Progressive Ratio Paradigm Research Articles

Using naltrexone to validate a human laboratory test system to screen new medications for alcoholism (TESMA)- a randomized clinical trial

This registered clinical trial sought to validate a laboratory test system devised to screen medications for alcoholism treatment (TESMA) under different contingencies of alcohol reinforcement. Forty-six nondependent, but at least medium-risk drinkers were given the opportunity to earn intravenous infusions of ethanol, or saline, as rewards for work in a progressive-ratio paradigm. Work demand pattern and alcohol exposure dynamics were devised to achieve a gradual shift from low-demand work for alcohol (WFA) permitting quickly increasing breath alcohol concentrations (BrAC) to high-demand WFA, which could only decelerate an inevitable decrease of the previously earned BrAC. Thereby, the reward contingency changed, modeling different drinking motivations. The experiment was repeated after at least 7 days of randomized, double-blinded treatment with naltrexone, escalated to 50 mg/d, or placebo. Subjects treated with naltrexone reduced their cumulative WFA (cWFA) slightly more than participants receiving placebo. This difference was not statistically significant in the preplanned analysis of the entire 150 min of self-administration, i.e., our primary endpoint (p = 0.471, Cohen’s d = 0.215). Naltrexone serum levels correlated with change in cWFA (r = −0.53; p = 0.014). Separate exploratory analyses revealed that naltrexone significantly reduced WFA during the first, but not the second half of the experiment (Cohen’s d = 0.643 and 0.14, respectively). Phase-dependent associations of WFA with changes in subjective stimulation, wellbeing and desire for alcohol suggested that the predominant reinforcement of WFA was positive during the first phase only, and might have been negative during the second. We conclude that the TESMA is a safe and practical method. It bears the potential to quickly and efficiently screen new drugs for their efficacy to attenuate positively reinforced alcohol consumption. It possibly also provides a condition of negative reinforcement, and for the first time provides experimental evidence suggesting that naltrexone’s effect might depend on reward contingency.

The Motivation for Alcohol Reward: Predictors of Progressive-Ratio Intravenous Alcohol Self-Administration in Humans.

The Progressive Ratio (PR) self-administration paradigm is a common pre-clinical method used to examine the motivation for a drug attributed to a craving, reward, or the relief of negative affect. The Computer-assisted Alcohol Infusion System (CAIS) enables intravenous alcohol self-administration behavior in humans. This system provides the investigator with control over the trajectory of each incremental breath alcohol concentration (BrAC) reward and the maximum BrAC allowed in a session. This paradigm allows participants to earn these alcohol rewards using a sequence of button presses specified by the investigator. The system employs a physiologically-based pharmacokinetic model-based algorithm to achieve the same incremental BrAC exposure in every participant. Participants (n = 11) took part in two identical sessions to examine test-retest reliability, and an additional group (n = 73) completed a single session. Sessions began with a 25 min priming phase: participants were instructed to press a button an increasing number of times per reward, accumulating four standardized incremental BrAC trajectories. The second phase comprised an ad-lib, PR paradigm lasting 125 min. Each reward required an increasing number of button presses. Measures of self-administration included: average and peak BrAC, total rewards earned, total grams of ethanol consumed per unit of total body water, the total number of button presses, and the average rate of button pressing. Self-administration measures were highly correlated both between and within sessions, demonstrating test-retest reliability and internal consistency. Recent drinking history was strongly associated with self-administration measures; heavier drinkers chose greater alcohol self-administration. These results indicate the reliability and sensitivity of this progressive-ratio intravenous alcohol self-administration method for assessing the motivational properties of alcohol, with the potential for improved testing of the efficacy of new medications thought to reduce consumption of alcohol. This method can be used to understand the genetic and environmental determinants of alcohol self-administration in humans.

The Motivation for Alcohol Reward: Predictors of Progressive-Ratio Intravenous Alcohol Self-Administration in Humans

The Progressive Ratio (PR) self-administration paradigm is a common pre-clinical method used to examine the motivation for a drug attributed to a craving, reward, or the relief of negative affect. The Computer-assisted Alcohol Infusion System (CAIS) enables intravenous alcohol self-administration behavior in humans. This system provides the investigator with control over the trajectory of each incremental breath alcohol concentration (BrAC) reward and the maximum BrAC allowed in a session. This paradigm allows participants to earn these alcohol rewards using a sequence of button presses specified by the investigator. The system employs a physiologically-based pharmacokinetic model-based algorithm to achieve the same incremental BrAC exposure in every participant. Participants (n = 11) took part in two identical sessions to examine test-retest reliability, and an additional group (n = 73) completed a single session. Sessions began with a 25 min priming phase: participants were instructed to press a button an increasing number of times per reward, accumulating four standardized incremental BrAC trajectories. The second phase comprised an ad-lib, PR paradigm lasting 125 min. Each reward required an increasing number of button presses. Measures of self-administration included: average and peak BrAC, total rewards earned, total grams of ethanol consumed per unit of total body water, the total number of button presses, and the average rate of button pressing. Self-administration measures were highly correlated both between and within sessions, demonstrating test-retest reliability and internal consistency. Recent drinking history was strongly associated with self-administration measures; heavier drinkers chose greater alcohol self-administration. These results indicate the reliability and sensitivity of this progressive-ratio intravenous alcohol self-administration method for assessing the motivational properties of alcohol, with the potential for improved testing of the efficacy of new medications thought to reduce consumption of alcohol. This method can be used to understand the genetic and environmental determinants of alcohol self-administration in humans.

Evaluation of N-acetylcysteine on ethanol self-administration in ethanol-dependent rats

Many components of ethanol addiction such as reinforcement, withdrawal, extinction, and relapse are known to involve glutamate transmission. NAC could counteract glutamatergic dysregulation underlying ethanol addiction. We previously demonstrated the efficacy of N-acetylcysteine (NAC) treatment to reduce ethanol consumption, motivation, seeking, and relapse in rats displaying a binge drinking-like phenotype. The current study assessed whether acute NAC could reduce ethanol self-administration, ethanol-seeking behavior, motivation, and reacquisition of ethanol self-administration following abstinence in ethanol-dependent rats. Ethanol dependence was induced by chronic intermittent ethanol (CIE) vapor exposure for 10 weeks in male Wistar rats. Effects of NAC (0, 25, 50 or 100 mg/kg; i.p.) were evaluated during acute withdrawal, 8 h after inhalation chambers were turned off. We evaluated NAC effect on the expression of the xCT protein expression (the target of NAC) and glutamate transporters (GLT-1) in dependent rats. We showed that in dependent rats, the low dose of NAC (25 mg/kg) reduced ethanol self-administration and motivation to consume ethanol, evaluated in a progressive ratio paradigm. At 50 mg/kg, but not 25 mg/kg, NAC reduced extinction responding and reacquisition of self-administration after 1 month abstinence. The xCT protein expression was decreased in the nucleus accumbens in dependent compared with ethanol-naïve rats. Thus, NAC may be effective by decreasing glutamate transmission through presynaptic mechanisms (i.e. the stimulation of xc−-mediated increase in extrasynaptic glutamate levels). Our results demonstrate that NAC decreased ethanol self-administration, extinction responding, and relapse in ethanol-dependent animals, and thus strongly support clinical development of NAC for alcohol use disorders.

3207 Relation between Dopamine Transporter (DAT1) polymorphism and subjective effects of alcohol among non-dependent drinkers

OBJECTIVES/SPECIFIC AIMS: Dopamine transporter (DAT1) gene variation is associated with reward-related phenotypes including alcohol response. There is also evidence for a potential moderating role for mu-opioid receptor (OPRM1) gene variation on the relationship between DAT1 variation and alcohol response measures. We aimed at studying the interaction between the DAT1 VNTR and OPRM1 A118G polymorphisms on alcohol consumption and subjective responses among non-dependent drinkers. METHODS/STUDY POPULATION: We employed a progressive ratio (PR) paradigm of intravenous alcohol self-administration (IV-ASA) using the Computer-Assisted Infusion System (CAIS) to assess the motivation for alcohol seeking and consumption in a sample of nondependent drinkers. We used the Drug Effects Questionnaire (DEQ) and Biphasic Alcohol Effects Questionnaire (BAES) to assess subjective response. IV-ASA measures included average breath alcohol concentration (BrAC) and total ethanol infused. Peripheral blood samples were collected for genotyping. Ethics approval was obtained from the NIH Addictions Institutional Review Board. RESULTS/ANTICIPATED RESULTS: Fifty participants completed the PR IV-ASA session after informed consent. There were significant interactions between the DAT1 and OPRM1 genotypes in subjective effects of alcohol. Simple main effects analysis showed that DAT1 10a allele carriers that were also OPRM1 G allele carriers had significantly higher scores for several measures: “feel the drug effects” (F (1,46)=6.573, P = 0.014), “feel intoxicated”(F(1,46)=8.613, P = 0.005) and “feeling high” (F(1,46)=10.889, P = 0.002) in DEQ and higher sedation (F(1,46)=4.575, P = 0.038) in BAES. The genotypes statistically significantly predicted average breath alcohol (F (1,61) =3.295, p=0.044) and total ethanol infused(F(1,61)=3.632, p=0.032. DAT1 VNTR and OPRM1 A118G polymorphisms taken together accounted for 6.9 and 7.8% of variations in average breath alcohol and total ethanol infused respectively. DISCUSSION/SIGNIFICANCE OF IMPACT: Polymorphic variations in DAT1 and OPRM1 interact with each other in determining subjective effects of alcohol in intravenous alcohol infusion assessing motivation for alcohol seeking and consumption in nondependent drinkers. These epistatic interactions in subjective effects of alcohol are salient in the context of predicting and understanding neurobiological effects of alcohol and thereby the therapeutic responses in treating alcohol use disorders.

Lamotrigine attenuates the motivation to self-administer ketamine and prevents cue- and prime-induced reinstatement of ketamine-seeking behavior in rats

BackgroundLamotrigine is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. A case report has demonstrated that a ketamine addict experienced a significant reduction in craving and ketamine use after taking lamotrigine. The present study determined whether lamotrigine can reduce the motivation for ketamine and prevent the relapse to ketamine seeking behavior in rats. MethodsMale Sprague-Dawley rats were trained to respond for intravenous ketamine (0.5 mg/kg/infusion) self-administration or food pellets. The effects of lamotrigine on the motivation for ketamine or food were assessed using breakpoint test under a progressive ratio (PR) paradigm. Furthermore, the effects of lamotrigine on reinstatement of ketamine-seeking and food-seeking behaviors were examined after extinction. ResultsLamotrigine significantly decreased the breakpoint for ketamine and prevented cue- and ketamine priming-induced reinstatement of ketamine seeking behavior. However, lamotrigine did not affect the breakpoint for food reinforcement, cue-induced reinstatement of food-seeking behavior, or spontaneous locomotor activity. ConclusionsOur data reveal that lamotrigine is capable of attenuating the reinforcing efficacy of ketamine and reducing ketamine craving and relapse risk, which lays the foundation for conducting clinical trials in patients with ketamine use disorder.

Validation and optimisation of a touchscreen progressive ratio test of motivation in male rats

RationaleAcross species, effort-related motivation can be assessed by testing behaviour under a progressive ratio (PR) schedule of reinforcement. However, to date, PR tasks for rodents have been available using traditional operant response systems only.ObjectivesTouchscreen operant response systems allow the assessment of behaviour in laboratory rodents, using tasks that share high face validity with the computerised assessments used in humans. Here, we sought to optimise a rat touchscreen variant of PR and validate it by assessing the effects of a number of manipulations known to affect PR performance in non-touchscreen paradigms.MethodsSeparate groups of male Sprague-Dawley rats were trained on PR schedules with either linear (PR4) or exponential (PREXP) schedules of reinforcement. PR performance was assessed in response to manipulations in reward outcome. Animals were tested under conditions of increased reward magnitude and following reward devaluation through a prefeeding procedure. Subsequently, the effects of systemic administration of the dopamine D2/D3 receptor antagonist raclopride and the psychostimulant d-amphetamine were examined as traditional pharmacological methods for manipulating motivation.ResultsRats reinforced under PR4 and PREXP schedules consistently showed differential patterns of response rates within sessions. Furthermore, both PR4 and PREXP schedules were sensitive to suppression by prefeeding or raclopride administration. Performance under both schedules was facilitated by increasing reward magnitude or d-amphetamine administration.ConclusionsTaken together, these findings mirror those observed in lever-based PR paradigms in rats. This study therefore demonstrates the successful validation of the rat touchscreen PR task. This will allow for the assessment of motivation in rats, within the same touchscreen apparatus used for the assessment of complex cognitive processes in this species.

Cebranopadol, a Mixed Opioid Agonist, Reduces Cocaine Self-administration through Nociceptin Opioid and Mu Opioid Receptors.

Cocaine addiction is a widespread psychiatric condition still waiting for approved efficacious medications. Previous studies suggested that simultaneous activation of nociceptin opioid (NOP) and mu opioid (MOP) receptors could be a successful strategy to treat cocaine addiction, but the paucity of molecules co-activating both receptors with comparable potency has hampered this line of research. Cebranopadol is a non-selective opioid agonist that at nanomolar concentration activates both NOP and MOP receptors and that recently reached phase-III clinical trials for cancer pain treatment. Here, we tested the effect of cebranopadol on cocaine self-administration (SA) in the rat. We found that under a fixed-ratio-5 schedule of reinforcement, cebranopadol (25 and 50 µg/kg) decreased cocaine but not saccharin SA, indicating a specific inhibition of psychostimulant consumption. In addition, cebranopadol (50 µg/kg) decreased the motivation for cocaine as detected by reduction of the break point measured in a progressive-ratio paradigm. Next, we found that cebranopadol retains its effect on cocaine consumption throughout a 7-day chronic treatment, suggesting a lack of tolerance development toward its effect. Finally, we found that only simultaneous blockade of NOP and MOP receptors by concomitant administration of the NOP antagonist SB-612111 (30 mg/kg) and naltrexone (2.5 mg/kg) reversed cebranopadol-induced decrease of cocaine SA, demonstrating that cebranopadol activates both NOP and classical opioid receptors to exert its effect. Our data, together with the fairly advanced clinical development of cebranopadol and its good tolerability profile in humans, indicate that cebranopadol is an appealing candidate for cocaine addiction treatment.

Progressive ratio (PR) schedules and the sipometer: Do they measure wanting, liking, and/or reward? A tribute to Anthony Sclafani and Karen Ackroff

This paper honors the contributions made by Anthony (Tony) Sclafani and Karen Ackroff to both the Columbia University Seminar on Appetitive Behavior and to the field of ingestive behavior in general. We review their use of the progressive ratio (PR) licking paradigm, to determine whether the taste of sucrose, independent of its post-ingestive effects, is always positively reinforcing in animals. They demonstrated a monotonic increase in licking as concentration increased, and obtained results identical to those obtained with a lever-pressing paradigm, but licking was easier and more natural than lever pressing. The PR paradigm was translated to evaluate liquid food reward value in humans. An instrument (the sipometer) was devised that initially permitted a few seconds access to small amounts of a sweet beverage as the participants increased the time to obtain it in 3–5-sec increments. The device went through two refinements and currently delivers the reinforcer and measures the pressure exerted to obtain it. The sipometer is compared with other techniques for measuring motivation and reward. The use of the sipometer and the PR method are discussed in relation to the theoretical challenges inherent in measuring motivation and pleasure, from both psychological and behavioral economics perspectives, and why it is or is not important to separate these processes for both theoretical and practical applications.

Measuring Motivation and Reward-Related Decision Making in the Rodent Operant Touchscreen System.

This unit is designed to facilitate implementation of the fixed and progressive ratio paradigms and the effort-related choice task in the rodent touchscreen apparatus to permit direct measurement of motivation and reward-related decision making in this equipment. These protocols have been optimized for use in the mouse and reliably yield stable performance levels that can be enhanced or suppressed by systemic pharmacological manipulation. Instructions are also provided for the adjustment of task parameters to permit use in mouse models of neurodegenerative disease. These tasks expand the utility of the rodent touchscreen apparatus beyond the currently available battery of cognitive assessment paradigms.

The reinforcing properties of ethanol are quantitatively enhanced in adulthood by peri-adolescent ethanol, but not saccharin, consumption in female alcohol-preferring (P) rats

Alcohol drinking during adolescence is associated in adulthood with heavier alcohol drinking and an increased rate of alcohol dependence. Past research in our laboratory has indicated that peri-adolescent ethanol consumption can enhance the acquisition and reduce the rate of extinction of ethanol self-administration in adulthood. Caveats of the past research include reinforcer specificity, increased oral consumption during peri-adolescence, and a lack of quantitative assessment of the reinforcing properties of ethanol. The current experiments were designed to determine the effects of peri-adolescent ethanol or saccharin drinking on acquisition and extinction of oral ethanol self-administration and ethanol seeking, and to quantitatively assess the reinforcing properties of ethanol (progressive ratio). Ethanol or saccharin access by alcohol-preferring (P) rats occurred during postnatal day (PND) 30–60. Animals began operant self-administration of ethanol or saccharin after PND 85. After 10 weeks of daily operant self-administration, rats were tested in a progressive ratio paradigm. Two weeks later, self-administration was extinguished in all rats. Peri-adolescent ethanol consumption specifically enhanced the acquisition of ethanol self-administration, reduced the rate of extinction for ethanol self-administration, and quantitatively increased the reinforcing properties of ethanol during adulthood. Peri-adolescent saccharin consumption was without effect. The data indicate that ethanol consumption during peri-adolescence results in neuroadaptations that may specifically enhance the reinforcing properties of ethanol during adulthood. This increase in the reinforcing properties of ethanol could be a part of biological sequelae that are the basis for the effects of adolescent alcohol consumption on the increase in the rate of alcoholism during adulthood.

Concurrent progressive-ratio schedules: built-in controls in the study of delayed reward efficacy.

Delayed rewards maintain lower rates of operant responding than immediate rewards, and when given a choice between immediate and delayed rewards, individuals typically choose the immediate reward, even when it is smaller (a phenomenon called delay discounting). The behavioral and neural mechanisms underlying these behavioral patterns, however, are not conclusively understood. The present study developed a method to examine the efficacy of delayed rewards in a way that is suitable for pharmacological manipulation of delayed reward efficacy (while controlling for general changes in reward efficacy). The progressive ratio (PR) paradigm often used to examine reward efficacy was modified such that two PR schedules for lever pressing concurrently yet independently were presented. Across a series of conditions, a range of delays (3-81s) were arranged on one of the levers while the reward on the other lever remained immediate. PR breakpoints (the highest ratio completed on each lever, our measure of reward efficacy) systematically decreased on the delayed, but not on the immediate reward lever, suggesting that delays decreased reward efficacy. This decrease in breakpoint resulted in bias in within-session responding that was accounted for by models that adjusted reward value by the delay to that reward. Unlike the standard PR paradigm, the present arrangement provided the controls needed to differentiate delay specific from general changes in reward efficacy. The present method should be helpful in the study of the behavioral and neural mechanisms of delayed reward efficacy. Modifications of the present paradigm should be useful for pharmacological studies.

S27 * INNOVATIVE TECHNIQUES IN HUMAN LABORATORY ALCOHOL RESEARCH

S27 * INNOVATIVE TECHNIQUES IN HUMAN LABORATORY ALCOHOL RESEARCH

S10 * EMERGING DRUGS FOR TREATING ALCOHOL USE DISORDERS: PRECLINICAL EVIDENCE

S10 * EMERGING DRUGS FOR TREATING ALCOHOL USE DISORDERS: PRECLINICAL EVIDENCE

Brain‐derived neurotrophic factor mediates the suppression of alcohol self‐administration by memantine

Brain-derived neurotrophic factor (BDNF) within the striatum is part of a homeostatic pathway regulating alcohol consumption. Memantine, a non-competitive antagonist of N-methyl-D-aspartate receptors, induces expression of BDNF in several brain regions including the striatum. We hypothesized that memantine could decrease ethanol (EtOH) consumption via activation of the BNDF signalling pathway. Effects of memantine were evaluated in Long-Evans rats self-administering moderate or high amounts of EtOH 6, 30 and 54 hours after an acute injection (12.5 and 25 mg/kg). Motivation to consume alcohol was investigated through a progressive ratio paradigm. The possible role for BDNF in the memantine effect was tested by blockade of the TrkB receptor using the pharmacological agent K252a and by the BDNF scavenger TrkB-Fc. Candidate genes expression was also assessed by polymerase chain reaction array 4 and 28 hours after memantine injection. We found that memantine decreased EtOH self-administration and motivation to consume EtOH 6 and 30 hours post-injection. In addition, we found that inhibition or blockade of the BDNF signalling pathway prevented the early, but not the delayed decrease in EtOH consumption induced by memantine. Finally, Bdnf expression was differentially regulated between the early and delayed timepoints. These results demonstrate that an acute injection of memantine specifically reduces EtOH self-administration and motivation to consume EtOH for at least 30 hours. Moreover, we showed that BDNF was responsible for the early effect, but that the delayed effect was BDNF-independent.

Voluntary intravenous self-administration of alcohol detects an interaction between GABAergic manipulation and GABRG1 polymorphism genotype: a pilot study.

Operant responding paradigms quantify a subject's motivation for reward, but such studies employing ingested alcohol cannot assure the same incremental increase in brain exposure to alcohol across subjects because of substantial variability in absorption kinetics. We developed a human progressive ratio (PR) paradigm using the computer-assisted self-infusion of ethanol (CASE) system that overcomes such variability and conducted a pilot study to assess its utility for detecting an interaction of subjects' GABRA2 or GABRG1 genotype and pretreatment with 1 mg of lorazepam (LZ) vs. placebo on their willingness to work for alcohol rewards. Twenty healthy, nondependent drinkers, aged 21 to 27, were balanced on rs279871 and rs2350439 single nucleotide polymorphisms in the GABRA2 and GABRG1 genes, respectively. Subjects worked for alcohol, with water as an alternative reinforcer (AR), using a progressive schedule of a task that required constant attention and adapted to both fatigue and drug effects. Testing began 1 hour after pretreatment with 1 mg LZ or placebo in a crossover design. The CASE system performed well, and the constant attention task was perceived as work by all subjects. GABRA2 homozygosity did not significantly predict either breakpoint or cumulative work, whereas a significant GABRG1 genotype by LZ pretreatment interaction for cumulative work was detected (p = 0.04). Breakpoint revealed a weak trend toward pretreatment drug effects (p = 0.11), and a somewhat stronger interaction of LZ pretreatment with GABRG1 genotype (p = 0.06). GABRG1 status revealed a more complex relationship with respect to motivation for alcohol with and without LZ pretreatment; AG and GG individuals worked more for alcohol under both pretreatment conditions, while AA individuals worked more for the AR. The CASE PR paradigm shows promise as a laboratory method for use in drug development and phenotyping studies.

Ghrelin increases the motivation to eat, but does not alter food palatability.

Homeostatic eating cannot explain overconsumption of food and pathological weight gain. A more likely factor promoting excessive eating is food reward and its representation in the central nervous system (CNS). The anorectic hormones leptin and insulin reduce food reward and inhibit related CNS reward pathways. Conversely, the orexigenic gastrointestinal hormone ghrelin activates both homeostatic and reward-related neurocircuits. The current studies were conducted to identify in rats the effects of intracerebroventricular ghrelin infusions on two distinct aspects of food reward: hedonic valuation (i.e., "liking") and the motivation to self-administer (i.e., "wanting") food. To assess hedonic valuation of liquid food, lick motor patterns were recorded using lickometry. Although ghrelin administration increased energy intake, it did not alter the avidity of licking (initial lick rates or lick-cluster size). Several positive-control conditions ruled out lick-rate ceiling effects. Similarly, when the liquid diet was hedonically devalued with quinine supplementation, ghrelin failed to reverse the quinine-associated reduction of energy intake and avidity of licking. The effects of ghrelin on rats' motivation to eat were assessed using lever pressing to self-administer food in a progressive-ratio paradigm. Ghrelin markedly increased motivation to eat, to levels comparable to or greater than those seen following 24 h of food deprivation. Pretreatment with the dopamine D1 receptor antagonist SCH-23390 eliminated ghrelin-induced increases in lever pressing, without compromising generalized licking motor control, indicating a role for D1 signaling in ghrelin's motivational feeding effects. These results indicate that ghrelin increases the motivation to eat via D1 receptor-dependent mechanisms, without affecting perceived food palatability.

Diet-induced obesity blunts the behavioural effects of ghrelin: studies in a mouse-progressive ratio task

The ghrelinergic system is implicated in the development of obesity and in modulating central reward systems. It has been reported that diet-induced obesity causes blunted responding on food intake to ghrelin administration, associated with central ghrelin resistance. Here we investigate whether the stimulatory effects of ghrelin on the reward system are altered in diet-induced obese mice. Obesity was induced in C57BL/6J mice by feeding high-fat diet for 13 weeks. Mice were trained in an operant fixed and exponential progressive ratio task to respond for sucrose rewards. In an ad libitum fed state, ghrelin and a ghrelin receptor antagonist were administered in the progressive ratio. Alterations in the central ghrelin system in diet-induced obese mice were assessed. Obese mice showed attenuated acquisition and performance in the fixed and progressive ratio paradigm. Most importantly, diet-induced obesity inhibited the stimulatory effects of ghrelin (2 nmol, 3 nmol/10 g) on progressive ratio responding whereas lean animals presented with increased responding. Administration of the ghrelin-receptor antagonist (D-Lys(3))-GHRP-6 (66.6 nmol/10 g) decreased performance in lean but not obese mice. This insensitivity to ghrelin receptor ligands in mice on high-fat diet was further supported by decreased mRNA expression of the ghrelin receptor in the hypothalamus and the nucleus accumbens in obese mice. This study demonstrates that the modulatory effects of ghrelin receptor ligands are blunted in a mouse model of diet-induced obesity in a progressive ratio task. Thereby, our data extend the previously described ghrelin resistance in these mice from food intake to reward-associated behaviours.

Progressive ratio responding in an obese mouse model: Effects of fenfluramine

The progressive ratio schedule of operant responding is a well utilised task for assessing the rewarding aspects of abused drugs and natural rewards including food. Interestingly, progressive ratio paradigms have mainly been neglected in the field of animal research in obesity. Among the most widely studied mouse models of obesity is the leptin-deficient ob/ob mouse, characterised by hyperphagia and obesity. To date there are no studies on the behaviour of these mice in progressive ratio responding, thus we sought to validate the utility of the progressive ratio paradigm in obese mice and demonstrate its sensitivity to an anorectic drug challenge. Ob/ob mice and their lean controls were tested in fixed ratio paradigms of different demand, extinction learning, and progressive ratio schedules with linear and exponential increments, followed by an anorectic drug challenge with fenfluramine (5 and 10 mg/kg). Obese animals showed equal fixed ratio-acquisition and -responding for ratios 1 and 3, but displayed lower responding in ratios 6 and 9. Interestingly, obese animals showed equal motivation to respond in progressive ratio schedules. Fenfluramine dose-dependently induced anorectic effects in both genotypes and reduced progressive ratio responding significantly. This study, for the first time, describes motivational food intake in an operant progressive ratio paradigm in ob/ob mice. Leptin deficiency did not alter appetitive learning or motivation in the progressive ratio. The utility and sensitivity of the progressive ratio task for studies on motivational food intake was demonstrated by a challenge with the anorectic agent fenfluramine.

Dopamine release in motivated behaviour

Event Abstract Back to Event Dopamine release in motivated behaviour Jorge Mendez1* 1 a, Albania Goal-directed behavior is powerfully shaped by rewarding and aversive stimuli. Changes in DA concentration in the nucleus accumbens (NAc), a region of the basal ganglia critical for goal-directed behavior, are correlated with reward-directed behavior. Recently, phasic (millisecond) changes in dopamine activity have received particular attention as they relate to reward-related learning and action selection. We have shown, using fast-scan cyclic voltammetry in awake and behaving rats, that spontaneous, phasic changes in DA concentration in the NAc time-average to what appears to be a steady-state level. We delivered both rewarding (sucrose) and aversive (quinine) taste stimuli directly into the oral cavity of the awake rat. Unconditioned reward evoked an increase in DA concentration from the time-averaged steady-state level while unconditioned aversion evoked a decrease. Individual trials revealed that this modulation was due to changes in the probability of observing phasic DA release. Kappa opioid receptors play a critical role in behavioral responses to stressful and aversive stimuli and are expressed on DA terminals and cell bodies. We characterized the effects of the kappa opioid receptor agonist salvinorin A (salvA) on phasic DA signaling. Administration of salvA (2mg/kg, i.p.) suppressed phasic DA release evoked by electrical stimulation to 37±2% of baseline. SalvA also shifted the frequency-response function for DA release to the right. The implications of these findings for goal-directed behavior were investigated using the progressive ratio paradigm. SalvA dose-dependently decreased operant responding on a progressive ratio. This deficit was compensable when a fixed ratio 5 paradigm was used and eliminated the possibility of motor impairment. Taken together, the data support the idea that phasic DA signaling is differentially modulated by rewarding and aversive stimuli and this modulation can have profound effects on motivated behavior. Conference: 41st European Brain and Behaviour Society Meeting, Rhodes Island, Greece, 13 Sep - 18 Sep, 2009. Presentation Type: Oral Presentation Topic: Symposia lectures Citation: Mendez J (2009). Dopamine release in motivated behaviour. Conference Abstract: 41st European Brain and Behaviour Society Meeting. doi: 10.3389/conf.neuro.08.2009.09.046 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 05 Jun 2009; Published Online: 05 Jun 2009. * Correspondence: Jorge Mendez, a, a, Albania, mroitman@uic.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Jorge Mendez Google Jorge Mendez Google Scholar Jorge Mendez PubMed Jorge Mendez Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.