Neural basis of cognitive control signals in anterior cingulate cortex during delay discounting.

Cognitive control involves allocating cognitive effort according to internal needs and task demands and the Anterior Cingulate Cortex (ACC) is hypothesized to play a central role in this process. We investigated the neural basis of cognitive control in the ACC of rats performing an adjusting-amount delay discounting task. Decision-making in this this task can be guided by using either a lever-value tracking strategy, requiring a 'resource-based' form of cognitive effort or a lever-biased strategy requiring a 'resistance-based' form of cognitive effort. We found that ACC ensembles always tightly tracked lever value on each trial, indicative of a resource-based control signal. These signals were prevalent in the neural recordings and were influenced by the delay. A shorter delay was associated with devaluing of the immediate option and a longer delay was associated with overvaluing of the immediate option. In addition, ACC theta (6-12Hz) oscillations were observed at the choice point of rats exhibiting a resistance-based strategy. These data provide candidates of neural activity patterns in the ACC that underlie the use of 'resource-based' and 'resistance-based' cognitive effort. Furthermore, these data illustrate how strategies can be engaged under different conditions in individual subjects.

Flexible coding schemes in dorsomedial prefrontal cortex underlie decision-making during delay discounting.

Determining how an agent decides between a small, immediate versus a larger, delayed reward has provided insight into the psychological and neural basis of decision-making. The tendency to excessively discount the value of delayed rewards is thought to reflect deficits in brain regions critical for impulse control such as the prefrontal cortex (PFC). This study tested the hypothesis that dorsomedial PFC (dmPFC) is critically involved in flexibly managing neural representations of strategies that limit impulsive choices. Optogenetic silencing of neurons in the rat dmPFC increased impulsive choices at an 8 sec, but not 4 sec, delay. Neural recordings from dmPFC ensembles revealed that, at the 8-sec delay, the encoding landscape transitions to reflect a deliberative-like process rather than the schema-like processes observed at the 4-sec delay. These findings show that changes in the encoding landscape reflect changes in task demands and that dmPFC is uniquely involved in decisions requiring deliberation.

A critical review of front-loading: A maladaptive drinking pattern driven by alcohol's rewarding effects.

Front-loading is a drinking pattern in which alcohol intake is skewed toward the onset of reward access. This phenomenon has been reported across several different alcohol self-administration protocols in a wide variety of species, including humans. The hypothesis of the current review is that front-loading emerges in response to the rewarding effects of alcohol and can be used to measure the motivation to consume alcohol. Alternative or additional hypotheses that we consider and contrast with the main hypothesis are that: (1) front-loading is directed at overcoming behavioral and/or metabolic tolerance and (2) front-loading is driven by negative reinforcement. Evidence for each of these explanations is reviewed. We also consider how front-loading has been evaluated statistically in previous research and make recommendations for defining this intake pattern in future studies. Because front-loading may predict long-term maladaptive alcohol drinking patterns leading to the development of alcohol use disorder (AUD), several future directions are proposed to elucidate the relationship between front-loading and AUD.

Evaluating habit formation across pairs of female and male selectively bred alcohol-preferring and non-preferring rats.

Some individuals with alcohol use disorder (AUD) continue to drink because they have developed a habit where they do not consider the consequences of their actions. Genetically selected lines of alcohol-preferring and non-preferring rats allow for exploration of how specific endophenotypes, such as tendency to form habits, may be risk factors that interact with a genetic predisposition of AUD. While high alcohol drinking (HAD) and alcohol-preferring (P) rats were selectively bred to consume high amounts of freely available ethanol, they exhibit differences in alcohol-seeking behaviors as well as impulsive behaviors, and may represent different behavioral models of AUD. The goal of the current study was to compare the tendency to develop habitual behaviors across female and male HAD1, HAD2, and P rats and their respective alcohol non-preferring counterparts. Alcohol-naïve rats were trained on a variable interval schedule using a non-ethanol reinforcer and were then tested in two extinction sessions, one prior to a reinforcer devaluation (conditioned taste aversion) procedure and one after. There were no differences in total lever presses between P and alcohol non-preferring (NP) rats, but there were differences between HAD and low-alcohol drinking (LAD) rats. All six strains decreased lever pressing after reinforcer devaluation. However, P and NP females did not increase latency to first lever press after devaluation, suggesting some inclination toward habitual behavior that was not apparent in either the HAD or LAD lines. Selective breeding for alcohol preference does not seem to influence the tendency to form habits, whereas background strain and sex may have an influence on this behavior.

Differential effects of quinine adulteration of alcohol on seeking and drinking.

Alcohol dependence is characterized by compulsive alcohol use. Alcohol-paired stimuli can drive compulsive alcohol use, induce craving, and lead to relapse. Alcohol dependence is highly heritable, and individuals with a family history are at elevated risk to develop an alcohol use disorder. Understanding the association between genetic vulnerability to alcohol dependence and neural alterations that promote an addiction phenotype are critical to the prevention and treatment of alcohol dependence. Here we use selectively bred alcohol-preferring P rats and their progenitor strain, Wistar rats, to investigate the relationship between genetic liability and alcohol-seeking and drinking behaviors in a discriminative stimuli paradigm. To further investigate strain differences in motivated responding, alcohol was adulterated with quinine, and intake and responding were assessed. While both strains learned to discriminate between stimuli that predicted alcohol availability, P rats learned faster and consumed more alcohol. Quinine adulteration reduced ethanol intake in both strains with no effect on ethanol-seeking measures. These data suggest genetic vulnerability to alcohol dependence is associated with increased motivated behaviors and highlight the utility of P rats in teasing apart the neural mechanisms associated with this phenotype. Additionally, these data suggest a dissociation between the neural systems that engage ethanol drinking versus compulsive ethanol seeking.

Differential COMT expression and behavioral effects of COMT inhibition in male and female Wistar and alcohol preferring rats.

Polymorphisms of the catechol-O-methyl transferase (COMT) gene have been associated with alcoholism, suggesting that alterations in the metabolism of catecholamines may be a critical component of the neuropathology of alcoholism. In the current experiments, the COMT inhibitor tolcapone was utilized in an operant behavioral model of reinforcer-seeking and drinking to determine if this compound was capable of remediating the excessive seeking and drinking phenotype of the alcohol-preferring P rat. Tolcapone was administered to male and female alcohol-reinforced P and Wistar rats. Additionally, tolcapone was administered to male sucrose-reinforced P and Wistar rats to determine if its effects also extended to a natural reinforcer. Animals were trained to make an operant response that resulted in 20 min uninterrupted access to the reinforcer solutions. Tolcapone had no effect in female rats on either seeking or consumption of ethanol. However, reductions of both reinforcer seeking and consumption were observed in male P rats, but only of seeking in Wistars. In separate experiments, using reinforcer naïve male and female animals, COMT expression was assessed via Western Blot analysis. Sex differences in COMT expression were also observed, where male P rats exhibited a marked reduction in protein expression relative to females in the PFC. Sex differences were not observed for Wistars or in the striatum and hippocampus. These data complement our previous findings in which tolcapone reduced cue-evoked responses in P rats and further suggest clinical utility of COMT inhibitors in the treatment of addiction disorders, specifically in male high drinkers.

Effects of group II metabotropic glutamate receptor modulation on ethanol- and sucrose-seeking and consumption in the rat.

Previous studies suggest that group II metabotropic glutamate receptors (mGluR2/3) are involved in regulating ethanol-seeking and consumption. The mGluR2/3 agonist LY379268 (LY37) and selective mGluR2 positive allosteric modulator biphenyl­indanone A (BINA) were used to investigate the relative contribution of mGlu2 and mGlu3 receptors on ethanol- and sucrose-seeking and consumption. A microinjection study was then performed to examine the role of nucleus accumbens (NAc) core mGluR2/3 on ethanol-seeking. For the systemic experiments, separate groups of male Wistar rats [LY37 (0-2.0 mg/kg); BINA (0-20 mg/kg)] were trained to complete a response requirement (RR) resulting in access to 10% ethanol or 2% sucrose (in separate groups) for a 20­min drinking period. Animals then underwent consummatory testing (weekly drug injections with RR1) followed by appetitive testing (weekly drug injections followed by extinction session). A separate group of male Wistar rats was surgically implanted with bilateral guide cannulae directed toward the NAc core and had weekly microinjections followed by an extinction session. Systemic administration of the mGluR2/3 agonist LY37 significantly reduced ethanol- and sucrose-seeking. The same treatment also reduced sucrose consumption and body weight (24­h post injection). Systemic administration of the selective mGluR2 PAM BINA, however, had no effect on either seeking or consumption of ethanol or sucrose. Intra-accumbens core LY37 significantly reduced ethanol-seeking. These findings suggest that systemic mGluR2/3 agonism, but not allosteric modulation of mGluR2, reduces reinforcer-seeking. In particular, NAc core group II mGluR may be involved in regulating ethanol-seeking.

The Effects of Long-Term Varenicline Administration on Ethanol and Sucrose Seeking and Self-Administration in Male P Rats.

BACKGROUND: Varenicline, a partial agonist at α4ß2 and full agonist at α7 nicotinic cholinergic receptors, is FDA-approved for treatment of smoking cessation and has been found to reduce alcohol craving in clinical populations. In rodents, varenicline decreases free-choice ethanol (EtOH) intake with somewhat mixed findings in operant paradigms that utilize a combined appetitive/consummatory response. METHODS: The present experiment utilized an operant paradigm that procedurally separates appetitive from consummatory responding and a "reward-blocking" approach (i.e., rats were able to consume EtOH during treatment) to better understand the efficacy of varenicline as a treatment for EtOH self-administration and subsequent EtOH seeking. Separate groups of EtOH- and sucrose-reinforced alcohol-preferring, male P rats experienced alternating cycles of vehicle (2-week cycles) and varenicline (0.3, 1.0, and 2.0 mg/kg self-administered in a gelatin preparation) treatment (3-week cycles) prior to daily sessions where a single lever press resulted in 20 minutes of reinforcer access. At the end of each cycle, a single extinction session assessed the seeking response in the absence of drug pretreatment. RESULTS: Varenicline dose dependently decreased EtOH intake. Sucrose intake was largely unaffected, with no overall treatment effects and only sporadic days where the medium and high dose differed from vehicle. Neither sucrose nor EtOH seeking was significantly decreased by varenicline, and there were no treatment effects on either lick or lever-press latency. Overall effect sizes were much greater for both drinking and seeking in the EtOH group as compared to the sucrose group. CONCLUSIONS: Varenicline effectively attenuates EtOH self-administration during treatment, but the experience with EtOH consumption while varenicline is "on board" is not sufficient to alter subsequent EtOH seeking. The overall pattern of findings indicates that varenicline blocks the rewarding properties of EtOH while not substituting for EtOH, that the nonspecific effects on an alternate reinforcer are negligible, and that blood levels of varenicline need to be maintained in order for treatment to remain effective.

Low-dose prazosin alone and in combination with propranolol or naltrexone: effects on ethanol and sucrose seeking and self-administration in the P rat.

RATIONALE: Evidence suggests that the noradrenergic system mediates ethanol reinforcement. However, preclinical studies suggest that noradrenergic antagonists block other oral reinforcers indicating possible unwanted secondary medication effects. METHODS: This study examined combinations of low-dose prazosin with propranolol or naltrexone using a behavioral paradigm that separately assesses reinforcer seeking and self-administration. Male alcohol-preferring (P) rats (n = 20/experiment) were trained to complete a response requirement (RR) resulting in access to 1 % sucrose (n = 10) or 10 % ethanol (n = 10) for 20 min. Rats received vehicle, prazosin alone (0.125, 0.25, 0.5, and 1.0 mg/kg, intraperitoneally (IP)), or prazosin in combination with propranolol (5 mg/kg (IP); Exp. 1) or in combination with naltrexone (0.03 mg/kg, subcutaneously (SC); Exp. 2). RESULTS: For Exp. 1, prazosin alone effectively decreased sucrose seeking more than ethanol seeking, but decreased ethanol self-administration only. Propranolol alone effectively decreased ethanol seeking more than sucrose seeking and decreased ethanol intake only. At some dose combinations, there was a greater attenuation of ethanol and sucrose intake relative to either drug alone. For Exp. 2, prazosin alone and naltrexone alone were effective in decreasing ethanol seeking and intake only. Combination treatment was more effective than either drug alone at decreasing ethanol seeking and consumption and sucrose intake, but not sucrose seeking. CONCLUSIONS: Propranolol and naltrexone alone were specific to ethanol indicating that low doses of either medication may be beneficial in treating alcohol use disorders. Prazosin in combination with propranolol or naltrexone was more effective than either drug alone and also reduced sucrose-reinforced behaviors. These data suggest that the noradrenergic system is a viable target for developing treatment approaches for problem drinkers.

Increased delay discounting tracks with a high ethanol-seeking phenotype and subsequent ethanol seeking but not consumption.

BACKGROUND: Increased levels of delay discounting have been associated with alcoholism and problematic levels of drinking. Attempts to assess the directionality of this relationship by studying individuals with a family history of alcoholism as well as rodent lines selectively bred for high home cage alcohol preference have yielded discordant results. One possible reason for this discordance is that increased levels of delay discounting may only track with specific processes that lead to addiction vulnerability. This study investigated this possibility by assessing 3 strains of rats previously identified to exhibit heritable differences in ethanol (EtOH) seeking and consumption. METHODS: In an adjusting amount delay discounting task, alcohol-preferring (P) rats who display high levels of both EtOH seeking and consumption were compared to high alcohol-drinking (HAD2) rats who only exhibit moderate EtOH seeking despite high levels of consumption, and Long Evans (LE) rats who display moderate seeking and consumption. EtOH-seeking and consumption phenotypes were subsequently confirmed in an operant self-administration task with a procedural separation between EtOH seeking and drinking. RESULTS: P rats discounted delayed rewards to a greater extent than both HAD2s and LE who did not show differences in discounting. Moreover, the EtOH-seeking and drinking phenotypes were replicated with P rats displaying greater EtOH seeking compared to both the HAD2s and LE, and both the HAD2s and P rats consuming more EtOH than LEs. CONCLUSIONS: Only the high-seeking strain, the P rats, exhibited increased levels of delay discounting. This suggests that this measure of behavioral under-control is specifically associated with alcohol-related appetitive, but not consummatory, processes as the moderate seeking/high drinking line did not show increased levels of impulsivity. This finding supports the hypothesis that delay discounting is specifically associated with only certain processes which are sufficient but not necessary to confer addiction vulnerability and therefore also supports increased levels of delay discounting as a predisposing risk factor for alcoholism.

Tolcapone suppresses ethanol intake in alcohol-preferring rats performing a novel cued access protocol.

BACKGROUND: Dopamine (DA) has been shown to play a central role in regulating motivated behavior and encoding reward. Chronic drug abuse elicits a state of hypodopaminergia in the mesocorticolimbic (MCL) system in both humans and preclinical rodent models of addiction, including those modeling alcohol use disorders (AUD). METHODS: Working under the hypothesis that reductions in the bioavailability of DA play an integral role in the expression of the excessive drinking phenotype, the catechol-O-methyltransferase (COMT) inhibitor tolcapone was used as a means to amplify cortical DA concentration and drinking behaviors were then assessed. Sucrose and ethanol (EtOH) consumption were measured in P and Wistar rats in both a free choice drinking protocol and a novel cued access protocol. RESULTS: Tolcapone attenuated the consumption of EtOH, and to a lesser extent sucrose, in P rats in the cued access protocol, while no effect was observed in the free choice drinking protocol. Tolcapone also decreased EtOH consumption in high drinking Wistar rats. A follow-up experiment using the indirect DA agonist d-amphetamine showed no change in EtOH consumption. CONCLUSIONS: Collectively, these data suggest that COMT inhibitors may be capable of alleviating the extremely motivating or salient nature of stimuli associated with alcohol. The hypothesis is put forth that the relative specificity of tolcapone for cortical DA systems may mediate the suppression of the high seeking/drinking phenotype.

Intravenous alcohol self-administration in the P rat.

Alcohol consumption produces a complex array of effects that can be divided into two types: the explicit pharmacological effects of ethanol (which can be temporally separate from time of intake) and the more temporally "relevant" effects (primarily olfactory and taste) that bridge the time from intake to onset of the pharmacological effects. Intravenous (IV) self-administration of ethanol limits the confounding "non-pharmacological" effects associated with oral consumption, allows for controlled and precise dosing, and bypasses first order absorption kinetics, allowing for more direct and better-controlled assessment of alcohol's effect on the brain. IV ethanol self-administration has been reliably demonstrated in mouse and human experimental models; however, models of IV self-administration have been historically problematic in the rat. An operant multiple-schedule study design was used to elucidate the role of each component of a compound IV-ethanol plus oral-sucrose reinforcer. Male alcohol-preferring P rats had free access to both food and water during all IV self-administration sessions. Animals were trained to press a lever for orally delivered 1% sucrose (1S) on a fixed ratio 4 schedule, and then surgically implanted with an indwelling jugular catheter. Animals were then trained to respond on a multiple FR4-FR4 schedule composed of alternating 2.5-min components across 30-min sessions. For the multiple schedule, two components were used: an oral 1S only and an oral 1S plus IV 20% ethanol (25 mg/kg/injection). Average total ethanol intake was 0.47 ± 0.04 g/kg. We found significantly higher earning of sucrose-only reinforcers and greater sucrose-lever error responding relative to the compound oral-sucrose plus IV-ethanol reinforcer. These response patterns suggest that sucrose, not ethanol, was responsible for driving overall responding. The work with a compound IV ethanol-oral sucrose reinforcer presented here suggests that the existing intravenous ethanol self-administration methodology cannot overcome the aversive properties of ethanol via this route in the rat.

Alterations in ethanol seeking and self-administration following yohimbine in selectively bred alcohol-preferring (P) and high alcohol drinking (HAD-2) rats.

Evidence suggests that stress increases alcohol drinking and promotes relapse in humans. Animal models that assess related behaviors include the sipper tube ethanol self-administration and the stress-induced reinstatement paradigms. While selectively bred for the same high-ethanol-drinking behavior, alcohol-preferring P rats appear to show greater sensitivity to ethanol reinforcement than high-alcohol-drinking HAD rats. The present experiment tested the effects of the pharmacological stressor, yohimbine, on the motivation to seek and consume ethanol implementing a combined sipper tube/reinstatement model using male P and HAD-2 rats. Following training to self-administer ethanol using the sipper tube procedure, rats were tested for the effects of yohimbine (0.625-2.5 mg/kg) on ethanol drinking. Subsequently, rats were tested for the effects of 1.25 mg/kg yohimbine on reinstatement of ethanol seeking. Yohimbine (0.625 and 1.25 mg/kg) increased ethanol self-administration, and the latter dose also decreased latency to complete the response requirement. Yohimbine elicited reinstatement of ethanol seeking in both lines. HAD-2 rats drank more ethanol, but showed similar responding on the ethanol-associated lever compared to P rats. These findings extend both the reinstatement and sipper tube models and justify further exploration of this unique combined paradigm. Despite prior evidence suggesting that P rats are more motivated to seek and consume ethanol, differences in these behaviors between P and HAD-2 rats were not systematic in the present experiment. Further investigation may elucidate whether either selected line may be more sensitive than other selectively bred or outbred rats to stress-related changes in ethanol's reinforcing effects.

Behavioral and neurotransmitter specific roles for the ventral tegmental area in reinforcer-seeking and intake.

BACKGROUND: The ventral tegmental area (VTA) is a pivotal relay site within the reinforcement circuit that has been shown to play a role in ethanol (EtOH)-motivated behaviors. The primary dopamine projections within this system originate in the VTA and innervate several areas including the nucleus accumbens (NAc) and prefrontal cortex (PFC), and the PFC has afferent glutamate projections to the VTA and the NAc. The following studies utilized 2 different operant paradigms, one focusing on reinforcer-seeking and the other on reinforcer drinking (both with an EtOH and a sucrose reinforcer solution), to elucidate regulation of these behaviors by the posterior VTA, and the specific roles of dopamine and glutamate in this region. METHODS: The present experiments assessed the effects of microinjections of the glutamate (AMPA/kainate) antagonist CNQX and the dopamine D1-like antagonist SCH23390 in the posterior VTA, as well as transient chemical inactivation of this region using tetrodotoxin (TTX). In 4 separate experiments (2 dopamine, 2 glutamate, both with TTX), male Long Evans rats were trained to complete a single response requirement that resulted in access to 10% EtOH or 2% sucrose for a 20-minute drinking period. RESULTS: Prior to microinjections, EtOH-reinforced subjects were consuming approximately 0.45 to 0.65 g/kg EtOH and making approximately 50 responses during intermittent nonreinforced artificial cerebrospinal fluid sessions (Sucrose groups had similar baseline response levels). Overall, TTX inactivation of the VTA consistently decreased reinforcer-seeking but not intake in all experiments. CNQX also dose-dependently decreased EtOH-seeking, with no significant effect on sucrose-seeking or reinforcer intake. SCH23390 had no significant effects on reinforcer-seeking, and very moderately decreased intake of both EtOH and sucrose. CONCLUSIONS: Inactivation of the posterior VTA implicated this region in reinforcer-seeking as opposed to reinforcer intake. Overall, the present findings provide support for the importance of posterior VTA glutamate activity specifically in EtOH-seeking behavior in animals consuming pharmacologically relevant amounts of EtOH.

Effects of prazosin, an α1-adrenergic receptor antagonist, on the seeking and intake of alcohol and sucrose in alcohol-preferring (P) rats.

BACKGROUND: Previous studies show that prazosin, an α(1) -adrenergic receptor antagonist, decreases alcohol drinking in animal models of alcohol use and dependence [Rasmussen et al. (2009) Alcohol Clin Exp Res 3:264-272; Walker et al. (2008) Alcohol 42:91-97] and in alcohol-dependent men [Simpson et al. (2009) Alcohol Clin Exp Res 33:255-263]. This study extended these findings by using a paradigm that allows for separate assessment of prazosin on motivation to seek versus consume alcohol or sucrose in selectively bred rats. METHODS: Alcohol-preferring (P) rats were trained to complete an operant response that resulted in access to either 2% sucrose or 10% alcohol. A 4-week Seeking Test Phase examined responding in single, weekly extinction sessions when no reinforcer could be obtained. A 4-week Drinking Test Phase consisted of rats lever-pressing to "pay" a specified amount up front to gain access to unlimited alcohol (or sucrose) for a 20-minute period. On Seeking and Drinking test days, prazosin (0.0, 0.5, 1.0, and 1.5 mg/kg) was administered intraperitoneally 30 minutes prior to behavioral sessions. RESULTS: Rats were self-administering an average of 0.9 (±0.09) g/kg alcohol on vehicle test day and had pharmacologically relevant blood ethanol concentrations. Prazosin significantly decreased alcohol seeking at all doses tested. The highest dose of prazosin also increased the latency to first response for alcohol and decreased alcohol intake. While sucrose-seeking and intake were similarly affected by prazosin, the high dose of prazosin did not increase response latency. CONCLUSIONS: These findings are consistent with and extend previous research and suggest that prazosin decreases motivation to initiate and engage in alcohol consumption. The specificity of prazosin in attenuating the initiation of alcohol- but not sucrose-seeking suggests that this effect is not because of prazosin-induced motor-impairment or malaise. Together with previous findings, these data suggest that prazosin may be an effective pharmacotherapy, with specific application in people that drink excessively or have a genetic predisposition to alcohol abuse.

Neuropeptide Y (NPY) in the central nucleus of the amygdala (CeA) does not affect ethanol-reinforced responding in binge-drinking, nondependent rats.

The central nucleus of the amygdala (CeA) has been implicated as having a significant role in mediating alcohol-drinking behavior. Neuropeptide Y (NPY) has been investigated as a potential pharmacotherapeutic due to its ability to attenuate ethanol intake, particularly when administered into the CeA. Previous research suggests, though the evidence is somewhat conflicting, that the efficacy of NPY is contingent upon genetic background and/or prior history of ethanol dependence in rats. However, studies looking at the effects of NPY in nonselected animals lacking a history of ethanol dependence have two factors that could impact the interpretation of the results: ethanol history/selection AND relatively low baseline ethanol intakes as compared to ethanol-dependent and/or genetically selected controls. The purpose of the present study was to generate higher baseline ethanol intakes upon which to examine the effects of NPY on ethanol and sucrose drinking in nonselected rats using a binge drinking model. Long Evans rats were trained to complete a single response requirement resulting in access to either 2% sucrose (Sucrose Group) or 2% sucrose/10% ethanol (Ethanol Group) for a 20-min drinking session. On treatment days, rats were bilaterally microinjected into the CeA with aCSF or one of three doses of NPY (0.25µg, 0.50µg, or 1.00µg/.5µL). Subjects in the Ethanol Group were consuming an average of 1.2g/kg of ethanol (yielding BELs of ~90mg%) during the 20min access period following aCSF treatments. The results revealed that NPY had no effect on either sucrose or ethanol consumption or on appetitive responding (latency to respond). Overall, the findings indicate that even a history of binge-like ethanol consumption is not sufficient to recruit CeA NPY activity, and are consistent with previous studies showing that the role of NPY in regulating ethanol reinforcement in the CeA may be contingent upon a prior history of ethanol dependence.

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

RATIONALE: Two pharmacotherapies are approved for treating alcohol craving (acamprosate and naltrexone), but both have shown mixed findings in animals and humans. OBJECTIVES: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 3-day exposure to 10% ethanol with 10% sucrose successfully initiates ethanol self-administration.

The initiation phase of ethanol self-administration is difficult to study using the well-established, sucrose-fading procedure due to the changing concentrations of ethanol in the first few days. The purpose of this experiment was to test whether a modified sucrose-substitution procedure in which rats are initially exposed to high concentrations of ethanol and sucrose for three days would successfully initiate ethanol self-administration. Male Long-Evans rats were trained to lever-press with a 10% sucrose solution in which four or 20 responses allowed 20-min access to the solution. Subsequently, rats were exposed to a 3-day period of operant self-administration of 10% sucrose+10% ethanol. This constant-concentration exposure was followed by the standard procedure in which sucrose is completely faded out. The establishment of ethanol self-administration was determined by ethanol intake, pre- and postprocedure two-bottle choice preference tests, and extinction trials. The mean ethanol intake was 2.2 times higher on day 2 compared with day 1 on the 10% sucrose+10% ethanol solution. After fading out the sucrose, the daily intake of 10% ethanol solution over 5 days was stable at approximately 0.57 g/kg. Ethanol preference was approximately threefold higher after the modified sucrose-fading procedure. Responding during a single session extinction test was dramatically increased from 4 to 61+/-13 or 20 to 112+/-22 responses in 20 min. Similar to the standard sucrose-fading method, we did not observe a significant relationship between extinction responding and ethanol intake. Blood alcohol concentrations were 4.5 mM 20 min after consumption began. We conclude that initiation and establishment of ethanol self-administration will occur using this modified sucrose-fading procedure.

Volume and dose effects of experimenter-administered ethanol preloads on ethanol seeking and self-administration.

The present experiment used a behavioral model developed to separate the initial behavior required to obtain access to ethanol (appetitive responding or lever presses) from the actual self-administration (consummatory responding or intake) to test the hypothesis that these responses are under the control of different behavioral/physiological processes, and therefore differentially affected by an ethanol priming dose. In male, Long Evans rats, "preload" volume (0.5 and 2.0ml) and dose (approximately 10%, 25%, and 50% of the total normally consumed in nontreatment sessions translating to 0.1, 0.25, and 0.5g/kg) of ethanol were varied and administered by the experimenter via oral gavage prior to an operant session. Overall, there were no priming effects, or increases, in ethanol-reinforced responding resulting from the ethanol preloads. The findings showed that the low preload volume produced linear, dose-dependent decreases in both intake and seeking. However, while the high volume also produced a linear dose-dependent decrease in ethanol seeking, there was a decrease in intake at every dose. That is, ethanol seeking was insensitive to preload volume, while intake was affected in a dose-dependent manner except at the lowest dose when preload volume did play a role in intake regulation. These findings indicate that "fullness" and pharmacological cues differentially impact the appetitive and consummatory behaviors reinforced by ethanol solutions, with intake being more sensitive to preload volume and seeking being more sensitive to preload pharmacology.

Ethanol and sucrose seeking and consumption following repeated administration of the GABA(B) agonist baclofen in rats.

BACKGROUND: Baclofen, a GABA(B) agonist, has been found to decrease alcohol craving in humans and to nonselectively decrease ethanol intake in some rodent models. This experiment assessed the effects of repeated administration of baclofen on reinforcer seeking and consumption using the sipper tube appetitive/consummatory model of ethanol access. METHODS: Subjects were divided into 2 groups and trained to make 30 lever press responses that resulted in access to either 10% ethanol or 2% sucrose in a sipper tube-drinking spout for 20 minutes. Three doses of baclofen were tested (0.3, 1.0, and 3.0 mg/kg) and each drug treatment was assessed using the following schedule: Monday, saline; Tuesday to Thursday, baclofen; and Friday, saline. RESULTS: The low dose of baclofen had no effect on the seeking or intake of either sucrose or ethanol, and the 1.0 mg/kg dose also had no effect on the appetitive, seeking response. However, the 1.0 mg/kg dose significantly decreased sucrose intake (from an average of 0.56 to 0.41 g/kg) and significantly increased ethanol intake (from an average of 0.77 to 1.00 g/kg). Similarly, the high dose (3.0 mg/kg) decreased sucrose intake and had a tendency to increase ethanol intake while decreasing both sucrose seeking and ethanol seeking. CONCLUSIONS: Overall, baclofen treatment affected reinforcer intake at doses that had no effect on reinforcer seeking, and effective doses decreased both sucrose seeking and ethanol seeking. Moreover, the effects on reinforcer intake were disparate, in that baclofen increased ethanol drinking and decreased sucrose drinking. The nonspecific effects of baclofen suggest that the GABA(B) system may be involved in general consummatory or drinking behaviors and does not appear to specifically regulate ethanol-motivated responding.