Schedule Of Food Reinforcement Research Articles

Reversal of the motivational effects of tetrabenazine by NMDA receptor blockade.

Apathy is a syndrome of decreased goal-directed activity, one of the main features of different brain disorders. Despite its high prevalence and life-threatening potential, there are currently very few options for its pharmacological treatment, which may be related to the lack of valid animal models. The vesicular monoamine transporter 2 inhibitor tetrabenazine (TBZ) was used in this study to model apathy-related behavior in pathologies linked to a depletion of dopamine. The atypical dopamine transporter inhibitor CE-123 and the NMDA receptor antagonist MK-801 were evaluated for their effects on goal-directed activity in intact and TBZ-treated rats to compare dopamine and non-dopamine approaches. To assess goal-directed behavior, the progressive ratio 3 (PR3) operant schedule of food reinforcement was conducted in adult male rats. To assess the motivational changes underlying the schedule, a model analysis based on the mathematical principles of reinforcement was applied. Treatment with TBZ (0.3 mg/kg) induced a decrease in response rate as the number of required responses increased. This effect was not accompanied by a decrease in the incentive value of the reinforcer or locomotor disturbances, suggesting that decreased tolerance to high effort demands was the underlying mechanism of the decrease in goal-directed activity. Treatment with MK-801 increased operant activity in both TBZ-treated and pharmacologically naïve rats. Our results support the previously proposed view that the TBZ-treated rats can be a model of apathy-related behavior in pathologies linked to a depletion of dopamine and suggest that NMDA receptors are a potential therapeutic target for the development of novel approaches to the treatment of apathy in both dopamine-depleted and dopamine-intact states.

Contrasting the reinforcing effects of the novel dopamine transport inhibitors JJC8-088 and JJC8-091 in monkeys: Potential translation to medication assisted treatment

Despite considerable efforts, there remains no Food and Drug Administration-approved medications for cocaine use disorder. One strategy to mitigate cocaine craving and relapse is to elevate dopamine. The dopamine transport inhibitor and releaser d-amphetamine has been shown to decrease cocaine self-administration (SA), although it has abuse liability. Recently, several modafinil analogs reduced cocaine SA in rats and monkeys, including JJC8-088, characterized as “cocaine-like” in rats, and JJC8-091, characterized as “atypical” and not SA by rats. The present study evaluated the reinforcing effects of both compounds in monkeys under several conditions. For experiment 1, 4 male cocaine-experienced rhesus monkeys self-administered cocaine (0.001–0.3 mg/kg per injection), JJC8-088 (0.001–0.3 mg/kg per injection), and JJC8-091 (0.1–3.0 mg/kg per injection) under a progressive-ratio schedule of reinforcement. Both JJC compounds functioned as reinforcers with equal reinforcing strength to cocaine. Although JJC8-091 was less potent than cocaine, JJC8-088 and cocaine had similar potencies. For experiment 2, 1 male and 2 female drug-naïve cynomolgus monkeys responded on a fixed-ratio schedule of food reinforcement. JJC8-091 was self-administered at rates higher than saline in all 3 monkeys. In experiment 3, monkeys from experiment 2 responded under a concurrent drug versus food choice paradigm and given access to cocaine or JJC8-091 under these conditions. At doses equal to or one-half log-units higher than doses used in experiment 2, cocaine, but not JJC8-091, was chosen over food. Together, these results demonstrate that although JJC8-091 may be reinforcing under some conditions, its reinforcing strength, in the presence of an alternative reinforcer, is substantially less than cocaine. Significance StatementJJC8-088 and JJC8-091 have shown efficacy is reducing cocaine self-administration (SA) in rats and in nonhuman primates. This study found that both compounds maintained SA in monkeys responding under several conditions. However, when given access to an alternative reinforcer during the SA session, JJC8-091 was not reinforcing, suggesting that JJC8-091 may have lower abuse liability than cocaine and may be a viable candidate for cocaine use disorder because, in the human population, alternatives to drug use are often available.

Impact of Serine Racemase Deletion on Nicotine Discrimination.

The high comorbidity between schizophrenia and cigarette smoking points to a possible shared heritable factor predisposing individuals with schizophrenia to nicotine addiction. The N-methyl-d-aspartate (NMDA) receptor has been highly implicated in both schizophrenia and nicotine addiction. In the present study, we used mice with a null mutation on the serine racemase gene (srr), an established risk gene for schizophrenia, which encodes the enzyme to produce the NMDA receptor co-agonist d-serine, to model the pathology of schizophrenia and to determine whether NMDA receptor hypofunction reduced the ability of srr-/- mice to identify nicotine's subjective effects. Established nicotine discrimination procedures were used to train srr-/- and wild-type (WT) mice to discriminate 0.4 mg/kg nicotine under a 10-response fixed-ratio (FR10) schedule of food reinforcement. Results show that WT mice reliably acquired 0.4 mg/kg nicotine discrimination in about 54 training sessions, whereas srr-/- mice failed to acquire robust 0.4 mg/kg nicotine discrimination even after extended (>70) training sessions. These results show that NDMA receptor hypofunction in srr-/- mice decreased sensitivity to the interoceptive effects of nicotine. Projected to humans, NMDA receptor hypofunction caused by mutations to the serine racemase gene in schizophrenia may reduce sensitivity to nicotine's subjective effects leading to increased nicotine consumption to produce the same effects as those unaffected by schizophrenia. There is high comorbidity between schizophrenia and nicotine dependence as well as possible shared genetic risk factors between the two. The serine racemase knockout mouse (srr-/-) with NMDA receptor hypofunction has been developed as a model for schizophrenia. We found that srr-/- mice were unable to acquire 0.4 mg/kg nicotine discrimination, while WT mice readily discriminated nicotine. These results show that decreased NMDA receptor function present in srr-/- mice and patients with schizophrenia may result in reduced sensitivity to nicotine's interoceptive effects, leading to increased nicotine consumption to produce the same subjective effects as those unaffected by schizophrenia.

The fatigue-inducing effects of cancer and its therapy are characterized by decreased physical activity in the absence of any motivational deficit

Although cancer and its therapy are well known to be associated with fatigue, the exact nature of cancer-related fatigue remains ill-defined. We previously reported that fatigue-like behavior induced independently by tumor growth and by the chemotherapeutic agent cisplatin is characterized by reduced voluntary wheel running and an intact motivation to expand effort for food rewards. The present set of experiments was initiated to characterize the functional consequences of fatigue induced by chemoradiotherapy in tumor-bearing mice and relate them to changes in the expression of genes coding for inflammation, mitochondria dynamics and metabolism. Two syngeneic murine models of cancer were selected for this purpose, a model of human papilloma virus-related head and neck cancer and a model of lung cancer. In both models, tumor-bearing mice were submitted to chemoradiotherapy to limit tumor progression. Two dimensions of fatigue were assessed, the physical dimension by changes in physical activity in mice trained to run in wheels and the motivational dimension by changes in the performance of mice trained to nose poke to obtain a food reward in a progressive ratio schedule of food reinforcement. Chemoradiotherapy reliably decreased wheel running activity but had no effect on performance in the progressive ratio in both murine models of cancer. These effects were the same for the two murine models of cancer and did not differ according to sex. Livers and brains were collected at the end of the experiments for qRT-PCR analysis of expression of genes coding for inflammation, mitochondria dynamics, and metabolism. The observed changes were mainly apparent in the liver and typical of activation of type I interferon and NF-κB-dependent signaling, with alterations in mitochondrial dynamics and a shift toward glycolysis. Although the importance of these alterations for the pathophysiology of cancer-related fatigue remains to be explored, the present findings indicate that fatigue brought on by cancer therapy in tumor-bearing mice is more physical than motivational.

Hyperdopaminergia in rats is associated with reverse effort-cost dependent performance.

Dopamine is implicated in the effort-based control of motivational processes; however, whether tonic dopamine regulates the effort-cost impact on motivation, is still debated. The rats lacking the dopamine transporter (DAT), which have dramatically increased levels of the synaptic dopamine, were used in the present study to elucidate the role of the synaptic dopamine in motivational processes. To study the reward-related processes, the progressive ratio 3 (PR3) operant schedule of food reinforcement (the ratio increases by 3 after each earned reinforcer) was performed in adult male rats (DAT knockouts (DAT-KO), heterozygotes (DAT-HT) and wild-types (DAT-WT)). During the PR3 session, the response rate of DAT-KO rats was gradually increased following the augmented required number of responses. In contrast, the local response rate of DAT-WT and DAT-HT decreased. d-Amphetamine sulfate salt (3 mg/kg, i.p.) altered the local response rate dynamics in DAT-WT, which became similar to that of DAT-KO. Interestingly, the reduction in response rate at low effort demands was associated with decreased rate of entries into the magazine tray in DAT-WT rats treated with amphetamine (3 mg/kg) but not in DAT-KO rats. Our results suggest that the elevated tonic synaptic dopamine can strongly affect motivation/effort-cost relation in rodents.

Effects of cannabinoid agonists and antagonists in male rats discriminating the synthetic cannabinoid AM2201

The synthetic forms of delta-9-tetrahydrocannabinol (Δ9-THC), dronabinol or nabilone, have been approved to treat several indications. However, due to safety concerns their clinical utility remains limited. Consequently, there is a need for developing cannabinoid (CB) ligands that display better behavioral pharmacological profiles than Δ9-THC. Here, we utilized drug discrimination methods to compare the interoceptive effects of CB ligands that vary in potency, efficacy, and selectivity at the CB receptors, including two ligands, AM411 and AM4089, that show CB1 partial agonist-like actions in vitro. Male rats were trained to discriminate 0.1 mg/kg AM2201 from saline under a fixed-ratio (FR) 10 response schedule of food reinforcement. After establishing AM2201's discriminative-stimulus effects, pretreatment tests with the CB1 antagonist/inverse agonist rimonabant blocked AM2201's effects, whereas the peripherally-restricted antagonist AM6545 had no effect. Next, the generalization profiles of AM411 and AM4089 with CB1 full agonists (JWH-018, CP-55,940, AM8936), partial agonist (Δ9-THC), and non-cannabinoids (fentanyl, atropine) were compared. The CBs either fully (AM2201, CP-55,940, JWH-018, AM8936, Δ9-THC) or partially (AM411, AM4089) substituted for AM2201, whereas fentanyl and atropine did not produce AM2201-like effects. All CB drugs were more potent than Δ9-THC and correlation analysis confirmed that the relative behavioral potencies of CBs corresponded strongly with their relative affinities at the CB1 but not CB2 receptors. Together, our results further demonstrate that AM411 and AM4089 exhibit better pharmacological profiles compared to Δ9-THC, in that they are more potent and display in vivo partial agonist-like actions that are centrally mediated via CB1 receptors.

Environmental enrichment accelerates the acquisition of schedule-induced drinking in rats

Environmental enrichment (EE) provides an improvement in the housing conditions of experimental animals, such as laboratory rats, with greater physical and social stimulation through toys and company in the home cages. Its use is known to influence performance of experimental protocols, but these effects have not been well determined in the schedule-induced drinking (SID) procedure. The main goal of this study was to investigate the effects of EE on the acquisition of SID in 24 12-week-old male Wistar rats, divided into two groups, a group with EE housed with toys and companions, and a group without enrichment in individual housing conditions without toys (social isolation and no environmental enrichment, INEE). A total of 25 sessions, under a fixed time 30 s food reinforcement schedule and with access to water in the experimental chambers were carried out. Sessions lasted 30 min. The results showed that the EE group developed faster the excessive drinking pattern of SID, and drank to higher levels, than the INEE group. The greater development of SID in the EE group contradicts the view of schedule-induced behavior as linked to stress reduction and better suits with the conception of induction related to positive reinforcement.

Food Restriction Level and Reinforcement Schedule Differentially Influence Behavior during Acquisition and Devaluation Procedures in Mice.

Behavioral strategies are often classified based on whether reinforcer value controls reinforcement. Value-sensitive behaviors, in which animals update their actions when reinforcer value is changed, are classified as goal-directed; conversely, value-insensitive actions, where behavior remains consistent when the reinforcer is removed or devalued, are considered habitual. Basic reinforcement schedules can help to bias behavior toward either process: random ratio (RR) schedules are thought to promote the formation of goal-directed behaviors while random intervals (RIs) promote habitual control. However, how the schedule-specific features of these tasks interact with other factors that influence learning to control behavior has not been well characterized. Using male and female mice, we asked how distinct food restriction levels, a strategy often used to increase task engagement, interact with RR and RI schedules to control performance during task acquisition and devaluation procedures. We determined that food restriction level has a stronger effect on the behavior of mice following RR schedules compared with RI schedules, and that it promotes a decrease in response rate during devaluation procedures that is best explained by the effects of extinction rather than devaluation. Surprisingly, food restriction accelerated the decrease in response rates observed following devaluation across sequential extinction sessions, but not within a single session. Our results support the idea that the relationships between schedules and behavioral control strategies are not clear-cut and suggest that an animal's engagement in a task must be accounted for, together with the structure of reinforcement schedules, to appropriately interpret the cognitive underpinnings of behavior.

Cisplatin decreases voluntary wheel-running activity but does not impair food-motivated behavior in mice

Cisplatin is a chemotherapeutic agent that is still commonly used to treat solid tumors. However, it has several toxic side effects due in large part to the mitochondrial damage that it induces. As this mitochondrial damage is likely to result in a decrease in the amount of metabolic energy that is available for behavioral activities, it is not surprising that fatigue develops in cancer patients treated with cisplatin. The present preclinical study was initiated to determine whether the detrimental effects of cisplatin were more pronounced on physical effort requiring a lot of energy versus effort that not only requires less energy but also procures energy in the form of food. For this purpose, mice were either trained to run in a wheel or to work for food in various schedules of food reinforcement before being treated with cisplatin. The experiments were carried out only in male mice as we had already reported that sex differences in cisplatin-induced neurotoxicities are minimal. Cisplatin was administered daily for one cycle of five days, or two cycles separated by a five-day rest. As observed in previous experiments, cisplatin drastically reduced voluntary wheel running. In contrast, when cisplatin was administered to food-restricted mice trained to work for a food reward in a progressive ratio schedule or in a fixed-interval schedule, it tended to increase the number of responses emitted to obtain the food rewards. This increase was not associated with any change in the temporal distribution of responses during the interval between two reinforcements in mice submitted to the fixed interval schedule of food reinforcement. When cisplatin was administered to food-restricted mice trained in an effort-based decision-making task in which they had to choose between working for a grain pellet with little effort and working for a preferred chocolate pellet with more effort, it decreased the total number of responses emitted to obtain food rewards. However, this effect was much less marked than the decrease in wheel running induced by cisplatin. The decrease in the effort invested in the procurement of food rewards was not associated with any change in the relative distribution of effort between low reward and high reward during the time course of the test session. These findings show that cisplatin decreases energy-consuming activities but not energy-procuring activities unless they require a choice between options differing in their cost-benefit ratio. Furthermore, they indicate that the physical dimension of fatigue is more likely to develop in cisplatin-treated individuals than the motivational dimension of fatigue.

Lack of sex and estrous stage effects on compulsive behavior assessed using a schedule-induced polydipsia procedure in rats.

Preclinical behavior models used for screening pharmacological treatments for mental disorders have generally used only male research subjects, and for studies that have included female subjects, few have utilized sex as a study variable. In fact, many mental disorders vary by prevalence and symptomatology between sexes, creating a need to evaluate established subject models for sex differences. Compulsive behavior is a feature shared across many mental disorders and effective treatments have been examined pre-clinically using the schedule-induced polydipsia procedure in rats. Drugs effective for reducing polydipsia include psychostimulants, such as d -amphetamine. Virtually no studies have examined sex differences using this procedure. For the present study, male and female rats were examined in the schedule-induced polydipsia paradigm. Rats were food-restricted and trained on a fixed-interval food reinforcement schedule and given free access to water during experimental sessions. Estrous stages were assessed during training and test sessions. The psychostimulant d -amphetamine was also tested once stable water consumption occurred. Excessive water intake developed over the course of training. Females required significantly more sessions to reach a stable level of drinking. Treatment with d -amphetamine (1.0 mg/kg, but not 0.25 or 0.5 mg/kg) significantly reduced drinking in both male and female rats. No sex differences were observed across other study variables including comparisons between diestrus and proestrus stages. Overall, these findings suggest that schedule-induced polydipsia procedures that employ similar methods can produce results generalizable across male and female subjects.

Topographical aspects of brief-stimulus presentations: A re-examination of the problem of conditioned reinforcement

Three pigeons were exposed to second-order schedules in which responding under a fixed-interval (FI) component schedule was reinforced according to a variable-interval (VI) schedule of food reinforcement. Completion of each component resulted in either (1) brief presentation of a stimulus present during reinforcement (paired brief stimulus), (2) brief presentation of a stimulus not present during reinforcement (nonpaired brief stimulus), or (3) no stimulus presentation (tandem schedule). Under the two nonpaired brief stimulus conditions, either a change in keylight color or onset of houselight illumination was used as the brief stimulus. Similar patterns of keypecking occurred under tandem and nonpaired keylight brief-stimulus presentations, whereas nonpaired houselight brief-stimulus presentations generated positively accelerated within-component keypeck patterning for two pigeons. When the same keylight brief stimulus was paired with food, positively accelerated patterns of keypecking were obtained for all pigeons. Differences in the effects of nonpaired brief-stimulus presentations on second-order schedule performance suggest that component schedule patterning under nonpaired brief-stimulus procedures is a function of the particular type of stimulus used (i.e., houselight versus keylight). These results suggest that (1) brief houselight illumination may function as a sensory reinforcer, and (2) a briefly presented food-paired stimulus can function as an effective conditioned reinforcer.

Efectos de variar el nivel de privación de comida sobre el valor reforzante del agua en el beber inducido por el programa

Scheduled-induced drinking (SID) occurs when food-deprived rats are exposed to intermittent schedules of food reinforcement. In recent years, SID has been considered as operant behavior reinforced directly by water and it has been suggested that food deprivation may function as a motivating operation that increases the reinforcing value of water. The purpose of the study was to determine the effects of varying food-deprivation levels on water reinforcing efficacy during SID sessions. In successive phases, three rats were maintained at their free-feeding weights, or were food deprived at 90 or 80% of their free-feeding weights. Rats were exposed to SID sessions in which food was delivered according to a tandem fixed- time 176- s, differential-reinforcement-of-other-behavior 4-s. Lever presses were reinforced with water according to a progressive-ratio 5 schedule. In general, response rates for water and break points increased with increases in food-deprivation level. The results complement earlier findings showing that SID is operant behavior reinforced directly by water.

Chronic restraint stress impairs voluntary wheel running but has no effect on food-motivated behavior in mice

Chronic restraint stress is known to cause significant alterations of mitochondrial biology. However, its effects on effort-based behavior and the sensitivity of these effects to treatments that restore mitochondrial function have not been assessed. Based on the hypothesis that the behavioral consequences of this stressor should be more severe for an energy demanding activity than for an energy procuring activity, we compared the effects of chronic restraint stress on the performance of male mice trained to use a running wheel or to nose poke for a food reward in an operant conditioning cage. In accordance with our hypothesis, we observed that exposure of mice to 2-hour daily restraint sessions for 14 to 16 days during the light phase of the cycle reliably decreased voluntary wheel running but had no effect on working for food in a fixed ratio 10 schedule of food reinforcement or in a progressive ratio schedule of food reinforcement. This dissociation between the two types of behavioral activities could reflect an adaptive response to the constraint imposed by chronic restraint stress on mitochondria function and its negative consequences on energy metabolism. To determine whether it is the case, we administered mesenchymal stem cells intranasally to chronically restrained mice to repair the putative mitochondrial dysfunction induced by chronic restraint stress. This intervention had no effect on wheel running deficits. Assessment of mitochondrial gene expression in the brain of mice submitted to chronic restraint stress revealed an increase in the expression of genes involved in mitochondrial biology that showed habituation with repetition of daily sessions of restraint stress. These original findings can be interpreted to indicate that chronic restraint stress induces behavioral and mitochondrial adjustments that contribute to metabolic adaptation to this stressor and maintain metabolic flexibility.

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.

Characterization of 3,4-methylenedioxypyrovalerone discrimination in female Sprague-Dawley rats.

3,4-Methylenedioxypyrovalerone (MDPV), one of several synthetic cathinones, is a popular constituent of illicit 'bath salts'. In preclinical studies utilizing drug discrimination methods with male rodents, MDPV has been characterized as similar to both cocaine and 3,4-methylenedioxymethamphetamine-hydrochloride (MDMA). Whereas few drug discrimination studies have utilized female rats, the current study evaluated the discriminative stimulus effects of MDPV in 12 adult female Sprague-Dawley rats trained to discriminate 0.5 mg/kg MDPV from saline under a fixed ratio 20 schedule of food reinforcement. Stimulus substitution was assessed with MDPV and its enantiomers, other synthetic cathinones [alpha pyrrolidinopentiophenone-hydrochloride(α-PVP), 4-methylmethcathinone (4-MMC)], other dopamine agonists (cocaine, [+)-methamphetamine] and serotonin agonists [MDMA, lysergic acid diethylamide (LSD)] Stimulus antagonism was assessed with the dopamine D1 receptor antagonist, Sch 23390 and the D2 receptor antagonist, haloperidol. Cocaine and (+)-methamphetamine engendered full stimulus generalization to MDPV with minimal effects on response rate. LSD produced partial substitution, whereas MDMA and 4-MMC produced complete substitution, and all these serotonergic compounds produced dose-dependent response suppression. (S)-MDPV and α-PVP engendered full substitution with similar potency to the racemate, while (R)-MDPV failed to substitute up to 5 mg/kg. Both Sch 23390 and haloperidol attenuated the discrimination of low MDPV doses and essentially shifted the dose-response curve to the right but failed to block discrimination of the training dose. These findings are generally consistent with previous reports based exclusively on male rodents. Moreover, they confirm the contribution of dopaminergic mechanisms but do not rule out the possible contribution of other neurotransmitter actions to the interoceptive stimulus effects of MDPV.

Pentylenetetrazol-like stimulus is not produced following naloxone-precipitated mitragynine withdrawal in rats.

Kratom (Mitragyna speciosa Korth), a native medicinal plant of Southeast Asia, is proposed to exhibit potential therapeutic value as an opioid substitute. However, studies of its negative emotional states resulting from withdrawal particularly of its main psychoactive compound, mitragynine (MG), are limited. Using the pentylenetetrazol (PTZ) discrimination assay, this study aims to investigate the effects of MG in responding to the PTZ stimulus and to assess the generalisation effects of withdrawal from MG to the PTZ stimulus. Rats (n = 20) were trained on a tandem (FR-10, VI-15) schedule of food reinforcement to press one lever after administration of the anxiogenic compound PTZ (16mg/kg, i.p.) and an alternate lever after vehicle. Following acute tests, training was suspended, and rats were chronically treated with MG or morphine at 8-h intervals for 9days and withdrawal was precipitated on the tenth day using naloxone (1mg/kg, i.p.). The rats were tested for generalisation to PTZ at 2, 8 and 24h after the last dose of MG or morphine administration. Unlike morphine that produced dose-related PTZ-like stimulus, MG at 3, 10, 30 and 45mg/kg doses showed no substitution to the PTZ discriminative stimulus. In contrast to morphine which produced a time-dependent generalisation to the PTZ stimulus, naloxone did not precipitate withdrawal effects in MG-treated rats as they selected the vehicle lever at three withdrawal time points. These results demonstrate that MG produces a very different response to morphine withdrawal that is not associated with anxiogenic-like subjective symptoms. These characteristics of MG may provide further support for use as a novel pharmacotherapeutic intervention for managing opioid use disorder.

Assessment of the ‘timing’ function of schedule-induced behavior on fixed-interval performance.

It has been suggested that schedule-induced behaviors allow organisms to adapt better to temporal regularities of the environment. The main goal of the present study was to observe the effect of schedule-induced drinking (SID) on the performance in fixed-interval (FI) schedules. Rats were exposed to a FI 15-, 30-, or 60-s food reinforcement schedule, and only half of them had access to water in the experimental chamber. Rats with access to water developed SID, which occurred in the first part of the interval, regardless of the FI value, and was followed by an increase in lever pressing rate. There were no substantial differences in the quantitative measures of timing between groups that had or did not have access to water, except for the rats in the FI 15-s group with access to water, who showed longer postreinforcement pauses, possibly attributable to competition between SID and lever pressing. SID did not manifest the scalar property, contrary to lever pressing, but it is proposed that behaviors are displayed serially until the last behavior before the target operant response becomes a discriminative stimulus for that behavior. It is not assumed that the purpose of schedule-induced behaviors is to aid timing, but the development of behavioral patterns might determine the performance of organisms on temporal tasks. Additionally, in some cases competition between responses might exert more control on when the operant behavior occurs than timing. Timing seems to consist in the temporal organization of available behaviors that leads to a specific behavior occurring at a specified time, a single characteristic that typically had come to indicate accurate timing. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Interactive effects of (±)-trans-U50488 and its stereoisomers with cannabinoids

The adverse effects of mu opioid agonists have spurred a renewed interest in using kappa opioid receptor (KOR) agonists as analgesics. KOR agonists also have potential for development as diuretics for the treatment of edema and hypertension. Here, we evaluated the discriminative stimulus, antinociceptive, and diuretic effects of the kappa agonist (±)-trans-U-50488 and its stereoisomers (−)-(1S,2S)-U-50488 or (+)-(1R,2R)-U-50488) alone and in combination with the cannabinoid agonist (−)-CP 55,940. To establish (±)-U-50488 as a discriminative stimulus, rats (n = 12) were trained to discriminate intraperitoneal (i.p.) administration of 5.6 mg/kg of (±)-trans-U-50488 from saline under a fixed-ratio 20 (FR-20) schedule of food reinforcement. Then, antinociception was assessed using two procedures: warm water tail withdrawal and von Frey paw withdrawal. Diuretic effects were assessed in separate rats (n = 6/group). Doses of (±)-U-50488 and (−)-U-50488 that served as discriminative stimuli produced significant increases in urine output, but at lower doses than those that produced antinociception. In contrast, (+)-U-50488 alone had no discriminative stimulus or diuretic effects at the doses tested, but did produce antinociception in the von Frey assay. When three cannabinoids and morphine were tested in the (±)-U-50488 discrimination procedure to determine the similarity of these drugs' discriminative stimulus effects to those for (±)-U-50488, the rank order similarity was (−)-CP 55,940 > (−)-trans-THC > (+)-WIN 55,212–2 ≥ morphine. (−)-CP 55,940 alone (0.056 mg/kg) partially substituted for the discriminative stimulus effects of (±)-U-50488 and produced significant diuretic and antinociceptive effects. (−)-CP 55,940 in combination with (±)-U-50488 also produced a two-fold leftward shift in the discriminative stimulus curve for (±)-U-50488, and near-additive antinociception with (±)-U-50488 and (+)-U-50488. Further, the diuretic effect of (−)-CP 55,940 was enhanced by a dose of (+)-U50488, which itself did not alter urine output. These data together indicate that a combination of cannabinoid and kappa opioid agonists can enhance diuresis, but may have limited potential for serving as opioid-sparing pharmacotherapeutics for treatment of pain.

Effects of kappa opioid receptor agonists on fentanyl vs. food choice in male and female rats: contingent vs. non-contingent administration

Strategies are needed to decrease the abuse liability of mu opioid receptor (MOR) agonists. One strategy under consideration is to combine MOR agonists with kappa opioid receptor (KOR) agonists. The effects of KOR agonists (U50488, nalfurafine) on fentanyl-vs.-food choice were compared under conditions where the KOR agonists were added to the intravenously self-administered fentanyl (contingent delivery) or administered as subcutaneous pretreatments (non-contingent delivery) in male and female rats. Rats were trained to respond under a concurrent schedule of fentanyl (0, 0.32-10μg/kg/infusion) and food reinforcement. In experiment 1, U50488 and nalfurafine were co-administered with fentanyl as fixed-proportion mixtures (contingent administration). In experiment 2, U50488 (1-10mg/kg) and nalfurafine (3.2-32μg/kg) were administered as acute pretreatments (non-contingent administration). The selective KOR antagonist, nor-BNI (32mg/kg), was administered prior to contingent and non-contingent KOR-agonist treatment in experiment 3. Both U50488 and nalfurafine decreased fentanyl choice when administered contingently, demonstrating that KOR agonists punish opioid choice. However, evidence for punishment corresponded with an elimination of operant responding in the majority of rats. Non-contingent U50488 and nalfurafine administration only decreased the number of choices made during the behavioral session without altering fentanyl choice. Contingent and non-contingent KOR-agonist effects on fentanyl choice were both attenuated by nor-BNI. These results illustrate that the effects of KOR agonists on fentanyl reinforcement are dependent upon the contingencies under which they are administered.