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Background: Alcohol priming can modulate the value of rewards, as observed through the effects of acute alcohol administration on cue reactivity. However, little is known about the psychophysiological mechanisms driving these effects. Here we examine how alcohol-induced changes in bodily states shape the development of implicit attentional biases and explicit cue reactivity. Aims: To characterize the interoceptive correlates of alcohol priming effects on alcohol attentional biases and cue reactivityMethods: In a two-session double blind alcohol administration procedure, participants (n=31) were given a 0.4g/kg dose of alcohol or a placebo drink. Cardiovascular responses were measured before and after alcohol administration to observe the effects of alcohol on viscero-afferent reactivity, as indexed through changes in heart-rate variability (HRV) at or near 0.1Hz (0.1Hz HRV). Next, participants completed a modified Flanker task to examine implicit alcohol attentional biases and provided subjective valence and arousal ratings of alcohol cues to examine explicit cue reactivity. Results: We found that changes in 0.1Hz HRV after alcohol administration positively correlated with attentional biases, and negatively correlated with alcohol valence ratings; breath alcohol content was a null predictor. Conclusion: This is novel evidence that suggests alcohol-induced changes in bodily states may mediate the occurrence of alcohol priming effects, and highlights the potentially generative role of interoceptive mechanisms in alcohol-related behaviors. The differential patterns revealed by implicit biases and explicit response tendencies is considered within the context of the dissociation between wanting and liking.

Evidence suggests a role for the opioid system in the control of ethanol reinforcement and drinking. Previous findings have shown that naltrexone, an opioid antagonist that decreases ethanol consumption in humans and experimental animals, reduces the acquisition of acute ethanol tolerance in rats. However, there are few data regarding the role of the opioid system in the acquisition of ethanol tolerance, particularly in brain areas involved in the rewarding actions of ethanol.This study investigates the effects of systemic and of intra-accumbens injections of naltrexone on the development of rapid tolerance to ethanol.Wistar rats received intraperitoneal injections of naltrexone (0.1-3.0 mg/kg) or microinjections into the core or shell portions of the nucleus accumbens (5-20 microg) before ethanol (2.7 g/kg i.p.). The animals were tested for motor coordination on the tilting plane apparatus. Tolerance was assessed 24 h later by administering the same dose of ethanol to all animals and retesting them on the tilting plane.The second injection of ethanol resulted in less motor incoordination on Day 2, suggesting the development of rapid tolerance. Pretreatment with naltrexone, either i.p. (0.3 and 0.6 mg/kg) or intra-accumbens (5-20 microg), on Day 1, blocked the development of rapid tolerance to the motor-incoordinating effects of ethanol on Day 2 without affecting the motor performance of the animals on Day 1.The results suggest that the opioid system may be involved in the development of ethanol tolerance, and that the nucleus accumbens may play a role in this phenomenon.

Brain nitric oxide is involved in the mechanisms that regulate ingestive behavior. To test whether this compound plays a role in alcohol preference, we studied the effects of different doses of NG-nitro-L-arginine (L-NO arg), an inhibitor of nitric oxide synthase (NOS), on voluntary consumption of ethanol and on blood alcohol levels produced by a single intraperitoneal dose of alcohol in the rat. L-NO arg produced a significant and dose-dependent reduction of ethanol intake (P < 0.001) without influencing total fluid consumption or feeding behavior. L-NO arg did not influence the kinetics of alcohol. Our data show that inhibition of nitric oxide formation accompanies reduction of ethanol intake and suggest a possible role for nitric oxide in ethanol self-administration.

N-Methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels essential for glutamatergic transmission and plasticity. NMDARs are inhibited by acute ethanol and undergo brain region-specific adaptations after chronic alcohol exposure. In previous studies, we reported that knock-in mice expressing ethanol-insensitive GluN1 or GluN2A NMDAR subunits display altered behavioral responses to acute ethanol and genotype-dependent changes in drinking using protocols that do not produce dependence. A key unanswered question is whether the intrinsic ethanol sensitivity of NMDARs also plays a role in determining behavioral adaptations that accompany the development of dependence. To test this, we exposed mice to repeated cycles of chronic intermittent ethanol (CIE) vapor known to produce a robust escalation in ethanol consumption and preference. As expected, wild-type mice showed a significant increase from baseline in ethanol consumption and preference after each of the four weekly CIE cycles. In contrast, ethanol consumption in male GluN2A(A825W) mice was unchanged following cycles 1, 2, and 4 of CIE with a modest increase appearing after cycle 3. Wild-type and GluN2A(A825W) female mice did not show a clear or consistent escalation in ethanol consumption or preference following CIE treatment. In male GluN1(F639A) mice, the increase in ethanol consumption observed with their wild-type littermates was delayed until later cycles of exposure. These results suggest that the acute ethanol sensitivity of NMDARs especially those containing the GluN2A subunit may be a critical factor in the escalation of ethanol intake in alcohol dependence.

Model-based assessments of behavioral control have been used to study the acute effects of alcohol on the ability to execute and inhibit behavioral responses. Response inhibition appears more vulnerable to the impairing effects of alcohol than response execution. Current information processing models have yet to account for this observation.The present study used a reductionist approach to determine if the particular vulnerability of response inhibition to the effects of alcohol occurs at the level of the action (motor program). The study examined the effects of alcohol on the ability to execute and inhibit behavior in a context in which preliminary information signaled the likelihood that a response should be executed or suppressed. The engagement and disengagement of responses were directly compared under alcohol.Adults (N = 24) performed a cued go/no-go task that required quick responses to go targets and suppression of responses to no-go targets. Response requirements were manipulated by varying the nature of the action required whereby half of the participants made key press responses (response engagement) and the other half released ongoing key presses (response disengagement). Performance was tested under three doses of alcohol: 0.00, 0.45, and 0.65 g/kg.Dose-dependent increases in commission errors were only observed with response engagement and not with response disengagement. Reaction times were faster for response engagement than response disengagement.Response disengagement affords some protection against alcohol-induced impairment of inhibition, indicating that not all aspects of motor processing requiring inhibition are equally impaired by alcohol.

The purpose of this experiment was to determine whether attenuation of ethanol consumption by naltrexone is the result of selective changes in the reinforcing effectiveness of drug and non-drug reinforcers. A range of naltrexone doses (0.1-1.0 mg/kg) was administered for 5 days, and the effects on the reinforcing effects of orally delivered 8% (w/v) ethanol, 0.25 mg/ml phencyclidine (PCP), 0.03% (w/v) saccharin and food were studied in eight rhesus monkeys. Food and liquids were available under independent and concurrent progressive-ratio (PR) schedules (ratio range 8-4096) during daily 3-h sessions. Ethanol-maintained responding was attenuated by 0.3 and 1.0 mg/kg doses of naltrexone, while saccharin-maintained responding was decreased at the 1.0 mg/kg dose. Furthermore, there was a significant linear trend that consumption of available ethanol and saccharin was attenuated dose-dependently by naltrexone. Following 5 days of naltrexone pretreatment, ethanol- and saccharin-maintained responding immediately returned to or exceeded baseline levels. Food- and PCP-maintained responding and intake were not significantly affected by any of the naltrexone doses examined. The decreased break point (BP) values for ethanol and saccharin suggest that their reinforcing effects are mediated through opioid reinforcement mechanisms. The lack of naltrexone attenuation of PCP- and food-maintained responding suggests that these reinforcers: 1) are not sensitive to naltrexone antagonism at the doses examined, 2) are mediated by non-opioid reinforcement mechanisms, and/or 3) have less intrinsic palatability.

Studies on laboratory animals have provided conflicting results regarding the actions of stressors on the rewarding effects of alcohol. In the present study, we first examined the effects of footshock or social defeat, given during deprivation, on the alcohol deprivation effect (ADE). We then tested the effects of stressors on place conditioning to alcohol, another technique used to measure drug reward.Male Wistar rats were trained to drink 10% alcohol in a 24 h access, free-choice design and received intermittent footshock or defeat 5 times during a 2-week alcohol deprivation period, followed by 2 weeks of free access to alcohol. There were three such cycles. In the place conditioning studies, animals received footshock, defeat, or no stress immediately prior to conditioning sessions where they received alcohol (0.6 or 1.0 g/kg, i.p.) or vehicle injections.Alcohol intake of footshock-treated animals was significantly higher than that of controls following the first and second, but not the third period of alcohol deprivation and stress exposure. Defeat caused a smaller increase in alcohol intake that was significant only after the first deprivation and stress cycle. In the place conditioning studies, we found that either stressor blocked the place aversion induced by 1.0 g/kg alcohol.These results demonstrate that stressors can modify the rewarding and aversive properties of alcohol, measured using two different paradigms. Footshock and defeat produced transient, but significant increases in the magnitude of ADE, while exposure to either stressor reduced the aversive effects of a high dose of alcohol measured using the place conditioning paradigm.

Opiate antagonists are promising pharmacotherapeutic agents for the treatment of alcohol dependence, reducing craving and relapse rates in weaned alcoholics. However, preclinical findings indicate that they can also increase ethanol consumption and preference in animals with a strong liking for ethanol, depending on the dose and treatment regimen.The present study examined the effects of chronic, intermittent and acute opiate antagonist treatment on the alcohol deprivation effect (ADE) in long-term ethanol- experienced rats, which is an animal model of craving and relapse.Long-term ethanol-experienced rats were either implanted with mini-osmotic pumps delivering 0, 0.5 or 1 mg/kg per hour naloxone (chronic treatment) or received intermittent naltrexone injections (2x5 mg/kg per day SC). Effects of chronic and intermittent treatment on the ADE were studied in a four-bottle home cage drinking paradigm. In a second experiment, long-term ethanol-experienced rats trained in an operant ethanol self-administration paradigm received acute naltrexone treatment (0, 0.1, 1 or 10 mg/kg SC) before a 23-h session either during basal drinking or during the ADE.Chronic naloxone treatment increased ethanol preference during the ADE. Intermittent naltrexone treatment at a dose comparable to the lower dose of chronic treatment moderately attenuated the ADE. Acute naltrexone treatment selectively reduced lever pressing for ethanol both during the ADE and during basal drinking only at the lowest dose, whereas higher doses also suppressed water intake. The ethanol-specific suppressant effect on the ADE was long lasting. Concerning basal drinking, however, naltrexone had a long lasting reductive effect only on lever pressing for water.A low dose of naltrexone and an intermittent treatment regimen seem to be necessary to maintain a specific reduction in ethanol intake in individuals with a high motivation to consume ethanol. These findings are consistent with the notion that, at low doses, opiate antagonists reduce the reward value of reinforcers.