Dopamine D1-like receptor blockade and stimulation decreases operant responding for nicotine and food in male and female rats
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SUBMITTER: Chellian R
PROVIDER: S-EPMC9388990 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe reinforcing properties of nicotine play a critical role in smoking and vaping. There is a need for treatments that decrease the reinforcing properties of nicotine and thereby improve smoking and vaping rates. Dopamine plays a role in the reinforcing properties of nicotine, but little is known about the role of dopamine D2-like receptors in nicotine intake and whether there are sex differences in the effects of dopaminergic drugs on nicotine intake.AimThe goal of the present studies was to investigate the effects of the D1/D2-like receptor antagonist flupentixol and the D2-like receptor antagonist L-741626 on nicotine self-administration in male and female rats.MethodsThe effects of flupentixol and L-741626 on operant responding for nicotine and food and locomotor activity in a small open field were investigated.ResultsThere were no sex differences in baseline nicotine intake. The D1/D2-like receptor antagonist flupentixol and the D2-like receptor antagonist L-741626 decreased operant responding for nicotine. Blockade of D1/D2-like receptors and blockade of D2-like receptors also decreased operant responding for food and decreased locomotor activity. Flupentixol induced a greater decrease in operant responding for food in males than females. However, in the other tests, there were no sex differences in the effects of the dopamine receptor antagonists.ConclusionsBlockade of D1/D2-like receptors with flupentixol and D2-like receptors with L-741626 decreases nicotine and food intake in rats of both sexes. These compounds also decrease locomotor activity which might be indicative of a sedative effect.
| S-EPMC10704414 | biostudies-literature
Project description:Patients treated with cancer chemotherapeutics frequently report chemotherapy-induced peripheral neuropathy (CIPN), changes in mood (depression and anxiety) and functional impairments. Rodent models of CIPN elicit limited alterations in functional behaviors, which pose challenges in developing preclinical models of chemotherapy-induced behavioral depression. The study examined the consequences of chemotherapy-induced mechanical hypersensitivity (paclitaxel: 32 or 64 mg/kg, cumulative; oxaliplatin: 30 mg/kg, cumulative) on behavioral depression, as measured with operant responding for palatable food during periods of food restriction and ad libitum chow, consumption of noncontingently available palatable food in the presence of ad libitum chow, and voluntary wheel running. The study employed two inbred mouse strains (C57BL/6J and Balb/cJ) and examined potential sex differences. All chemotherapeutic regimens caused profound mechanical hypersensitivity for the duration of the observation periods (up to 7 months), but no treatments changed voluntary wheel running or consumption of noncontingent palatable food. The high dose of paclitaxel temporarily reduced operant responding for palatable food in male C57BL/6J mice undergoing food restriction or maintained on ad libitum chow. However, paclitaxel failed to decrease operant responding for palatable food in free-feeding female C57BL/6J mice or Balb/cJ mice of either sex. Moreover, oxaliplatin did not significantly alter operant responding for palatable food in male or female C57BL/6J mice maintained on ad libitum chow. These findings demonstrate a dissociation between chemotherapy-induced mechanical hypersensitivity and behavioral depression. The transient effects of paclitaxel on operant responding in male C57BL/6J mice may represent a fleeting behavioral correlate of chemotherapy-associated pain-like behaviors.
| S-EPMC8266730 | biostudies-literature
Project description:BackgroundWe recently reported that operant social choice-induced voluntary abstinence prevents incubation of methamphetamine craving. Here, we determined whether social choice-induced voluntary abstinence would prevent incubation of heroin craving. We also introduce a fully automatic social reward self-administration model that eliminates the intense workload and rat-human interaction of the original semiautomatic model.MethodsIn experiment 1, we trained male and female rats for social self-administration (6 days) and then for heroin self-administration (12 days). Next, we assessed relapse to heroin seeking after 1 and 15 abstinence days. Between tests, the rats underwent either forced or social choice-induced abstinence. In experiment 2, we developed a fully automatic social self-administration procedure by introducing a screen between the self-administration chamber and the social-peer chamber; the screen allows physical contact but prevents rats from crossing chambers. Next, we compared incubation of craving in rats with a history of standard (no-screen) or automatic (screen) social self-administration and social choice-induced abstinence.ResultsThe time-dependent increase in heroin seeking after cessation of drug self-administration (incubation of craving) was lower after social choice-induced abstinence than after forced abstinence. There were no differences in social self-administration, social choice-induced abstinence, and incubation of craving in rats trained in the standard semiautomatic procedure versus the novel fully automatic procedure.ConclusionsOur study demonstrates the protective effect of rewarding social interaction on heroin self-administration and incubation of heroin craving and introduces a fully automatic social self-administration and choice procedure to investigate the role of volitional social interaction in drug addiction and other psychiatric disorders.
| S-EPMC8383184 | biostudies-literature
Project description:Chemotherapies of varying classes often cause neuropathy and debilitating chemotherapy-induced neuropathic pain sufficient to limit treatment and reduce quality of life for many patients battling cancer. There are currently no effective preventive or alleviative treatments for chemotherapy-induced neuropathic pain. Preclinical models have been developed to test candidate chemotherapy-induced neuropathic pain treatments; however, studies using these models rarely provide direct comparisons of effects of different chemotherapies or assess the degree to which chemotherapies produce clinically relevant signs of pain-depressed behavior. Male and female Sprague-Dawley rats received four injections of vehicle, paclitaxel, oxaliplatin, vincristine, or bortezomib on alternate days. Mechanical hypersensitivity, body weight, and food-maintained operant responding were evaluated before, during, and for up to 42 days after initiation of treatment. Morphine potency and effectiveness to reverse chemotherapy-induced effects were also evaluated. All four chemotherapies produced dose-dependent and sustained mechanical hypersensitivity in all rats. Vincristine and oxaliplatin produced transient weight loss and decreases in food-maintained operant responding in all rats, whereas paclitaxel and bortezomib produced lesser or no effect. At 4 weeks after treatment, operant responding was depressed only in paclitaxel-treated males. Morphine reversed mechanical hypersensitivity in all rats but failed to reverse paclitaxel-induced depression of operant responding in males. We conclude that chemotherapy treatments sufficient to produce sustained mechanical hypersensitivity failed to produce sustained or morphine-reversible behavioral depression in rats. Insofar as pain-related behavioral depression is a cardinal sign of chemotherapy-induced neuropathic pain in humans, these results challenge the presumption that these chemotherapy-dosing regimens are sufficient to model clinically relevant chemotherapy-induced neuropathic pain in rats.
| S-EPMC7673225 | biostudies-literature
Project description:Dopamine acts through dopamine Type I receptors (comprising D1 and D5 subtypes) and dopamine Type II receptors (comprising D2, D3, and D4 subtypes). Intracranial self-stimulation (ICSS) is 1 experimental procedure that can be used to evaluate abuse-related effects of drugs targeting dopamine receptors. This study evaluated effects of dopamine receptor ligands on ICSS in rats using experimental procedures that have been used previously to examine abused indirect dopamine agonists such as cocaine and amphetamine. Male Sprague-Dawley rats responded under a fixed-ratio 1 schedule for electrical stimulation of the medial forebrain bundle, and frequency of stimulation varied from 56-158 Hz in 0.05 log increments during each experimental session. Drug potency and time course were determined for the D1 ligands A77636, SKF82958, SKF38393, fenoldopam, and SCH39166 and the D2/3 ligands sumanirole, apomorphine, quinpirole, PD128907, pramipexole, aripiprazole, eticlopride, and PG01037. The high-efficacy D1 agonists A77636 and SKF82958 produced dose-dependent, time-dependent, and abuse-related facilitation of ICSS. Lower efficacy D1 ligands and all D2/3 ligands failed to facilitate ICSS at any dose or pretreatment time. A mixture of SKF82958 and quinpirole produced a mixture of effects produced by each drug alone. Quinpirole also failed to facilitate ICSS after regimens of repeated treatment with either quinpirole or cocaine. These studies provide more evidence for divergent effects of dopamine D1- and D2-family agonists on ICSS procedure in rats and suggest that ICSS may be a useful complement to other approaches for preclinical abuse potential assessment, in part because of the reproducibility of results. (PsycINFO Database Record
| S-EPMC4891217 | biostudies-literature
Project description:Many different solid food pellets are available as reinforcers for rodents in operant behavior tests. Different reward formulations have not been compared, so it is unclear whether mice show strong preferences for different rewards and whether such preferences are consistent within or across sex and background strain. Here we show that mice have strong preferences for two balanced diet food rewards over sucrose pellets, and preference for one balanced diet pellet formulation over another, in a simultaneous choice test using a low effort fixed ratio operant test. All mice, of both sexes and both CD1 and C57 background strains, showed the same strong preferences among these three types of reinforcers. In contrast, flavorings added to the reward pellets had relatively small and more variable effects on preference. The preference for balanced diet pellets over sucrose pellets was seen also in the total numbers of rewards consumed in low effort tests with food pellets or only sucrose pellets available. However, progressive ratio testing showed that mice worked harder for sucrose pellets than for the preferred balanced diet pellets. These findings indicate that reinforcers with similar and very different preference profiles are readily available and that testing with different rewards can produce different, and sometimes unexpected, results.
| S-EPMC10497155 | biostudies-literature
Project description:IntroductionTobacco is highly addictive, and after the development of dependence, it is difficult to quit smoking. Therefore, it is important to understand the factors that play a role in the initiation of smoking. The rewarding effects of nicotine play a role in the initiation of smoking and the goal of the present study was to determine the rewarding effects of nicotine in adolescent and adult male and female rats.MethodsMale and female Wistar rats were prepared with intracranial self-stimulation (ICSS) electrodes between postnatal day (P) 23 and 33. They were then trained on the ICSS procedure and the effect of nicotine (0, 0.03, 0.1, 0.3 mg/kg) on the reward thresholds and response latencies was investigated during adolescence (P40-59) or adulthood (>P75).ResultsNicotine lowered the brain reward thresholds of the adult and adolescent male and female rats. The nicotine-induced decrease in the reward thresholds was the same in the adult male and adult female rats. However, nicotine induced a greater decrease in the reward thresholds of the adolescent female rats than the adolescent male rats. Nicotine decreased the response latencies of all groups and there was no effect of age or sex.ConclusionsNicotine enhances reward function and psychomotor performance in adolescent and adult male and female rats. Adolescent female rats are more sensitive to the acute rewarding effects of nicotine than adolescent male rats. Therefore, the rewarding effects of nicotine might play a greater role in the initiation of smoking in adolescent females than in adolescent males.ImplicationsThe great majority of people start smoking during adolescence. The present studies suggest that during this period female rats are more sensitive to the acute rewarding effects of low and intermediate doses of nicotine than male rats. The rewarding properties of nicotine play a role in the initiation of smoking and establishing habitual smoking. Therefore, the present findings might explain why adolescent females are at a higher risk for becoming nicotine dependent than adolescent males.
| S-EPMC8205503 | biostudies-literature
Project description:Sugar solutions promote hedonic feeding and increase the risk of obesity and binge-type behavior. In rodents, ingestion of sugar solutions enhances dopamine release to mesolimbic regions, suggesting changes in hedonic intake and brain reward processes. Moreover, dopaminergic D2R/D3R receptors contribute to the hedonic intake of palatable solutions. Although the experimental evidence indicate that the dopaminergic D4 receptor (D4R) modulates feeding at homeostatic levels, it is currently unknown whether D4R also regulate the hedonic intake of sugar solutions. In this study, we evaluated the effect of the central blockade of D4R on the consumption of a 20% sucrose solution, the drinking microstructure parameters, and levels of locomotor activity in sated rats. In the first experiment, male Wistar rats were daily exposed to a 20% sugar solution in the first hour of the light phase of the light:dark cycle. On day 10, rats received i.c.v injections of the D4R antagonist, L-745870 (0, 1 or 2 µg/5 µl) and sucrose consumption and drinking microstructure parameters (latency to start drinking, bouts, drinking duration, bout size, inter-bout interval, time in activity and time in resting) were evaluated. In the second experiment, rats were trained to receive the 20% sucrose solution as described in experiment 1. On day 10, after the 1 h of sucrose access, the rats were placed in the open field for 5-min (habituation phase). Then, rats received i.c.v injections of L-745870 (0, 1 or 2 µg/ 5 µl), and were placed again in the open-field test for 10-min (pharmacological phase). The number or crosses trough squares and number of rears were scored for both the habituation and pharmacological phase. Here we found that administration of L-745870 decreased the consumption of sucrose in a dose-depended manner. Moreover, L-745870-treated rats displayed microstructural changes, including greater number of bouts and reduced drinking duration, bout size and inter-bout intervals. Furthermore, the number of crosses and number of rears in the open field test remained unchanged for habituation and pharmacological phase. Finally, present findings suggest that D4R modulates the consumption of sugar solutions by alteration of hedonic responses, but the contribution of homeostatic systems is discussed. These results open perspectives for the potential use of the D4R antagonists for treating obesity or binge-eating behavior. Highlights • The DR4 antagonist, L-745870, decreased the hedonic intake for a sucrose solution.• The DR4 antagonist, L-745870, modified the drinking microstructure.• The DR4 antagonist, L-745870, did not alter the locomotor activity.• The DR4 may be a pharmacological target against binge eating or obesity.
| S-EPMC9958424 | biostudies-literature
Project description:The neurobiological mechanisms underlying social learning (ie, in which an animal's learning is influenced by another) are slowly being unraveled. Previous work with systemic treatments shows that dopamine (DA) D1-type receptors mediate social learning in the social transmission of food preferences (STFP) in mice. This study examines the involvement of one brain region underlying this effect. The ventral tegmental area has dopaminergic projections to many limbic structures, including the hippocampus-a site important for social learning in the STFP in rodents. In this study, adult male and female CD-1 mice received a dorsal hippocampal microinfusion of the D1-like receptor antagonist SCH23390 at 1, 2, 4, or 6 μg/μl 15 min before a 30 min social interaction with a same-sex conspecific, in which mice had the opportunity to learn a socially transmitted food preference. Results show that social learning was blocked in female mice microinfused with 6 μg/μl, and in males infused with 1, 4, or 6 μg/μl of SCH23390. This social learning impairment could not be explained by changes in total food intake, or olfactory discrimination. A detailed analysis of the social interactions also revealed that although SCH23390 did not affect oronasal investigation for either sex, drug treatments affected other social behaviors in a sex-specific manner; there was primarily a reduction in agonistic-related behaviors among males, and social investigatory-related behaviors among females. Thus, this study shows that dorsal hippocampal D1-type receptors mediate social learning and social behaviors in male and female mice.
| S-EPMC5645744 | biostudies-literature
Project description:Tobacco smoking is a well-known risk factor for subsequent alcohol abuse, but the neural events underlying this risk remain largely unknown. Alcohol and nicotine reinforcement involve common neural circuitry, including the mesolimbic dopamine system. We demonstrate in rodents that pre-exposure to nicotine increases alcohol self-administration and decreases alcohol-induced dopamine responses. The blunted dopamine response was due to increased inhibitory synaptic transmission onto dopamine neurons. Blocking stress hormone receptors prior to nicotine exposure prevented all interactions with alcohol that we measured, including the increased inhibition onto dopamine neurons, the decreased dopamine responses, and the increased alcohol self-administration. These results indicate that nicotine recruits neuroendocrine systems to influence neurotransmission and behavior associated with alcohol reinforcement.
| S-EPMC3755901 | biostudies-literature