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Oleoylethanolamide (OEA) is a satiety factor that controls motivational responses to dietary fat. Here we show that alcohol administration causes the release of OEA in rodents, which in turn reduces alcohol consumption by engaging peroxisome proliferator-activated receptor-alpha (PPAR-α). This effect appears to rely on peripheral signaling mechanisms as alcohol self-administration is unaltered by intracerebral PPAR-α agonist administration, and the lesion of sensory afferent fibers (by capsaicin) abrogates the effect of systemically administered OEA on alcohol intake. Additionally, OEA is shown to block cue-induced reinstatement of alcohol-seeking behavior (an animal model of relapse) and reduce the severity of somatic withdrawal symptoms in alcohol-dependent animals. Collectively, these findings demonstrate a homeostatic role for OEA signaling in the behavioral effects of alcohol exposure and highlight OEA as a novel therapeutic target for alcohol use disorders and alcoholism.

Background: The misuse and abuse of alcohol is a major public health issue. However, available treatments are limited with variable efficacy. Recently, preclinical studies show that glucagon‐like‐peptide‐1 (GLP‐1) and its analogue Exendin‐4 (Ex4) potently reduce a range of alcohol intake behaviors, thus highlighting its potential as a treatment for alcohol use disorders. However, the neural mechanisms and sites of action mediating the effects of Ex4 on alcohol intake behaviors remain to be characterized. This study examined the ventral tegmental area (VTA) as a site of action for the effects of GLP‐1 on alcohol intake. Methods: Male Long‐Evans rats were given intermittent access to 20% alcohol and trained to nose poke for 20% alcohol. Rats received intra‐VTA injections of Ex4 (vehicle, 0.01, 0.05 μg), and the effects of VTA Ex4 on alcohol self‐administration, motivation, and relapse were assessed. Results: When compared to vehicle treatment, intra‐VTA Ex4 (0.01, 0.05 μg) delivery significantly reduced alcohol self‐administration, an effect that was particularly prominent in high alcohol drinkers. However, VTA Ex4 did not reduce reacquisition of alcohol self‐administration after extinction nor the motivation to obtain alcohol. Importantly, the lower dose of Ex4 (0.01 μg) used had no effect on food intake or locomotor activity, suggesting that the reduction in alcohol self‐administration observed was not secondary to caloric intake or motor deficits. Conclusions: Together, these findings provide support for the VTA as a key site of action for GLP‐1 on alcohol self‐administration but not the reacquisition of alcohol self‐administration or motivation to work for alcohol. [ABSTRACT FROM AUTHOR]

RationaleA major clinical concern with the use of cannabinoid receptor 1 (CB1) direct agonists is that these compounds increase alcohol drinking and drug abuse-related behaviours. As an alternative approach, CB1-receptor-mediated activity can be facilitated by increasing anandamide levels with the use of hydrolase fatty acid amide hydrolase (FAAH) inhibitors.ObjectiveUsing the selective FAAH inhibitor URB597, we investigated whether activation of the endogenous cannabinoid tone increases alcohol abuse liability, as what happens with the CB1 receptor direct agonists.Materials and methodsURB597 was tested on alcohol self-administration in Wistar rats and on homecage alcohol drinking in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. In Wistar rats, URB597 effects on alcohol-induced anxiety and on stress-, yohimbine- and cue-induced reinstatement of alcohol seeking were also evaluated. For comparison, the effect of the CB1 receptor antagonist rimonabant on ethanol self-administration was also tested.ResultsUnder our experimental condition, intraperitoneal (IP) administration of URB597 (0.0, 0.3 and 1.0 mg/kg) neither increased voluntary homecage alcohol drinking in msP rats nor facilitated fixed ratio 1 and progressive ratio alcohol self-administration in nonselected Wistars. In the reinstatement tests, the compound did not have effects on cue-, footshock stress- and yohimbine-induced relapse. Conversely, URB597 completely abolished the anxiogenic response measured during withdrawal after an acute IP administration of alcohol (3.0 g/kg). Rimonabant (0.0, 0.3, 1.0 and 3.0 mg/kg) significantly reduced ethanol self-administration.ConclusionsResults demonstrate that activation of the endocannabinoid anandamide system by selective inhibition of FAAH does not increase alcohol abuse risks but does reduce anxiety associated to alcohol withdrawal. We thus can speculate that medication based on the use of endocannabinoid system modulators such as URB597 may offer important advantages compared to treatment with direct CB1 receptor activators.

Rationale and objectives: Alpha-1 adrenoceptor antagonists, such as prazosin, show promise in treating alcoholism. In rats, prazosin reduces alcohol self-administration and relapse induced by footshock stress and the alpha-2 antagonist yohimbine, but the processes involved in these effects of prazosin are not known. Here, we present studies on the central mechanisms underlying the effects of prazosin on yohimbine-induced reinstatement of alcohol seeking. Methods: In experiment 1, we trained rats to self-administer alcohol (12 % w/ v, 1 h/day), extinguished their responding, and tested the effects of prazosin, administered ICV (2 and 6 nmol) or systemically (1 mg/kg) on yohimbine (1.25 mg/kg)-induced reinstatement. In experiment 2, we determined potential central sites of action by analyzing effects of prazosin (1 mg/kg) on yohimbine (1.25 mg/kg)-induced Fos expression. In experiment 3, we determined the effects of doxazosin (1.25, 2.5, and 5 mg/kg), an alpha-1 antagonist with a longer half-life on yohimbine-induced reinstatement. Results: Yohimbine-induced reinstatement of alcohol seeking was reduced significantly by ICV and systemic prazosin (50 and 69 % decreases, respectively). Systemic prazosin reduced yohimbine-induced Fos expression in the prefrontal cortex, accumbens shell, ventral bed nucleus of the stria terminalis, and basolateral amygdala (46-67 % decreases). Doxazosin reduced yohimbine-induced reinstatement of alcohol seeking (78 % decrease). Conclusions: Prazosin acts centrally to reduce yohimbine-induced alcohol seeking. The Fos mapping study suggests candidate sites where it may act. Doxazosin is also effective in reducing yohimbine-induced reinstatement. These data provide information on the mechanisms of alpha-1 antagonists on yohimbine-induced alcohol seeking and indicate their further investigation for the treatment of alcoholism. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: Relapse to alcohol use during abstinence or maladaptive eating habits during dieting is often provoked by stress. The anxiogenic drug yohimbine, which causes stress-like responses in humans and non-humans, reliably reinstates alcohol and food seeking in a rat relapse model. Yohimibine is a prototypical alpha-2 adrenoceptor antagonist, but results from studies on noradrenaline's role in yohimbine-induced reinstatement of drug and food seeking are inconclusive. Here, we further addressed this issue by studying the effect of the alpha-1 adrenoceptor antagonist prazosin and the alpha-2 adrenoceptor agonist guanfacine on yohimbine-induced reinstatement. Methods: In exp. 1, we trained rats to self-administer alcohol (12% w/ v, 1 h/day), and after extinction of alcohol-reinforced lever pressing, we tested prazosin's (0.5, 1.0, and 2.0 mg/kg, i.p.) or guanfacine's (0.125, 0.25, and 0.5 mg/kg, i.p.) effect on yohimbine (1.25 mg/kg, i.p.)-induced reinstatement; we also examined prazosin's effect on intermittent-footshock-stress-induced reinstatement. In exp. 2, we trained food-restricted rats to self-administer 45 mg food pellets and first examined prazosin's or guanfacine's effects on food-reinforced responding, and then, after extinction of lever presses, on yohimbine-induced reinstatement. Results: Prazosin (0.5-2.0 mg/kg) blocked yohimbine-induced reinstatement of food and alcohol seeking, as well as footshock-induced reinstatement of alcohol seeking. Guanfacine attenuated yohimbine-induced reinstatement of alcohol seeking at the highest dose (0.5 mg/kg), but its effect on yohimbine-induced reinstatement of food seeking was not significant. Neither prazosin nor guanfacine affected high-rate food-reinforced responding. Conclusions: Results demonstrate an important role of postsynaptic alpha-1 adrenoceptors in stress-induced reinstatement of alcohol and food seeking. [ABSTRACT FROM AUTHOR]

Yohimbine is an alpha-2 adrenoreceptor antagonist that provokes stress- and anxiety-like responses in both humans and laboratory animals. In rats, yohimbine increases operant alcohol self-administration and reinstates alcohol seeking. In this study, we assess whether these effects of yohimbine are attenuated by systemic injections of the corticotrotropin-releasing factor 1 (CRF1) receptor antagonist antalarmin. In Exp. 1, we trained rats to lever press for alcohol solutions (12% w/ v, 1 h/day) over several weeks; during training, the response requirement was increased from a fixed-ratio-1 (FR-1) to a fixed-ratio-3 (FR-3) reinforcement schedule. We then tested the effect of antalarmin (10 or 20 mg/kg) on yohimbine (1.25 mg/kg)-induced increases in operant alcohol self-administration (FR-3 reinforcement schedule). Subsequently, we assessed the effect of antalarmin on yohimbine-induced increases in plasma corticosterone levels in the previously self-administering rats. In Exp. 2, we trained the rats to self-administer alcohol as in Exp. 1, and after extinction of the alcohol-reinforced lever responding over 13 days, we tested antalarmin’s effect on yohimbine-induced reinstatement of alcohol seeking. Yohimbine increased operant alcohol self-administration and reinstated alcohol seeking after extinction. These effects of yohimbine were attenuated by antalarmin. Antalarmin injections in the absence of yohimbine had no effect on either operant alcohol self-administration or extinction responding. Antalarmin had no effect on yohimbine-induced corticosterone release in alcohol-experienced rats. These results suggest that extrahypothalamic CRF1 receptors are involved in the effect of yohimbine on operant alcohol self-administration and on relapse to alcohol seeking and support the notion that CRF1 receptor antagonists should be considered in alcohol addiction treatment. [ABSTRACT FROM AUTHOR]

Abstract: We have recently shown that the alcohol self-administration context can reinstate extinguished responding for alcohol when that extinction occurs in a different context [Burattini, C., Gill, T. M., Aicardi, G., & Janak, P. H. (2006)]. The ethanol self-administration context as a reinstatement cue: acute effects of naltrexone. Neuroscience, in press; Zironi, I., Burattini, C., Aicardi, G., & Janak, P. H. (2006). Context is a trigger for relapse to alcohol. Behav Brain Res 167, 150–155). Here, we test whether the C57BL/6 mice will also show context-induced reinstatement for alcohol, and whether presentation of an alcohol-associated cue will alter the observed responding. Male C57BL/6 mice were trained to lever press on a fixed ratio-3 schedule for a 10% ethanol solution in a context made distinctive using visual, tactile, and olfactory stimuli. Each ethanol delivery was paired with a compound tone-light stimulus. After training, extinction sessions were given in a distinct context, comprised of different visual, tactile, and olfactory stimuli; the compound cue and the alcohol were not available during these sessions. In Experiment 1, after response extinction, subjects were tested by placement into both the alcohol self-administration context and, on a subsequent test, by response-contingent presentation of the cue following placement into the alcohol self-administration context. In Experiment 2, after response extinction, subjects were tested in both of these conditions, with the addition of a test of the effects of response-contingent presentation of the cue in the extinction context. The results indicate that the alcohol self-administration context produces a mild increase in responding at the alcohol lever, and that presentation of the alcohol-associated cue in the alcohol context, but not the extinction context, strongly increases responding on the alcohol lever. These findings suggest that the power of an alcohol-associated cue can be modulated by the context. The observed effects of alcohol contexts and cues on alcohol-seeking behavior in the C57BL/6 mouse suggest that this reinstatement model may be useful for understanding the neurobiological and genetic mechanisms of relapse triggered by conditioned environmental stimuli. [Copyright &y& Elsevier]

Presents a study which characterized the effects of social defeat or a cue associated with the defeat experience on reinstatement of alcohol seeking in rats. Examination into the effect of unconditioned and conditioned social defeat on alcohol self-administration; Effects of peppermint odor cue on self-administration; Interpretation of the study findings.

Discusses a research on the role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats. Effect of lofexidine and yohimbine on alcohol self-administration; Impact of stress on craving and relapse to alcohol and drugs; Investigation of the neuropharmacological basis of stress-induced alcohol.

Rationale. Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the opioid-like orphan receptor NOP, was shown to reduce home-cage ethanol consumption, ethanol-induced conditioned place preference and stress-induced reinstatement of alcohol-seeking behaviour. Objectives. The present study, using genetically selected Marchigian Sardinian alcohol-preferring (msP) rats, was designed to evaluate the effect of this opioid peptide on 10% ethanol and 10% sucrose self-administration, under a fixed-ratio 1 (FR 1) or a progressive-ratio (PR) schedule of reinforcement. Furthermore, using an experimental model of relapse in which rats were trained to lever press for ethanol in the presence of the discriminative stimulus of an orange odour (S[sup +]) and a 1-s cue light (CS[sup +]) or for water in the presence of anise odour (S[sup -]) and 1-s white noise (CS[sup -]), the effect of N/oFQ on cue-induced reinstatement of extinguished ethanol responding was investigated. Results. Sub-chronic (6 days) intracerebroventricular (i.c.v.) injection of 0.5 μg or 1.0 μg N/OFQ per rat significantly reduced alcohol self-administration under both the FR 1 and PR schedules of reinforcement. Conversely, i.c.v. administration of 0.5, 1.0 or 4.0 μg of the peptide per rat did not affect sucrose self-administration. In addition, i.c.v. N/OFQ (1.0–2.0 μg per rat) significantly inhibited the reinstatement of extinguished ethanol responding under an S[sup +]/CS[sup +] condition, whereas lever pressing under S[sup -]/CS[sup -] was not altered. Conclusions. The present study demonstrates that the reinforcing effects of ethanol are markedly blunted by activation of the opioidergic N/OFQ receptor system. Moreover, the data provide evidence of the efficacy of N/OFQ to prevent reinstatement of ethanol-seeking behaviour elicited by environmental conditioned stimuli. [ABSTRACT FROM AUTHOR]

Lead (Pb) is a neurotoxic heavy metal pollutant. Despite the efforts to reduce Pb environmental exposure and to prevent Pb poisoning, exposure in human populations persists. Studies of adults with history of childhood lead exposure have consistently demonstrated cognitive impairments that have been associated with sustained glutamate signaling. Additionally, some clinical studies have also found correlations between Pb exposure and increased proclivity to drug addiction. Thus, here we sought to investigate if developmental Pb exposure can increase propensity to alcohol consumption and relapse using an alcohol self-administration paradigm. Because Pb exposure is associated with increased glutamatergic tone, we also studied the effects on the expression of synaptic and non-synaptic glutamate transporters in brain regions associated with drug addiction such as the nucleus accumbens (NAc), dorsomedial striatum (DMS), dorsolateral striatum (DLS), and medial prefrontal cortex (mPFC). We found that while developmental Pb exposure did not increase risk for alcohol self-administration, it did play a role in relapsing to alcohol. The effects were associated with differential expression of the glutamate transporter 1 (GLT1) and the glutamate/cystine antiporter (xCT). In the NAc and DLS the expression of GLT1 was found to be significantly reduced, while no changes were found in DMS or mPFC. Contrastingly, xCT was found to be upregulated in NAc but downregulated in DLS, with no changes in DMS or mPFC. Our data suggest that lead exposure is involved in relapse to alcohol seeking, an effect that could be associated with downregulation of GLT1 and xCT in the DLS. • Developmental Pb exposure does not increase alcohol self-administration. • Low-level Pb exposure increase the risk of relapse to alcohol seeking. • Decreased expression of GLT1 and xCT glutamate transporters in dorsolateral striatum after relapsing to alcohol seeking. [ABSTRACT FROM AUTHOR]