Ethanol Seeking Research Articles

Effects of histamine H3 receptor ligands on the rewarding, stimulant and motor-impairing effects of ethanol in DBA/2J mice

Histamine H3 receptor (H3R) antagonists are currently being investigated for the possible therapeutic use in various cognitive deficits such as those in schizophrenia, attention deficit hyperactivity disorder and Alzheimer’s disease. Our previous studies suggest a role for H3Rs in ethanol-related behaviors in rat and mice. Here we have examined the role of different H3R ligands on the effects of ethanol in conditioned place preference (CPP) paradigm, stimulation of locomotor activity and motor impairment in rotarod and balance beam in male DBA/2J mice. We found that H3R antagonists ciproxifan and JNJ-10181457 inhibited the ethanol-evoked CPP whereas H3R agonist immepip did not alter ethanol-induced place preference. Acute stimulatory response by ethanol was also modulated by H3R ligands. Ciproxifan increased ethanol activation when ethanol was given 1 g/kg but not at 1.5 g/kg dose. Immepip pretreatment diminished ethanol stimulation and increased motor-impairing effects of ethanol on the balance beam. In conclusion, these findings give further evidence of the involvement of H3R in the regulation of the effects of ethanol. The inhibition of ethanol reward by H3R antagonism implies that H3R might be a possible target to suppress compulsory ethanol seeking. This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’.

The Orexin-1 Receptor Antagonist SB-334867 Reduces Alcohol Relapse Drinking, but not Alcohol-Seeking, in Alcohol-Preferring (P) Rats

The orexin system has been hypothesized to regulate drug-seeking and drug self-administration behaviors, including ethanol (EtOH) seeking and consumption. However, studies on the effects of orexin receptor antagonists have not been conducted on robust alcohol-relapse behavior. This study assessed the effects of the orexin-1 receptor antagonist, SB-334867, on alcohol-seeking behavior and responding for alcohol under relapse conditions. Adult alcohol-preferring (P) rats self-trained in 2-lever operant chambers to administer 15% EtOH (vol/vol) on a fixed-ratio-5 and water on a fixed-ratio-1 schedule of reinforcement. After 10 weeks, rats underwent extinction training for 7 sessions. Animals were then maintained in their home cages for 2 weeks before being tested for Pavlovian Spontaneous Recovery (PSR; a measure of alcohol seeking) for 4 sessions. Rats were then allowed a week in their home cages before being returned to the operant chamber with access to EtOH and water (relapse). Thirty minutes before the PSR and relapse test sessions, rats received 0, 10, or 20 mg/kg SB-334867. Responses on the EtOH lever during the 1st PSR test session were ~70 presses/session (3-fold higher than baseline); SB-334867 did not alter responses on the EtOH lever. Under relapse conditions, P rats increased responding on the EtOH lever from 250 (at baseline) to 350 responses/session; both doses of SD-334867 prevented this increase. The results of this study suggest that activation of orexin-1 receptors is not involved in intrinsically initiated EtOH seeking, but may regulate the consummatory behavior of EtOH consumption.

Effects of the mGlu2/3 Agonist LY379268 and the mGlu5 Antagonist MTEP on Ethanol Seeking and Reinforcement Are Differentially Altered in Rats with a History of Ethanol Dependence

Growing evidence supports a role of metabotropic glutamate receptors (mGluRs) in ethanol reinforcement, ethanol seeking, and ethanol withdrawal. To extend the understanding of the role of mGluRs in the addiction-relevant effects of ethanol as well as of the treatment target potential of these receptors for alcohol abuse, the effects of a selective mGlu2/3 agonist (LY379268) and a selective mGlu5 antagonist (MTEP) were tested on two processes central to alcohol addiction: ethanol reinforcement and stress-induced reinstatement of ethanol seeking in rats with a history of ethanol dependence. Following operant ethanol self-administration training, male Wistar rats were made dependent by intragastric ethanol intubations. Ethanol dependence was confirmed by the presence of somatic withdrawal signs. Following 2 weeks of withdrawal, stable ethanol self-administration was reestablished, and the effects of LY379268 (0-3 mg/kg subcutaneous) and MTEP (0-3 mg/kg, intraperitoneal) on ethanol self-administration were determined in both nondependent and postdependent rats. A second set of rats underwent extinction training and then was tested for the effects of LY379268 or MTEP on reinstatement of ethanol seeking induced by footshock stress. LY379268 and MTEP dose-dependently reduced both ethanol self-administration and reinstatement of ethanol seeking induced by footshock stress. Additionally, LY379268 was more effective than MTEP in inhibiting both behaviors in postdependent than in nondependent animals. These findings suggest that neuroadaptation associated with chronic ethanol exposure or withdrawal alters the sensitivity of mGlu2/3 receptors, with implications for the understanding of the neural basis of alcohol dependence and the treatment target potential of these receptors.

Ethanol seeking triggered by environmental context is attenuated by blocking dopamine D1 receptors in the nucleus accumbens core and shell in rats

RationaleConditioned behavioral responses to discrete drug-associated cues can be modulated by the environmental context in which those cues are experienced, a process that may facilitate relapse in humans. Rodent models of drug self-administration have been adapted to reveal the capacity of contexts to trigger drug seeking, thereby enabling neurobiological investigations of this effect.ObjectivesWe tested the hypothesis that dopamine transmission in the nucleus accumbens, a neural structure that mediates reinforcement, is necessary for context-induced reinstatement of responding for ethanol-associated cues.MethodsRats pressed one lever (active) for oral ethanol (0.1 ml; 10% v/v) in operant conditioning chambers distinguished by specific visual, olfactory, and tactile contextual stimuli. Ethanol delivery was paired with a discrete (4 s) light-noise stimulus. Responses on a second lever (inactive) were not reinforced. Behavior was then extinguished by withholding ethanol but not the discrete stimulus in a different context. Reinstatement, expressed as elevated responding for the discrete stimulus without ethanol delivery, was tested by placing rats into the prior self-administration context after administration of saline or the dopamine D1 receptor antagonist, SCH 23390 (0.006, 0.06, and 0.6 μg/side), into the nucleus accumbens core or shell.ResultsCompared with extinction responding, active lever pressing in saline-pretreated rats was enhanced by placement into the prior ethanol self-administration context. SCH 23390 dose-dependently reduced reinstatement after infusion into the core or shell.ConclusionThese findings suggest a critical role for dopamine acting via D1 receptors in the nucleus accumbens in the reinstatement of responding for ethanol cues triggered by placement into an ethanol-associated context.

Agonism of the endocannabinoid system modulates binge-like alcohol intake in male C57BL/6J mice: involvement of the posterior ventral tegmental area

Recent studies have indicated a role for the endocannabinoid system in the behavioral and physiological effects of alcohol (ethanol), particularly ethanol seeking behaviors. However, its role in modulating binge-like intake and/or the mechanism by which it may exert these effects remain poorly understood. The current study used a newly developed strain-specific animal model of binge drinking, dubbed ‘Drinking In the Dark’ (DID), to determine if facilitation of the endocannabinoid system with the synthetic cannabinoid agonist WIN 55-212,2 (WIN) modulates binge-like ethanol intake in male C57BL/6J (B6) mice. Based on the results of these systemic (i.p.) manipulations, and evidence in support of the involvement of subregions of the Ventral Tegmental Area (VTA) in governing self-administration of ethanol ( Rodd-Henricks et al., (2000) Psychopharmacology (Berl) 149(3):217–224) as well as binge-like intake using the DID model (Moore & Boehm, (2009 Behav Neurosci 123(3):555–563), we extended these findings to evaluate the role of the endocannabinoid system within the anterior and posterior sub regions of the VTA using site-specific microinjections. Consistent with previous research, the lowest systemic dose of WIN (0.5 mg/kg) significantly increased ethanol intake in the first 30 minutes of access whereas the two highest doses (1 and 2 mg/kg) decreased ethanol intake within this time interval. Intra-posterior ventral tegmental area (pVTA) (but not aVTA (anterior ventral tegmental area) microinjections elicited time-dependent and dose-dependent increases (0.25 and 0.5 μg/side) and decreases (2.5 μg/side) in ethanol intake. Importantly, follow-up studies revealed that in some cases alterations in fluid consumption may have been influenced by competing locomotor activity (or inactivity). The present data are consistent with previous research in that agonism of the endocannabinoid system increases ethanol intake in rodents and implicate the pVTA in the modulation of drinking to intoxication. Moreover, the dose-dependent alterations in locomotor activity emphasize the importance of directly assessing multiple (possibly competing) behaviors when evaluating drug effects on voluntary consumption.

Persistent Increase of Alcohol-Seeking Evoked by Neuropeptide S: an Effect Mediated by the Hypothalamic Hypocretin System

The association of ethanol's reinforcing effects with specific environmental stimuli is thought to be a critical factor for relapse risk in alcoholism. This study examined in rats the effects of a newly deorphanized neuropeptide receptor and its cognate ligand, Neuropeptide S (NPS), on ethanol consumption and reinstatement of ethanol-seeking by environmental cues previously associated with ethanol availability. In the self-administration experiments, the stable response rates observed for ethanol reinforcement were not modified by intracerebroventricular (ICV) injection of NPS (1.0 and 2.0 nmol per rat). In the reinstatement experiments, ethanol-associated cues induced robust rates of ethanol seeking, which were highly resistant to extinction over repeated sessions of reinstatement testing. ICV NPS treatment (1.0, 2.0 and 4.0 nmol per rat) resulted in a significant increase of ethanol seeking elicited by ethanol-associated cues. In contrast, NPS did not affect the reinstatement of responding to water-paired stimuli. Site-specific NPS injection (0.1 and 0.5 nmol per rat) into the lateral hypothalamus also reinstated extinguished responding to ethanol. This effect was selectively blocked by pre-treatment with the hypocretin-1/orexin-A antagonist SB-334867 (10 mg/kg, i.p.). At the dose tested, SB-334867 did not modify alcohol reinstatement per se. These results provide the first demonstration that activation of NPS receptors in the LH intensifies relapse to ethanol-seeking elicited by environmental conditioning factors. This effect is selective, and is mediated by activation of LH hypocretin neurones. Based on the present findings, we also predict that antagonism at NPS receptors could represent a novel pharmacological approach to alcohol relapse treatment.

PRECLINICAL STUDY: Conditioned cues and yohimbine induce reinstatement of beer and near‐beer seeking in Long‐Evans rats

Alcohol use disorders (AUDs) impact millions of individuals, yet there are few effective treatments. One major problem in treating AUDs is the high rate of relapse to drinking often induced by stress and/or anxiety states. Although beer accounts for over 81% of all alcohol consumed in hazardous amounts in the United States, the use of beer in pre-clinical research has been limited. It has been shown that rats will self-administer beer and near-beer using a standard operant self-administration paradigm; however, there have been few studies examining reinstatement of beer and near-beer seeking. We have determined that reward-associated cues and/or yohimbine will induce reinstatement of beer and near-beer seeking in a similar manner to that seen for 10% ethanol and sucrose seeking using standard operant self-administration and reinstatement paradigms. We show that rats will self-administer beer, near-beer and 4.5% ethanol using an operant self-administration paradigm and both conditioned cues, and yohimbine will induce reinstatement of beer, near-beer and 4.5% ethanol seeking in previously extinguished animals. This demonstrates that both environmental cues and yohimbine-stress will reinstate beer and near-beer seeking, as previously shown for both 10% ethanol and sucrose seeking.

Early Social Isolation in Male Long‐Evans Rats Alters Both Appetitive and Consummatory Behaviors Expressed During Operant Ethanol Self‐Administration

Postweaning social isolation in rats produces profound and long-lasting cognitive and behavioral deficits in adult animals. Importantly, this housing manipulation alters sensitivity to a number of drugs of abuse including ethanol. However, most studies with ethanol have utilized continuous or limited home-cage access to examine interactions between juvenile social experience and drinking. More recently, social isolation was shown to increased ethanol responding in a "dipper" model of self-administration (Deehan et al., 2007). In the current study, we utilize a "sipper" operant self-administration model to distinguish the effects of isolation rearing on ethanol seeking- and drinking-related behaviors. Postweaning juvenile male Long-Evans rats were placed into 2 housing groups for 6 weeks: one group consisted of individually housed animals; the second group was housed 4 animals per cage. Following the isolation period, anxiety-like behavior was assessed to confirm the efficacy of the isolation procedure. In some animals, ethanol drinking in the home cage was assessed using a continuous access, 2-bottle choice paradigm. All animals were then individually housed and trained to lever-press for a sipper tube containing either an ethanol solution or a sucrose solution. Postweaning social isolation increased the expression of anxiety-like behavior in the elevated plus maze but not the light-dark box. Ethanol consumption was also increased during continuous home-cage access with the 2-bottle choice paradigm. During operant self-administration, isolation housing increased the response rate and increased ethanol consumption but did not alter responding for or consumption of sucrose. The housing manipulation did not change the total number of lever responses during extinction sessions. Paired-pulse inhibition deficits that are characteristic of juvenile isolation remained intact after prolonged experience with sucrose self-administration. The effects of postweaning social isolation on ethanol drinking in the home cage are also manifest during operant self-administration. Importantly, these alterations in adult operant self-administration are ethanol-specific.

Acamprosate and naltrexone treatment effects on ethanol and sucrose seeking and intake in ethanol-dependent and nondependent rats

Two pharmacotherapies are approved for treating alcohol craving (acamprosate and naltrexone), but both have shown mixed findings in animals and humans. The present experiments utilized a "reinforcer blocking" approach (i.e., rats were able to consume ethanol during treatment) to better understand the efficacy of these treatments for ethanol seeking and drinking using ethanol-dependent and nondependent rats. In "nondependent" experiments, drugs (acamprosate 50, 100, and 200 mg/kg; naltrexone 0.1, 0.3, and 1.0 mg/kg) were administered over 3-week periods prior to operant sessions with a low response requirement to gain access to reinforcers for 20 min. For "dependent" experiments, rats were made dependent in vapor/inhalation chambers. Acamprosate and naltrexone had similar effects on intake in nondependent and dependent rats; neither drug was selective for ethanol over sucrose drinking. In nondependent animals, naltrexone was more efficacious at more doses than acamprosate, and acamprosate's effects were limited to a dose that also had adverse effects on body weight. Both pharmacotherapies showed more selectivity when examining reinforcer seeking. In nondependent rats, acamprosate and naltrexone had response-attenuating effects in ethanol, but not sucrose, groups. In dependent animals, acamprosate had selective effects limited to a decrease in sucrose seeking. Naltrexone, however, selectively decreased ethanol-seeking in nondependent rats. The naltrexone-induced decreases in seeking suggested a change in incentive motivation which was selective for ethanol in nondependent rats. The "nondependent" paradigm may model early stages of "problem drinking" in humans, and the findings suggest that naltrexone could be a good intervention for this level of alcohol abuse and relapse prevention.

A Blocker of N- and T-type Voltage-Gated Calcium Channels Attenuates Ethanol-Induced Intoxication, Place Preference, Self-Administration, and Reinstatement

There is a clear need for new therapeutics to treat alcoholism. Here, we test our hypothesis that selective inhibitors of neuronal calcium channels will reduce ethanol consumption and intoxication, based on our previous studies using knock-out mice and cell culture systems. We demonstrate that pretreatment with the novel mixed N-type and T-type calcium channel antagonist 1-(6,6-bis(4-fluorophenyl)hexyl)-4-(3,4,5-trimethoxybenzyl)piperazine (NP078585) reduced ethanol intoxication. NP078585 also attenuated the reinforcing and rewarding properties of ethanol, measured by operant self-administration and the expression of an ethanol conditioned place preference, and abolished stress-induced reinstatement of ethanol seeking. NP078585 did not affect alcohol responses in mice lacking N-type calcium channels. These results suggest that selective calcium channel inhibitors may be useful in reducing acute ethanol intoxication and alcohol consumption by human alcoholics.

Nucleus accumbens AGS3 expression drives ethanol seeking through Gβγ

Approximately 90% of alcoholics relapse within 4 years, in part because of an enhanced motivation to seek alcohol (EtOH). A novel G protein modulator (Gpsm1/AGS3) was up-regulated in the rat nucleus accumbens core (NAcore) but not in other limbic nuclei during abstinence from operant EtOH self-administration. Furthermore, NAcore AGS3 knockdown reduced EtOH seeking to pre-abstinence levels in a novel rat model of compulsive, human EtOH seeking. AGS3 can both inhibit G protein G i alpha-mediated signaling and stimulate G betagamma-mediated signaling. Accordingly, sequestration of G betagamma, but not G i alpha knockdown, significantly reduced EtOH seeking to pre-abstinence levels. Thus, AGS3 and G betagamma are hypothesized to gate the uncontrolled motivation to seek EtOH during abstinence. AGS3 up-regulation during abstinence may be a key determinant of the transition from social consumption to compulsion-like seeking during relapse.

Wheel running, voluntary ethanol consumption, and hedonic substitution

Few studies have examined the relationship between naturally rewarding behaviors and ethanol drinking behaviors in mice. Although natural and drug reinforcers activate similar brain circuitry, there is behavioral evidence suggesting food and drug rewards differ in perceived value. The primary goal of the present study was to investigate the relationships between naturally reinforcing stimuli and consumption of ethanol in ethanol preferring C57BL/6J mice. Mouse behaviors were observed after the following environmental manipulations: standard or enhanced environment, accessible or inaccessible wheel, and presence or absence of ethanol. Using a high-resolution volumetric drinking monitor and wheel running monitor, we evaluated whether alternating access to wheel running modified ethanol-related behaviors and whether alternating access to ethanol modified wheel running or subsequent ethanol-related behaviors. We found that ethanol consumption remains stable with alternating periods of wheel running. Wheel running increases in the absence of ethanol and decreases upon reintroduction of ethanol. Upon reintroduction of ethanol, an alcohol deprivation effect was seen. Collectively, the results support theories of hedonic substitution and suggest that female C57BL/6J mice express ethanol seeking and craving under these specific conditions.

Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long–Evans rats

RationalePrevious studies have shown that orexin-1/hypocretin-1 receptors play a role in self-administration and cue-induced reinstatement of food, drug, and ethanol seeking. In the current study, we examined the role of orexin-1/hypocretin-1 receptors in operant self-administration of ethanol and sucrose and in yohimbine-induced reinstatement of ethanol and sucrose seeking.Materials and methodsRats were trained to self-administer either 10% ethanol or 5% sucrose (30 min/day). The orexin-1 receptor antagonist SB334867 (0, 5, 10, 15, 20 mg/kg, i.p.) was administered 30 min before the operant self-administration sessions. After these experiments, the operant self-administration behaviors were extinguished in both the ethanol and sucrose-trained rats. Upon reaching extinction criteria, SB334867 (0, 5, 10 mg/kg, i.p.) was administered 30 min before yohimbine (0 or 2 mg/kg, i.p.). In a separate experiment, the effect of SB334867 (0, 15, or 20 mg/kg, i.p.) on general locomotor activity was determined using the open-field test.ResultsThe orexin-1 receptor antagonist, SB334867 (10, 15 and 20 mg/kg) decreased operant self-administration of 10% ethanol but not 5% sucrose self-administration. Furthermore, SB334867 (5 and 10 mg/kg) significantly decreased yohimbine-induced reinstatement of both ethanol and sucrose seeking. SB334867 did not significantly affect locomotor activity measured using the open-field test.ConclusionsThe results suggest that inhibition of OX-1/Hcrt-1 receptors modulates operant ethanol self-administration and also plays a significant role in yohimbine-induced reinstatement of both ethanol and sucrose seeking in rats.

Involvement of brain catalase activity in the acquisition of ethanol-induced conditioned place preference

It has been suggested that some of the behavioral effects produced by ethanol are mediated by its first metabolite, acetaldehyde. The present research addressed the hypothesis that catalase-dependent metabolism of ethanol to acetaldehyde in the brain is an important step in the production of ethanol-related affective properties. Firstly, we investigated the contribution of brain catalase in the acquisition of ethanol-induced conditioned place preference (CPP). Secondly, the specificity of the catalase inhibitor 3-amino-1,2,4-triazole (AT) was evaluated with morphine- and cocaine-induced CPP. Finally, to investigate the role of catalase in the process of relapse to ethanol seeking caused by re-exposure to ethanol, after an initial conditioning and extinction, mice were primed with saline and ethanol or AT and ethanol and tested for reinstatement of CPP. Conditioned place preference was blocked in animals treated with AT and ethanol. Morphine and cocaine CPP were unaffected by AT treatment. However, the reinstatement of place preference was not modified by catalase inhibition. Taken together, the results of the present study indicate that the brain catalase-H 2O 2 system contributes to the acquisition of affective-dependent learning induced by ethanol, and support the involvement of centrally-formed acetaldehyde in the formation of positive affective memories produced by ethanol.

Goal- and signal-directed incentive: conditioned approach, seeking, and consumption established with unsweetened alcohol in rats

Many theories of addictive behavior propose that cues signaling drug administration influence the likelihood of drug-taking and drug-seeking behavior. We investigated the behavioral impact of cues associated with unsweetened ethanol and their interaction with responding maintained by ethanol self-administration. Our goal was to establish the influence of such cues on ethanol seeking. The experiment used a matching contingency and saccharin-fading procedure to establish equal levels of responding to two spatially distinct levers using unsweetened 10% ethanol solution. After ethanol self-administration was established, a brief cue light located alternately over each lever location was either paired or unpaired (control) with the opportunity to consume the same ethanol solution. Finally, self-administration was re-established, and the effect of the cue was measured in a transfer design. The reaction to lights paired with the opportunity to ingest unsweetened ethanol had three main effects: (1) induction of operant behavior reinforced by ethanol, (2) stimulation of ethanol-seeking behavior (drinker entries), and (3) cue-directed approach and contact behavior (i.e. autoshaping or sign-tracking). Cue-directed behavior to the light interacted with choice behavior in a manner predicted by the location of the cue light, enhancing responding only when the approach response did not interfere with the operant response. These findings replicate and extend the effects of Pavlovian conditioning on ethanol-seeking and support-conditioned incentive theories of addictive behavior. Signals for ethanol influence spatial choice behavior and may be relevant to attentional bias shown to alcohol-associated stimuli in humans.

Alcohol Relapse Induced by Discrete Cues Activates Components of AP-1 Transcription Factor and ERK Pathway in the Rat Basolateral and Central Amygdala

Alcohol-related cues may induce relapse to heavy alcohol drinking and promote molecular adaptations in discrete brain regions. An exact nature of these molecular alterations is still unknown. In the present study, rats trained to self-administer ethanol were tested for cue-induced reinstatement of ethanol seeking after 30 days of abstinence. Next, a detailed immunocytochemical analysis of c-Fos activation was performed within seven nuclei of the amygdala. In the second experiment, c-Fos activation after reinstatement of ethanol seeking induced by discrete cues was compared with the activation pattern of its putative partner (c-Jun) and regulators (extracellular signal-regulated kinases and c-Jun N-terminal kinases). Reexposure to ethanol-associated context cues (an extinction session) potentiated c-Fos expression within the basolateral and central amygdala. Repeated presentation of ethanol-associated discrete cues in an extinction/reinstatement session led to even stronger c-Fos activation in the latter nuclei. In the second experiment, reexposure to the ethanol-associated context and discrete cues activated both c-Jun and extracellular signal-regulated kinases (ERK1/2) in the basolateral amygdala. Our observations suggest that the basolateral and central amygdala may be specifically involved in alcohol-seeking behavior induced by discrete cues.

Role of cannabinoidergic mechanisms in ethanol self-administration and ethanol seeking in rat adult offspring following perinatal exposure to Δ 9-tetrahydrocannabinol

The present study evaluated the consequences of perinatal Δ 9-tetrahydrocannabinol (Δ 9-THC) treatment (5 mg/kg/day by gavage), either alone or combined with ethanol (3% v/v as the only fluid available), on ethanol self-administration and alcohol-seeking behavior in rat adult offspring. Furthermore, the effect of the selective cannabinoid CB 1 receptor antagonist, SR-141716A, on ethanol self-administration and on reinstatement of ethanol-seeking behavior induced either by stress or conditioned drug-paired cues was evaluated in adult offspring of rats exposed to the same perinatal treatment. Lastly, microarray experiments were conducted to evaluate if perinatal treatment with Δ 9-tetrahydrocannabinol, ethanol or their combination causes long-term changes in brain gene expression profile in rats. The results of microarray data analysis showed that 139, 112 and 170 genes were differentially expressed in the EtOH, Δ 9-THC, or EtOH + Δ 9-THC group, respectively. No differences in alcohol self-administration and alcohol seeking were observed between rat groups. Intraperitoneal (IP) administration of SR-141716A (0.3–3.0 mg/kg) significantly reduced lever pressing for ethanol and blocked conditioned reinstatement of alcohol seeking. At the same doses SR-141716A failed to block foot-shock stress-induced reinstatement of alcohol seeking. The results reveal that perinatal exposure to Δ 9-THC ethanol or their combination results in evident changes in gene expression patterns. However, these treatments do not significantly affect vulnerability to ethanol abuse in adult offspring. On the other hand, the results obtained with SR-141716A emphasize that endocannabinoid mechanisms play a major role in ethanol self-administration, as well as in the reinstatement of ethanol-seeking behavior induced by conditioned cues, supporting the idea that cannabinoid CB 1 receptor antagonists may represent interesting agents for the pharmacotherapy of alcoholism.

Ethanol‐Associated Cues Produce General Pavlovian‐Instrumental Transfer

Conditioned stimuli are thought to play an important role in maintaining ethanol use and inducing relapse. Therefore, understanding the mechanisms through which such stimuli trigger ethanol seeking is of interest in the study and treatment of alcoholism. This series of experiments examined the impact of ethanol-associated cues on ethanol-seeking behavior using a Pavlovian-instrumental transfer design. Rats received Pavlovian training in which an auditory stimulus predicted ethanol (10%) delivery. In a separate instrumental training phase, animals were trained to press a lever for ethanol. In the test phase, the impact of the stimulus on instrumental performance was assessed in extinction by presenting the stimulus while animals were free to perform the lever-press response. Experiment 2 assessed the selectivity of the transfer effect; rats received training with 2 auditory stimuli which predicted either ethanol or sucrose (2%) delivery and were trained to perform 2 instrumental responses, one earning ethanol and the other earning sucrose. Finally, Experiment 3 examined the selectivity of PIT using 2 natural rewards (sucrose and polycose). The results from Experiment 1 show that ethanol supports excitatory conditioning and that ethanol-associated cues facilitate instrumental performance for ethanol. When the selectivity of the transfer effect was examined in Experiment 2, the ethanol-paired stimulus was found to have a general excitatory effect on reward-seeking behavior, affecting both ethanol-directed and sucrose-directed responding equally. In contrast, the sucrose-paired stimulus had a selective effect, elevating sucrose-directed responding only. Experiment 3 confirms that selective transfer is observed when 2 natural rewards are used to reinforce responding. These data provide further evidence that ethanol-associated cues can drive ethanol-seeking behaviors. Because ethanol-associated cues also enhanced seeking behavior for a nonalcohol reward, these results additionally suggest that the modulation of reward-directed behaviors by cues associated with ethanol versus natural rewards may rely on different behavioral and neural mechanisms.

Allopregnanolone influences the consummatory processes that govern ethanol drinking in C57BL/6J mice

Although systemic allopregnanolone (ALLO; a positive modulator of GABA A receptors) has been shown to enhance ethanol-reinforced responding and to modulate drinking patterns in rodents, the effects of centrally administered ALLO on ethanol intake are not known. The current work examined the effects of intracranial ALLO on operant ethanol self-administration in food- and water-satiated mice, with a procedure designed to estimate ALLO's influence on appetitive versus consummatory processes. Male C57BL/6J (B6) mice were trained to press an ethanol-appropriate lever by being reinforced with 30-min of continuous access to a 10% ethanol solution. Following surgical implantation of a guide cannula aimed at the lateral ventricle and subsequent habituation to vehicle infusions, ALLO (50–400 ng; ICV) was delivered immediately prior to session start. ALLO doses of 100 and 400 ng were further evaluated for their effects on locomotor behavior within activity chambers. ALLO selectively modulated ethanol intake patterns associated with the onset and maintenance of self-administration, while leaving appetitive (i.e., ethanol seeking) measures unaltered. The effects of ALLO on drinking patterns were dissociable from changes in locomotor behavior, as evidenced by the absence of ALLO's influence on response frequency and horizontal distance traveled. These findings support the premise that manipulations in brain ALLO levels may influence the regulatory processes governing ethanol consumption.

Cue-induced reinstatement of ethanol seeking in Sardinian alcohol-preferring rats

The purpose of the present study was to characterize cue-induced reinstatement of ethanol seeking in selectively bred Sardinian alcohol-preferring (sP) rats trained to lever press for ethanol in 30-min self-administration sessions. Four responses on an “active” lever led to presentation of 0.1ml of 15% (vol/vol) ethanol by a liquid dipper and concurrent activation of a set of discrete light and auditory cues. In a 70-min extinction/reinstatement session, responding was first extinguished for 60min. Subsequently, different stimuli were delivered in a noncontingent manner and reinstatement of nonreinforced responding was assessed. Fifteen presentations of the ethanol-predictive stimulus complex, including the dipper cup containing 5 or 15% ethanol, potently reinstated responding on the previously active lever. The magnitude of reinstatement increased with the number of stimulus presentations and concentration of ethanol presented by the dipper cup. Fifteen presentations of the ethanol-predictive stimulus complex, including the dipper cup filled with water (0% ethanol), did not produce any reinstatement. These results indicate that (1) noncontingent presentations of the ethanol-predictive stimulus complex may reinstate ethanol seeking in sP rats and (2) the orosensory properties of ethanol may play an important role in reinstatement of ethanol seeking in sP rats. The latter finding concurs with clinical observations that odor and taste of alcoholic beverages elicit immediate craving responses in abstinent alcoholics.