Fixed Ratio Schedule Of Reinforcement Research Articles

AM6527, a neutral CB1 receptor antagonist, suppresses opioid taking and seeking, as well as cocaine seeking in rodents without aversive effects.

Preclinical research has demonstrated the efficacy of CB1 receptor (CB1R) antagonists in reducing drug-taking behavior. However, clinical trials with rimonabant, a CB1R antagonist with inverse agonist profile, failed due to severe adverse effects, such as depression and suicidality. As a result, efforts have shifted towards developing novel neutral CB1R antagonists without an inverse agonist profile for treating substance use disorders. Here, we assessed AM6527, a CB1R neutral antagonist, in addiction animal models. Our findings revealed that AM6527 did not affect cocaine self-administration under fixed-ratio reinforcement schedules but dose-dependently inhibited it under progressive-ratio reinforcement schedules. Additionally, AM6527 dose-dependently inhibited heroin self-administration under both fixed-ratio and progressive-ratio reinforcement schedules and oral sucrose self-administration under a fixed-ratio reinforcement schedule, as well as cocaine- or heroin-triggered reinstatement of drug-seeking behavior in rats. However, chronic AM6527 administration for five consecutive days significantly inhibited heroin self-administration only during the initial two days, indicating tolerance development. Notably, AM6527 did not produce rewarding or aversive effects by itself in classical electrical intracranial self-stimulation and conditioned place preference tests. However, in optical intracranial self-stimulation (oICSS) maintained by optogenetic stimulation of midbrain dopamine neurons in DAT-cre mice, both AM6527 and rimonabant dose-dependently inhibited dopamine-dependent oICSS behavior. Together, these findings suggest that AM6527 effectively reduces drug-taking and seeking behaviors without rimonabant-like adverse effects. Thus, AM6527 warrants further investigation as a potential pharmacotherapy for opioid and cocaine use disorders.

Acquisition of cocaine reinforcement using fixed-ratio and concurrent choice schedules in socially housed female and male monkeys.

Previous studies in socially housed monkeys examining acquisition of cocaine self-administration under fixed-ratio (FR) schedules of reinforcement found that subordinate males and dominant females were more vulnerable than their counterparts. The present studies extended these findings in two ways: (1) to replicate the earlier study, in which female monkeys were studied after a relatively short period of social housing (~ 3months) using cocaine-naïve female monkeys (n = 9; 4 dominant and 5 subordinate) living in well-established social groups (~ 18months); and (2) in male monkeys (n = 3/social rank), we studied cocaine acquisition under a concurrent schedule, with an alternative, non-drug reinforcer available. In contrast to earlier findings, subordinate female monkeys acquired cocaine reinforcement (i.e., > saline reinforcement) at significantly lower cocaine doses compared with dominant monkeys. In the socially housed males, no dominant monkey acquired a cocaine preference (i.e., > 80% cocaine choice) over food, while two of three subordinate monkeys acquired cocaine reinforcement. In monkeys that did not acquire, the conditions were changed to an FR schedule with only cocaine available and after acquisition, returned to the concurrent schedule. In all monkeys, high doses of cocaine were chosen over food reinforcement. The behavioral data in females suggests that duration of social enrichment and stress can differentially impact vulnerability to cocaine reinforcement. The findings in socially housed male monkeys, using concurrent food vs. cocaine choice schedules of reinforcement, confirmed earlier social-rank differences using an FR schedule and showed that vulnerability could be modified by exposure to cocaine.

Working hard to avoid: Fixed-ratio response effort and maladaptive avoidance in humans.

Maladaptive avoidance of safe stimuli is a defining feature of anxiety and related disorders. Avoidance may involve physical effort or the completion of a fixed series of responses to prevent occurrence of, or cues associated with, the aversive event. Understanding the role of response effort in the acquisition and extinction of avoidance may facilitate the development of new clinical treatments for maladaptive avoidance. Despite this, little is known about the impact of response effort on extinction-resistant avoidance in humans. Here, we describe findings from two laboratory-based treatment studies designed to investigate the impact of high and low response effort on the extinction (Experiment 1) and return (Experiment 2) of avoidance. Response effort was operationalised as completion of fixed-ratio (FR) reinforcement schedules for both danger and safety cues in a multi-cue avoidance paradigm with behavioural, self-report, and physiology measures. Completion of the FR response requirements cancelled upcoming shock presentations following danger cues and had no impact on the consequences that followed safety cues. Both experiments found persistence of high response-effort avoidance across danger and safety cues and sustained (Experiment 1) and reinstated (Experiment 2) levels of fear and threat expectancy. Skin conductance responses evoked by all cues were similar across experiments. The present findings and paradigm have implications for translational research on maladaptive anxious coping and treatment development.

Effects of the cannabinoid CB1-receptor neutral antagonist AM4113 and antagonist/inverse agonist rimonabant on fentanyl discrimination in male rats

Evidence suggests the existence of a functional interaction between endogenous cannabinoid (CB) and opioid systems. Thus, targeting CB1 receptors might be a viable approach to develop new medications for opioid use disorders (OUD). The present studies were undertaken to evaluate the effects of the neutral CB1 antagonist AM4113 and the CB1 antagonist/inverse agonist rimonabant in male rats trained to discriminate 0.032 mg/kg fentanyl from saline under a 10-response fixed-ratio (FR-10) schedule of food reinforcement. Results show that the µ-opioid agonists (fentanyl, oxycodone, and morphine) substituted fully and dose-dependently for fentanyl, whereas pretreatment with the µ-opioid antagonist naltrexone antagonized fentanyl's discriminative-stimulus effects. In interaction studies, AM4113 (0.32 or 1.0 mg/kg) was more effective in blocking fentanyl discrimination at 10-fold lower doses that did not modify rates of food-maintained responding, whereas rimonabant (1.0–10 mg/kg) produced some attenuation of fentanyl's discriminative-stimulus effects at the highest dose tested which also significantly decreased response rates. These results extend our recent work showing that AM4113 can effectively block the behavioral effects of heroin without producing rimonabant-like adverse effects. Taken together, these data suggests that CB1 neutral antagonists effectively block the behavioral effects of structurally distinct morphinan (heroin) and phenylpiperidine-based (fentanyl) opioids and may provide a novel therapeutic option for the treatment of OUD.

Effects of Cannabinoid Agonists and Antagonists in Rats Discriminating Fentanyl

Extensive evidence suggests the existence of a functional interaction between endogenous cannabinoids and opioid systems. Targeting cannabinoid CB1 receptors might be a promising approach for developing new medications for opioid addiction. The present studies were undertaken to evaluate the effects of CB1 agonists and antagonists in rats (n=8) trained to discriminate, i.p., injections of 0.032 mg/kg fentanyl from saline on a 10‐response fixed‐ratio (FR‐10) schedule of food reinforcement. Results show that the µ‐opioid agonists (fentanyl, morphine, and oxycodone) substituted fully for fentanyl, whereas the muscarinic antagonist atropine did not substitute for fentanyl. The CB1 agonists Δ9‐THC, AM2201, and AM8936 all partially substituted for fentanyl’s discriminative‐stimulus effects suggesting some overlap in the discriminative‐stimulus effects of cannabinoid agonists and fentanyl. Pretreatment studies with a µ‐opioid receptor antagonist show that naltrexone antagonized fentanyl’s effects. Interestingly, pretreatment studies with CB1 antagonists show that rimonabant (inverse agonist) produced some attenuation of fentanyl’s discriminative‐stimulus effects at doses that significantly decreased response rates, whereas the neutral CB1 antagonist AM4113 blocked fentanyl discrimination at doses that did not modify rates of responding. Our findings are consistent with our recent work showing that AM4113 attenuates heroin self‐administration in rats, without producing depressive‐like effects. Collectively, these data suggests that CB1 neutral antagonists that block CB1 receptors with rimonabant‐like potency, devoid of unwanted side‐effects, may be therapeutically advantageous for countering the abuse‐related behavioral effects of opioids.

An optimized procedure for robust volitional cocaine intake in mice.

Substance use disorder (SUD) is a behavioral disorder characterized by volitional drug consumption. Mouse models of SUD allow for the use of molecular, genetic, and circuit-level tools, providing enormous potential for defining the underlying mechanisms of this disorder. However, the relevance of results depends on the validity of the mouse models used. Self-administration models have long been the preferred preclinical model for SUD as they allow for volitional drug consumption, thus providing strong face validity. While previous work has defined the parameters that influence intravenous cocaine self-administration in other species-such as rats and primates-many of these parameters have not been explicitly assessed in mice. In a series of experiments, we showed that commonly used mouse models of self-administration, where behavior is maintained on a fixed-ratio schedule of reinforcement, show similar levels of responding in the presence and absence of drug delivery-demonstrating that it is impossible to determine when drug consumption is and is not volitional. To address these issues, we have developed a novel mouse self-administration procedure where animals do not need to be pretrained on sucrose and behavior is maintained on a variable-ratio schedule of reinforcement. This procedure increases rates of reinforcement behavior, increases levels of drug intake, and results in clearer delineation between drug-reinforced and saline conditions. Together, these data highlight a major issue with fixed-ratio models in mice that complicates subsequent analysis and provide a simple approach to minimize these confounds with variable-ratio schedules of reinforcement. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Reinforcing and Stimulant-Like Effects of Methamphetamine Isomers in Rhesus Macaques.

Monoamine releasers such as d-methamphetamine (d-MA) can reduce cocaine use in laboratory studies and have been forwarded for the management of cocaine use disorder (CUD). However, the proven abuse liability of d-MA has limited enthusiasm for clinical use. The levorotatory isomer of MA, l-MA, appears to have lesser stimulant effects, possibly due to its preferential norepinephrine-releasing properties compared with dopamine. The present study evaluated the abuse potential of l-MA by comparing its reinforcing effects with known stimulant drugs of abuse in nonhuman primates. Adult rhesus macaques (N = 4) responded for intravenous injections of cocaine, d-MA, methcathinone (MCAT), or l-MA under a fixed-ratio (FR) schedule of reinforcement; reinforcing effectiveness was evaluated using behavioral economic demand procedures. In a separate cohort (N = 9), daily activity and food-reinforced responding were assessed during 100 days of treatment with daily dosages of l-MA (2.3 mg/kg per day, i.v.) or d-MA (0.74 mg/kg per day, i.v.) previously shown to decrease cocaine self-administration. Results show that all drugs maintained self-administration, with peak injections reaching ∼100 inj per session for cocaine, MCAT, and d-MA and ∼50 inj per session for l-MA . In demand studies, self-administration of each drug gradually decreased as FR size increased. The exponential model of demand indicated that the reinforcing effectiveness of l-MA was significantly less than the other drugs studied. Chronic l-MA treatment did not appreciably alter daily activity and only transiently suppressed food-reinforced responding. These data, coupled with previous findings that l-MA effectively reduces stimulant self-administration, suggest that l-MA, or other norepinephrine-preferring releasers, may serve as agonist medication for CUD with lesser abuse liability than common psychostimulants. SIGNIFICANCE STATEMENT: Development of pharmacotherapies for cocaine use disorder remains a formidable challenge. Agonist-based therapies show promise, but enthusiasm is tempered by the abuse liability of previously proposed medications. This study evaluated the abuse liability and chronic treatment effects of methamphetamine's levorotatory isomer (l-MA). l-MA demonstrated lower abuse liability compared with commonly abused stimulants and produced few untoward effects. In the context of recent studies demonstrating that l-MA attenuates stimulant self-administration, these findings support l-MA's potential as a pharmacotherapy for stimulant addiction.

Dorsolateral striatum dopamine-dependent cocaine seeking is resistant to pavlovian cue extinction in male and female rats

Cue exposure therapy (CET) reduces craving induced by drug-associated cues in individuals with substance use disorders. A preclinical model of CET, cue extinction, similarly reduces cue-induced cocaine seeking in rodent self-administration models; however, those models may not capture the habitual or compulsive aspects of drug use. Thus, the effectiveness of cue extinction was tested in male and female rats trained to self-administer cocaine using second-order (SO) or fixed-ratio (FR) schedules of reinforcement to facilitate dorsolateral striatum (DLS) dopamine-dependent or -independent response strategies, respectively. Cue extinction significantly reduced drug seeking in FR-trained rats, replicating prior results, but was ineffective in SO-trained rats. SO-trained rats also showed increased indices of glutamate signaling in the DLS relative to FR-trained rats, despite comparable levels of cocaine intake. Furthermore, in SO-trained rats, antagonism of AMPA receptors in the DLS rescued the efficacy of cue extinction to reduce drug seeking. Finally, the effectiveness of cue extinction was also revealed in SO-trained rats when they were taught to perform a new, non-habitual response for cocaine cue presentation. Overall, our findings indicate that habit-like drug seeking leads to plasticity in the DLS and behavior that is resistant to cue extinction, but that the effects of cue extinction are restored when DLS glutamatergic signaling is blocked. These results have implications for the effectiveness of clinical cue exposure therapy.

Cooperative responding in rats: II. Performance on fixed-ratio schedules of mutual reinforcement.

Coordinated responses of 5 dyads of rats were investigated under fixed-ratio (FR) schedules of mutual water reinforcement. Coordinated responding was defined as 2 consecutive lever-presses, 1 from each of 2 rats, occurring <.5 s apart. In the FR schedules, each coordinated episode was defined as 1 response in the FR sequence. The size of FR schedules was parametrically manipulated assuming the values of FR 1, 6, 12, 18, 24, 30, 50, and 9, in this order. Each FR remained in effect until responding reached stability. Under all conditions, pairs of rats received access to water simultaneously (mutual reinforcement). Rates and proportions of coordinated responding showed a bitonic inverted U-shaped function of ratio size. Postreinforcement pauses increased systematically as the interreinforcement interval increased. Local rates and proportions increased as a function of response location within ratios. Results of a control condition with relaxed temporal constraints for mutual reinforcement showed decreases in rates and proportion of coordinated responses, suggesting that the coordinated responses were controlled by the mutual reinforcement contingencies. The present experiment showed that coordinated responding is quantitatively affected by 3 properties of FR schedules: response requirement, reinforcement rates, and proximity to reinforcement.

The kappa-opioid receptor agonist, nalfurafine, blocks acquisition of oxycodone self-administration and oxycodone’s conditioned rewarding effects in male rats

Mu-opioid receptor (MOR) agonists are highly efficacious for the treatment of pain but have significant abuse liability. Recently, we reported that nalfurafine, when combined with oxycodone at a certain ratio, reduced the reinforcing effects of oxycodone in rats while producing additive antinociceptive effects. Questions remain, however, including if the combination will function as a reinforcer in drug-naïve rats, and if the combination produces aversive effects that could explain nalfurafine's ability to reduce oxycodone self-administration? In the present study, we investigated nalfurafine's ability to reduce acquisition of oxycodone self-administration when the two were self-administered as a mixture in drug-naïve rats and nalfurafine's ability to attenuate a conditioned place preference (CPP) induced by oxycodone. In the self-administration study, male Sprague-Dawley rats self-administered intravenous injections of oxycodone (0.056 mg/kg/injection), an oxycodone/nalfurafine combination (0.056/0.0032 mg/kg/injection), or saline under fixed-ratio schedules of reinforcement for 20 days to compare rates of acquisition of drug taking. In the CPP assay, male Sprague-Dawley rats received subcutaneous injections of either saline, oxycodone (3.2 mg/kg), nalfurafine (0.18 mg/kg), or an oxycodone/nalfurafine combination at the same ratio used in the self-administration study (3.2 mg/kg/0.18 mg/kg). All subjects self-administering oxycodone alone met acquisition criteria. However, only 13% of subjects self-administering oxycodone/nalfurafine met criteria, and no subjects acquired self-administration of saline. Oxycodone, but not nalfurafine alone or the oxycodone/nalfurafine combination, produced rewarding effects in rats in the CPP test. These findings suggest that the combination of oxycodone and nalfurafine will be less habit forming in opioid-naïve patients than oxycodone alone.

Effects of exposure to 12C and 4He particles on cognitive performance of intact and ovariectomized female rats

Exposure to the types of radiation encountered outside the magnetic field of the earth can disrupt cognitive performance. Exploratory class missions to other planets will include both male and female astronauts. Because estrogen can function as a neuroprotectant, it is possible that female astronauts may be less affected by exposure to space radiation than male astronauts. To evaluate the effectiveness of estrogen to protect against the disruption of cognitive performance by exposure to space radiation intact and ovariectomized female rats with estradiol or vehicle implants were tested on novel object performance and operant responding on an ascending fixed-ratio reinforcement schedule following exposure to 12C (290 MeV/n) or 4He (300 MeV/n) particles. The results indicated that exposure to carbon or helium particles did not disrupt cognitive performance in the intact rats. Estradiol implants in the ovariectomized subjects exacerbated the disruptive effects of space radiation on operant performance. Although estrogen does not appear to function as a neuroprotectant following exposure to space radiation, the present data suggest that intact females may be less responsive to the deleterious effects of exposure to space radiation on cognitive performance, possibly due to the effects of estrogen on cognitive performance.

Reinforcer quality matters: A test of the Mathematical Principles of Reinforcement with domestic hens (Gallus gallus domesticus)

This study evaluated the ability of Killeen's (1994) Mathematical Principles of Reinforcement to account for the effects of changes in reinforcer quality on hens' rates of responding on fixed-ratio schedules. Hens were trained to peck a key on a fixed-ratio schedule of reinforcement and then experienced an ascending series of ratio values in two separate conditions. In different conditions, the food reinforcer was either wheat or puffed wheat. Response rates initially increased with increases in ratio requirement before eventually decreasing at larger ratios. Quantitative fits of the model accounted for the data well. The fits revealed that different foods were systematically associated with changes in the specific activation parameter, a, and these were consistent with previous reports of preference for those food items.

Effects of early life stress on cocaine self-administration in post-pubertal male and female rhesus macaques.

Early life stress (ELS), including childhood maltreatment, is a predictive factor for the emergence of cocaine use disorders (CUDs) in adolescence. Accordingly, we examined whether post-pubertal male and female rhesus macaques that experienced infant maltreatment (maltreated, n = 7) showed greater vulnerability to cocaine self-administration in comparison with controls (controls, n = 7). Infant emotional reactivity was measured to assess differences in behavioral distress between maltreated and control animals as a result of early life caregiving. Animals were then surgically implanted with indwelling intravenous catheters and trained to self-administer cocaine (0.001-0.3mg/kg/infusion) under fixed-ratio schedules of reinforcement. Days to acquisition, and sensitivity to (measured by the EDMax dose of cocaine) and magnitude (measured by response rates) of the reinforcing effects of cocaine were examined in both groups. Maltreated animals demonstrated significantly higher rates of distress (e.g., screams) in comparison with control animals. When given access to cocaine, control males required significantly more days to progress through terminal performance criteria compared with females and acquired cocaine self-administration slower than the other three experimental groups. The dose that resulted in peak response rates did not differ between groups or sex. Under 5-week, limited-access conditions, males from both groups had significantly higher rates of responding compared with females. In control monkeys, these data support sex differences in cocaine self-administration, with females being more sensitive than males. These findings also suggest that ELS may confer enhanced sensitivity to the reinforcing effects of cocaine, especially in males.

An Operant Conditioning Task to Assess the Choice between Wheel Running and Palatable Food in Mice.

Wheel running, especially in the homecage, has been widely used to study the neurobiology of exercise because animal tends to use it voluntarily. However, as for each reward, its consumption (in the present case, running performance) does not specifically provide information on its incentive value, i.e., the extent to which animals are motivated to run independently from their consumption of that reward. This is a major drawback, especially when focusing on the neurobiology governing the pathological imbalances between exercise and e.g., feeding (obesity, anorexia nervosa). Yet, few studies have shown that operant conditioning wherein wheel-running is used as a reinforcer that can be "consumed" after nose-poking or lever-pressing allows to distinguish motivation from consumption. Thus, nose-poking or lever-pressing under a progressive ratio schedule of reinforcement in animals trained under fixed ratio reinforcement schedules provides, through the so-called breakpoint, an index of running motivation. As compared to wheel-running, numerous studies have used food as a reinforcer, which helped to uncover the neurobiology of feeding. However, to our knowledge, there is no paradigm allowing the assessment of the choice between running and feeding when presented in concurrence, with the possibility to measure a priori the motivation for each reward. Herein, we describe a protocol that first permits to measure the drive for each of these two rewards before it allows to measure the preference for one over the other in a reward choice setting. This paradigm could help to better characterize the neurobiology underlying pathological imbalances between physical activity and feeding, which is the core feature of eating disorders.

Operant Costs Modulate Dopamine Release to Self-Administered Cocaine.

The costs associated with obtaining illicit drugs can fluctuate depending upon the relative drug availability. As a consequence of the changing costs, the effort that one must exert to obtain drugs is dynamic. Considerable evidence illustrates a critical role for dopamine in the ventral medial striatum in mediating drug reinforcement. However, little is known regarding how dopamine release is affected by changes in the costs associated with earning drugs. We used fast-scan cyclic voltammetry to determine how changes in the operant requirement affected dopamine release to self-administered cocaine in male rats. Dopamine release to cocaine infusions increased across trials during self-administration sessions using a fixed-ratio reinforcement schedule with a low operant requirement. However, increasing the operant requirement abolished the within-session elevation in dopamine release to drug rewards. This effect was not due to underlying changes in preinfusion dopamine levels and was not explained by cocaine levels in the brain. This within-session increase in dopamine release to cocaine infusions reemerged when the operant requirement was lowered. Under a progressive ratio reinforcement schedule, there was no increase in dopamine release to drug rewards across trials, which contrasts with prior studies demonstrating an increase in dopamine release to food rewards. Collectively, these findings illustrate that the influence of operant costs on reward-evoked dopamine release depends upon type of reward that can be earned (e.g., food or drug).SIGNIFICANCE STATEMENT The mesolimbic dopamine system is involved with mediating drug reinforcement. Although the costs associated with earning drugs are dynamic, no studies to date have examined how dopamine release to drug rewards is affected by changing costs. By performing fast-scan cyclic voltammetry recordings in rats self-administering cocaine, the present work demonstrates that changing the operant costs reversibly modulates the dopamine response to cocaine rewards. Furthermore, these findings highlight that the influence of costs on dopamine release to drug rewards differs from the established effect of costs on dopamine release to food rewards.

Adolescent methylmercury exposure: Behavioral mechanisms and effects of sodium butyrate in mice

Methylmercury (MeHg), an environmental neurotoxicant primarily found in fish, produces neurobehavioral impairment when exposure occurs during gestation. Whether other developmental periods, such as adolescence, display enhanced vulnerability to the behavioral effects of MeHg exposure is only beginning to be explored. Further, little is known about the effects of repeated administration of lysine deacetylase inhibitors, such as sodium butyrate (NaB), on operant behavior. In Experiment 1, male C57BL6/n mice were exposed to 0, 0.3, and 3.0 ppm MeHg (n = 12 each) via drinking water from postnatal days 21 to 60 (murine adolescence). As adults, mice were trained to lever press under an ascending series of fixed-ratio schedules of milk reinforcement selected to enable the analysis of three important parameters of operant behavior using the framework provided by Mathematical Principles of Reinforcement. Adolescent MeHg exposure dose-dependently increased saturation rate, a measure of the retroactive reach of a reinforcer, and decreased minimum response time relative to controls. In Experiment 2, the behavioral effects of repeated NaB administration both alone and following adolescent MeHg exposure were examined. Male C57BL6/n mice were given either 0 or 3.0 ppm MeHg during adolescence and, before behavioral testing, two weeks of once daily i.p. injections of saline or 0.6 g/kg NaB (n = 12 in each cell). Adolescent MeHg exposure again increased saturation rate but did not significantly alter minimum response time. NaB also increased saturation rate in both MeHg exposure groups. These data suggest that the behavioral mechanisms of adolescent MeHg exposure and NaB may be related to the impact of reinforcement on prior responses. Specifically, MeHg and NaB concentrated the effects of reinforcers onto the most recent responses.

Expression and Treatment of Pain‐Related Depression of Fixed‐Ratio and Progressive‐Ratio Food‐Maintained Behavior in Rats

Pain‐related interference with behavior is a key clinical diagnostic indicator and target in the treatment of pain. Increasingly, preclinical studies on the expression, mechanisms, and treatment of pain have been aimed at improving understanding of pain‐related interference with behavior. Positively reinforced operant behavior is one category of target behaviors that are sensitive to depression by physiologically‐relevant pain stimuli. This pain‐related depression of behavior can be blocked by clinically‐effective analgesics including opioids and nonsteroidal anti‐inflammatory drugs. Most studies using operant conditioning procedures to examine pain‐related depression of behavior have used fixed‐ratio schedules of reinforcement. The primary dependent variable in these studies is the rate of behavior. In contrast, the primary dependent variable in studies using progressive ratio schedules of reinforcement is breakpoint. Breakpoint is often defined as the final ratio completed by the subject or total number of reinforcers earned, and is thought to be related to the efficacy of the reinforcer or the subject's motivation to obtain the reinforcer. The present studies compare the effects of a noxious pain stimulus and a clinically‐relevant analgesic on behavior maintained under fixed‐ratio and progressive‐ratio schedules of behavior in male Wistar rats. The first aim was to determine whether there were differences in the potency of an acute chemical noxious stimulus, intraperitoneal injection of dilute lactic acid, to depress operant behavior maintained by sucrose under fixed‐ and progressive‐ratio schedules of reinforcement. Under the fixed‐ratio schedule, rats were required to perform six lever presses to access 0.1 ml of 10% sucrose, under the progressive‐ratio schedule, the response requirement increased following the delivery of each reinforcer according to a logarithmic function. Lactic acid was more potent at depressing lever pressing under the fixed‐ratio schedule compared to the progressive‐ratio schedule. The second aim of the study was to examine the effects of the NSAID, ketoprofen, on lactic acid‐induced depression of lever pressing. Consistent with previous studies, ketoprofen was effective at blocking pain‐related depression of behavior maintained under both fixed‐ and progressive‐ratio schedules, and ketoprofen was equipotent in both procedures. Together, these findings support the validity of operant procedures as tools to examine candidate analgesics for the treatment of pain‐related depression of behavior. Moreover, the use of diverse schedules of reinforcement may yield important scientific information on the mechanisms underlying pain‐related interference with behavior. Specifically, the finding that, under the current experimental conditions, lactic acid was more potent to depress lever pressing maintained under a fixed‐ratio schedule than a progressive‐ratio schedule may reflect interference with the rats' ability to respond at a high rate at concentrations that did not impact their motivation to do so.Support or Funding InformationSupported by a University of Georgia‐Augusta University (AU) seed grant, the AU Center for Undergraduate Research and Scholarship, and the AU College of Science and Mathematics.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of lorcaserin (Belviq®) on nicotine- and food-maintained responding in non-human primates

BackgroundAccumulating evidence suggests that the FDA-approved serotonin 5-HT2C receptor agonist, lorcaserin (Belviq®), may be a promising candidate for the management of substance use disorders, including nicotine addiction. The present study was conducted to determine the efficacy and selectivity of acute or continuous lorcaserin treatment for decreasing the reinforcing effects of nicotine in a primate species. MethodsAdult rhesus monkeys (n=4) with a history of nicotine self-administration (>2years) responded for injections of nicotine (0.32–100μg/kg IV) or food pellets under a fixed-ratio schedule of reinforcement during daily 100-min sessions. When responding was stable, lorcaserin was administered either as an acute pretreatment (0.1–1.0mg/kg, IM) or by continuous infusion (0.1mg/kg/hr, SC for 3–5days). Daily activity patterns were also monitored immediately following experimental sessions. ResultsResults indicate that acute lorcaserin pretreatment produced significant and dose-dependent decreases in nicotine-maintained responding across a >100-fold range of self-administered nicotine doses. Continuous lorcaserin treatment decreased intake of 10μg/kg/inj nicotine to about 50% of baseline values. Food-maintained responding was only moderately decreased in 3 of 4 subjects after acute administration and unaffected in all subjects during continuous treatment. Daily activity also was significantly decreased—to ≤50% of control values—following experimental sessions in which acute lorcaserin was administered. ConclusionsThese data indicate that lorcaserin reduces IV self-administration of nicotine at a dose that decreases motoric activity but less consistently disrupts food-maintained responding. Further research into lorcaserin’s potential utility for the management of nicotine dependence is warranted.

About bouts: A heterogeneous tandem schedule of reinforcement reveals dissociable components of operant behavior in Fischer rats.

According to the biexponential refractory model (BERM) of variable-interval (VI) performance, operant behavior is organized in bouts, described by 3 dissociable components: between-bout interresponse times (IRTs), within-bout IRTs, and bout lengths. Research has shown that between-bout IRTs are sensitive to changes in rate of reinforcement and reinforcer efficacy, the length of some bouts is selectively sensitive to changes in response-reinforcer contingencies, and within-bout IRTs are relatively insensitive to both manipulations. BERM assumes that within- and between-bout IRTs are exponentially distributed, and bout lengths are described by a mixture of negative binomial and geometric distributions. To assess BERM assumptions and the interpretation of associated findings, Fischer 344/DuCrl rats were trained on a heterogeneous tandem VI fixed-ratio (FR) schedule of reinforcement intended to dissociate the components of operant behavior. Initial (VI) and terminal (FR) links were programmed on separate levers; no stimulus signaled the completion of the initial link. FR requirement, VI requirement, and deprivation level were varied. Typical performance consisted of single responses on the VI lever separated by response runs on the FR lever. It was hypothesized that (a) the interval between the end of each FR run and the first subsequent VI response (FR-VI IRTs) would constitute between-bout IRTs, and would be sensitive to changes in VI requirement and deprivation level, (b) FR runs would constitute response bouts, so the length of a fraction of them would be selectively sensitive to changes in FR requirement, and (c) intervals between consecutive FR responses (FR-FR IRTs) would constitute within-bout IRTs, and would be relatively robust to all manipulations. Findings were consistent with these expectations. The underlying distributions of FR-FR IRTs, FR-VI IRTs, and FR run lengths, however, were inconsistent with BERM assumptions. These data support the distinct components of operant performance, but challenge the simple processes assumed to underlie their generation. (PsycINFO Database Record

ハトにおけるトークン強化による定比率(FR)スケジュールの研究

ハトにおけるトークン強化による定比率(FR)スケジュールの研究