While housed in specialized cages containing computerized intake monitors (BioDAQ Laboratory Intake Monitoring System, Research Diets Inc., New Brunswick, NJ) that measure bouts of ethanol drinking, these rats were given PVN injections of OX (0.9 nmol), GAL (1.0 nmol), or the ENK analog D-Ala2-met-enkephalinamide (DALA) (14.2 nmol), as compared to saline vehicle. Results revealed clear differences between the effects of these peptides. While all 3 stimulated ethanol intake, they had distinct effects on patterns of drinking, with OX increasing the number of drinking bouts, GAL increasing the size of the drinking bouts, and DALA increasing both the size and duration of the bouts. In contrast, these peptides had little impact on water or food intake. These results support the idea that different peptides can increase ethanol consumption by promoting distinct aspects of the ethanol drinking response. The stimulatory effect of OX on drinking frequency may be related to its neuronally stimulatory properties, while the stimulatory effect of GAL and ENK on bout size and duration may reflect a suppressive effect of these neuronally inhibitory peptides on the satiety-controlling PVN. [ABSTRACT FROM AUTHOR]

The opioid system is known to enhance motivated behaviors, including ethanol drinking and food ingestion, by acting in various reward-related brain regions, such as the nucleus accumbens, ventral tegmental area and medial hypothalamus. There is indirect evidence, however, suggesting that opioid peptides may act differently in the perifornical lateral hypothalamus (PF/LH), causing a suppression of consummatory behavior. Using brain-cannulated SpragueeDawley rats trained to voluntarily drink 7% ethanol, the present study tested the hypothesis that opioids in the PF/LH can reduce the consumption of ethanol, with animals receiving PF/LH injections of the d-opioid receptor agonist D-Ala2-met-enkephalinamide (DALA), the m-receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO), the k-receptor agonist (±)-trans-U-50,488 methanesulfonate (U-50,488H), or the general opioid antagonist methylated naloxone (m-naloxone). The consumption of ethanol, lab chow, and water was monitored for 4 h after injection. The results showed that the three opioid receptor agonists injected into the PF/LH specifically and significantly reduced ethanol intake, while causing little change in chow or water intake, and the opposite effect, enhanced ethanol intake, was observed with the opioid antagonist. Of the three opioid agonists, the d-agonist appears to produce the most consistent and long-lasting suppression of consumption. This effect was not observed with injections 2 mm dorsal to this area, focusing attention on the PF/LH as the main site of action. These results suggest that the opioid peptides have a specific role in the PF/LH of reducing ethanol drinking, which is distinct from their more commonly observed appetitive actions in other brain areas. The additional finding, that m-naloxone in the PF/LH stimulates ethanol intake in contrast to its generally suppressive effect in other regions, focuses attention on this hypothalamic area and its distinctive role in contributing to the variable effects sometimes observed with opioid antagonist therapy for alcoholism. [ABSTRACT FROM AUTHOR]