Discrete-trial control of cocaine self-injection behaviour in squirrel monkeys: effects of morphine, naloxone, and chlorpromazine

1977 ◽  
Vol 55 (4) ◽  
pp. 778-790 ◽  
Author(s):  
Roger Stretch
Keyword(s):  
Fixed Ratio ◽  
Relative Sensitivity ◽  
Suppressive Effect ◽  
Dependent Manner ◽  
Self Administration ◽  
Drug Reinforcement ◽  
Discrete Trials ◽  
Small Doses ◽  
Large Injection ◽  
Unit Dose

Intravenous cocaine self-injection behaviour was studied using a new discrete-trials procedure in monkeys. Daily sessions consisted of two sets of 40 discrete trials, separated by a 5-min time out (TO) period; the intertrial interval during each segment of the session was equal to 50 s. In the first experiment, cocaine self-injection behaviour (15 μg/kg per injection) was suppressed in a dose-dependent manner by morphine pretreatment (1–5.6 mg/kg, im). When cocaine self-injection responding was suppressed by morphine pretreatment (3 or 5.6 mg/kg, im), the morphine antagonist, naloxone (0.01–1.0 mg/kg, im), reinstated drug-taking behaviour; the effect depended upon the dose of the antagonist and upon the amount of morphine given to suppress cocaine self-administration behaviour. When monkeys were pretreated with chlorpromazine (0.03–5.6 mg/kg, im) before a cocaine self-injection session, small doses marginally increased responding and larger doses exerted a suppressive effect. These effects were observed when cocaine was available at a unit dose of 15 μg/kg per injection. When the unit dose of cocaine was increased to 300 μg/kg per injection, small doses of chlorpromazine (0.03–1 mg/kg, im) exerted no clearly detectable effects, though responding for drug injections was profoundly suppressed when sessions were preceded by chlorpromazine pretreatment at doses of 3 and 5.6 mg/kg, im. In this experiment, drug intake per session was greater when a large injection dose (300 μg/kg per injection) was available for self-administration than when a small dose (15 μg/kg per injection) could be self-injected; the frequency of drug self-injection was reduced, however, when the larger unit dose of cocaine replaced the smaller one. When considered in relation to the results of other experiments, it is evident that control of cocaine self-injection responding by a discrete-trials procedure results in schedule-dependent behaviours that differ in relative sensitivity to drug pretreatments from cocaine-reinforced responding controlled by fixed-ratio schedules of drug reinforcement.

scholarly journals Maternal Separation Stress Affects Voluntary Ethanol Intake in a Sex Dependent Manner

2021 ◽  
Vol 12 ◽  
Author(s):  
Natalia Bonetti Bertagna ◽  
Cristiane Aparecida Favoretto ◽  
Ben Tagami Rodolpho ◽  
Paola Palombo ◽  
Thais Suemi Yokoyama ◽  
...  
Keyword(s):  
Maternal Separation ◽  
Fixed Ratio ◽  
Progressive Ratio ◽  
Ethanol Consumption ◽  
Ethanol Intake ◽  
Central Nucleus ◽  
Control Group ◽  
Dependent Manner ◽  
Self Administration ◽  
Extended Amygdala

Maternal separation (MS) stress is a predictive animal model for evaluating the effects of early stress exposure on alcohol use disorders (AUD). The extended amygdala (AMY) is a complex circuit involved in both stress- and ethanol-related responses. We hypothesized that MS stress may increase ethanol consumption in adulthood, as well as augment neuronal activity in extended AMY, in a sex-dependent manner. We aimed to investigate the influence of MS stress on the ethanol consumption of male and female mice, and the involvement of extended amygdala sub-nuclei in this process. The C57BL/6J pups were subjected to 180min of MS, from postnatal day (PND) 1 to 14. The control group was left undisturbed. On PND 45, mice (n=28) in cages were exposed to a bottle containing 20% ethanol (w/v) for 4h during the dark period of the light-dark cycle, for 3weeks. Afterward, mice underwent ethanol self-administration training in operant chambers under fixed ratio (FR) schedule. Then, subjects were tested under 2h sessions of a progressive-ratio (PR) schedule of reinforcement (the last ratio achieved was considered the breaking point), and at the end, a 4h session of FR schedule (binge-intake). An immunohistochemistry assay for Fos protein was performed in Nucleus Accumbens (NAcc), Bed Nucleus of Stria Terminalis (BNST), and AMY. Our results showed that in the third week of training, the female MS group consumed more ethanol than the respective control group. The MS group presented increased breakpoint parameters. Female control group and male MS group were more resistant to bitter quinine taste. Increased Fos-immunoreactive neurons (Fos-IR) were observed in the central nucleus of AMY, but not in NAcc nor BNST in male maternal-separated mice. Maternal separation stress may influence ethanol intake in adulthood, and it is dependent on the sex and reinforcement protocol.

scholarly journals β-caryophyllene, an FDA-Approved Food Additive, Inhibits Methamphetamine-Taking and Methamphetamine-Seeking Behaviors Possibly via CB2 and Non-CB2 Receptor Mechanisms

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiang-Hu He ◽  
Ewa Galaj ◽  
Guo-Hua Bi ◽  
Yi He ◽  
Briana Hempel ◽  
...  
Keyword(s):  
Fixed Ratio ◽  
Incentive Motivation ◽  
Brain Stimulation Reward ◽  
High Dose ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Cb2 Receptor ◽  
Self Administration ◽  
Cb2 Receptors

Recent research indicates that brain cannabinoid CB2 receptors are involved in drug reward and addiction. However, it is unclear whether β-caryophyllene (BCP), a natural product with a CB2 receptor agonist profile, has therapeutic effects on methamphetamine (METH) abuse and dependence. In this study, we used animal models of self-administration, electrical brain-stimulation reward (BSR) and in vivo microdialysis to explore the effects of BCP on METH-taking and METH-seeking behavior. We found that systemic administration of BCP dose-dependently inhibited METH self-administration under both fixed-ratio and progressive-ratio reinforcement schedules in rats, indicating that BCP reduces METH reward, METH intake, and incentive motivation to seek and take METH. The attenuating effects of BCP were partially blocked by AM 630, a selective CB2 receptor antagonist. Genetic deletion of CB2 receptors in CB2-knockout (CB2-KO) mice also blocked low dose BCP-induced reduction in METH self-administration, suggesting possible involvement of a CB2 receptor mechanism. However, at high doses, BCP produced a reduction in METH self-administration in CB2-KO mice in a manner similar as in WT mice, suggesting that non-CB2 receptor mechanisms underlie high dose BCP-produced effects. In addition, BCP dose-dependently attenuated METH-enhanced electrical BSR and inhibited METH-primed and cue-induced reinstatement of drug-seeking in rats. In vivo microdialysis assays indicated that BCP alone did not produce a significant reduction in extracellular dopamine (DA) in the nucleus accumbens (NAc), while BCP pretreatment significantly reduced METH-induced increases in extracellular NAc DA in a dose-dependent manner, suggesting a DA-dependent mechanism involved in BCP action. Together, the present findings suggest that BCP might be a promising therapeutic candidate for the treatment of METH use disorder.

Discrete-trial control of morphine self-injection behaviour in squirrel monkeys: effects of naloxone, morphine, and chlorpromazine

1977 ◽  
Vol 55 (3) ◽  
pp. 615-627 ◽  
Author(s):  
Roger Stretch
Keyword(s):  
Daily Basis ◽  
Self Administration ◽  
Small Unit ◽  
Discrete Trials ◽  
Time Out ◽  
Intravenous Morphine ◽  
Inter Trial Interval ◽  
Unit Dose ◽  
Response Output ◽  
Withdrawal Signs

Intravenous morphine self-injection behaviour was studied using a new discrete-trials procedure in monkeys. Morphine self-injection was most probable when small unit doses (10–100 μg/kg per injection) were available and least frequent, even in comparison with saline substitution, at doses of 300 and 400 μg/kg per injection. Despite variation of the inter-trial interval from 50 to 300 s small injection doses (25 and 100 μg/kg per injection) continued to sustain more frequent self-injection responding than a larger unit dose (400 μg/kg per injection). When daily sessions consisted of 40 trials at an inter-trial interval of 50 s, morphine self-injection behaviour (100 μg/kg per injection) was neither increased nor consistently decreased by naloxone pretreatment (0.1–1.0 mg/kg im). In subsequent experiments, daily sessions consisted of two sets of 40 discrete trials, separated by a time-out (TO) period. When monkeys were pretreated with morphine (5.6 mg/kg im) before a given session, responding for drug injections was suppressed; the effect was reversed by naloxone (1 mg/kg im) which, if injected at TO, reinstated morphine self-administration behaviour. When an injection of chlorpromazine (5.6 mg/kg im) preceded a given session, responding for morphine injections was also suppressed; naloxone (1 mg/kg im) failed to reinstate chlorpromazine-suppressed responding, indicating that naloxone acted as an acute morphine antagonist under some circumstances, but did not otherwise influence behaviour. When the unit dose of morphine was increased to 200 μg/kg per injection, naloxone (1–3 mg/kg im) elicited agitation and occasional vomiting in each monkey tested, but did not suppress their drug-taking behaviour. Though small increases in morphine intake were observed after naloxone pretreatment, substantial increases in response output during the inter-trial interval, with a consequent loss of stimulus control normally exerted by the trial signal, were observed. These results were interpreted in terms of acute, antagonist-precipitated withdrawal signs, not evident in response to naloxone pretreatment when drug self-injection responding was maintained on a daily basis by a limited number of smaller unit injection doses of morphine (50 or 100 μg/kg per injection).

scholarly journals Cocaine induces paradigm-specific changes to the transcriptome within the ventral tegmental area

2021 ◽  
Author(s):  
Rianne R. Campbell ◽  
Siwei Chen ◽  
Joy H. Beardwood ◽  
Alberto J. López ◽  
Lilyana V. Pham ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ventral Tegmental Area ◽  
Home Cage ◽  
Expression Patterns ◽  
Energy Regulation ◽  
Biological Processes ◽  
Cocaine Exposure ◽  
Self Administration ◽  
Drug Reinforcement ◽  
Ventral Tegmental

AbstractDuring the initial stages of drug use, cocaine-induced neuroadaptations within the ventral tegmental area (VTA) are critical for drug-associated cue learning and drug reinforcement processes. These neuroadaptations occur, in part, from alterations to the transcriptome. Although cocaine-induced transcriptional mechanisms within the VTA have been examined, various regimens and paradigms have been employed to examine candidate target genes. In order to identify key genes and biological processes regulating cocaine-induced processes, we employed genome-wide RNA-sequencing to analyze transcriptional profiles within the VTA from male mice that underwent one of four commonly used paradigms: acute home cage injections of cocaine, chronic home cage injections of cocaine, cocaine-conditioning, or intravenous-self administration of cocaine. We found that cocaine alters distinct sets of VTA genes within each exposure paradigm. Using behavioral measures from cocaine self-administering mice, we also found several genes whose expression patterns corelate with cocaine intake. In addition to overall gene expression levels, we identified several predicted upstream regulators of cocaine-induced transcription shared across all paradigms. Although distinct gene sets were altered across cocaine exposure paradigms, we found, from Gene Ontology (GO) term analysis, that biological processes important for energy regulation and synaptic plasticity were affected across all cocaine paradigms. Coexpression analysis also identified gene networks that are altered by cocaine. These data indicate that cocaine alters networks enriched with glial cell markers of the VTA that are involved in gene regulation and synaptic processes. Our analyses demonstrate that transcriptional changes within the VTA depend on the route, dose and context of cocaine exposure, and highlight several biological processes affected by cocaine. Overall, these findings provide a unique resource of gene expression data for future studies examining novel cocaine gene targets that regulate drug-associated behaviors.

scholarly journals Non-coding RNA suppresses FUS aggregation caused by mechanistic shear stress on pipetting in a sequence-dependent manner

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nesreen Hamad ◽  
Ryoma Yoneda ◽  
Masatomo So ◽  
Riki Kurokawa ◽  
Takashi Nagata ◽  
...  
Keyword(s):  
Shear Stress ◽  
Neurodegenerative Diseases ◽  
Suppressive Effect ◽  
Dependent Manner ◽  
Aggregation State ◽  
Fused In Sarcoma ◽  
Sequence Dependent ◽  
Non Coding Rna ◽  
Aggregation Inhibitors ◽  
Amorphous Aggregation

AbstractFused in sarcoma/translocated in liposarcoma (FUS/TLS) is a multitasking RNA/DNA binding protein. FUS aggregation is implicated in various neurodegenerative diseases. RNA was suggested to modulate phase transition of FUS. Here, we found that FUS transforms into the amorphous aggregation state as an instant response to the shear stress caused by usual pipetting even at a low FUS concentration, 100 nM. It was revealed that non-coding RNA can suppress the transformation of FUS into aggregates. The suppressive effect of RNA on FUS aggregation is sequence-dependent. These results suggested that the non-coding RNA could be a prospective suppressor of FUS aggregation caused by mechanistic stress in cells. Our finding might pave the way for more research on the role of RNAs as aggregation inhibitors, which could facilitate the development of therapies for neurodegenerative diseases.

scholarly journals Cannabinoid-Induced Conditioned Place Preference, Intravenous Self-Administration, and Behavioral Stimulation Influenced by Ghrelin Receptor Antagonism in Rats

2021 ◽  
Vol 22 (5) ◽  
pp. 2397
Author(s):  
Chrysostomos Charalambous ◽  
Tereza Havlickova ◽  
Marek Lapka ◽  
Nina Puskina ◽  
Romana Šlamberová ◽  
...  
Keyword(s):  
Conditioned Place Preference ◽  
Fixed Ratio ◽  
Place Preference ◽  
Self Administration ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Ghrelin Receptor ◽  
Addiction Therapy ◽  
Significant Efficacy ◽  
Lever Pressing

Cannabis/cannabinoids are widely used for recreational and therapy purposes, but their risks are largely disregarded. However, cannabinoid-associated use disorders and dependence are alarmingly increasing and an effective treatment is lacking. Recently, the growth hormone secretagogue receptor (GHSR1A) antagonism was proposed as a promising mechanism for drug addiction therapy. However, the role of GHS-R1A and its endogenous ligand ghrelin in cannabinoid abuse remains unclear. Therefore, the aim of our study was to investigate whether the GHS-R1A antagonist JMV2959 could reduce the tetrahydrocannabinol (THC)-induced conditioned place preference (CPP) and behavioral stimulation, the WIN55,212-2 intravenous self-administration (IVSA), and the tendency to relapse. Following an ongoing WIN55,212-2 self-administration, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 120-min IVSA sessions under a fixed ratio FR1, which significantly reduced the number of the active lever-pressing, the number of infusions, and the cannabinoid intake. Pretreatment with JMV2959 suggested reduction of the WIN55,212-2-seeking/relapse-like behavior tested in rats on the twelfth day of the forced abstinence period. On the contrary, pretreatment with ghrelin significantly increased the cannabinoid IVSA as well as enhanced the relapse-like behavior. Co-administration of ghrelin with JMV2959 abolished/reduced the significant efficacy of the GHS-R1A antagonist in the cannabinoid IVSA. Pretreatment with JMV2959 significantly and dose-dependently reduced the manifestation of THC-induced CPP. The THC-CPP development was reduced after the simultaneous administration of JMV2959 with THC during conditioning. JMV2959 also significantly reduced the THC-induced behavioral stimulation in the LABORAS cage. Our findings suggest that GHS-R1A importantly participates in the rewarding/reinforcing effects of cannabinoids.

scholarly journals The Adenosine A2A Receptor Activation in Nucleus Accumbens Suppress Cue-Induced Reinstatement of Propofol Self-administration in Rats

2021 ◽  
Author(s):  
Zhanglei Dong ◽  
Bingwu Huang ◽  
Chenchen Jiang ◽  
Jiangfan Chen ◽  
Han Lin ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
D2 Receptor ◽  
Fixed Ratio ◽  
Receptor Activation ◽  
Addictive Behaviors ◽  
Self Administration ◽  
A2a Receptors ◽  
Mediated Effects ◽  
Seeking Behavior ◽  
Adenosine A2a

AbstractPropofol has shown strong addictive properties in rats and humans. Adenosine A2A receptors (A2AR) in the nucleus accumbens (NAc) modulate dopamine signal and addictive behaviors such as cocaine- and amphetamine-induced self-administration. However, whether A2AR can modulate propofol addiction remains unknown. AAV-shA2AR was intra-NAc injected 3 weeks before the propofol self-administration training to test the impacts of NAc A2AR on establishing the self-administration model with fixed ratio 1 (FR1) schedule. Thereafter, the rats were withdrawal from propofol for 14 days and tested cue-induced reinstatement of propofol seeking behavior on day 15. The propofol withdrawal rats received one of the doses of CGS21680 (A2AR agonist, 2.5–10.0 ng/site), MSX-3 (A2AR antagonist, 5.0–20.0 μg/site) or eticlopride (D2 receptor (D2R) antagonist, 0.75–3.0 μg/site) or vehicle via intra-NAc injection before relapse behavior test. The numbers of active and inactive nose-poke response were recorded. Focal knockdown A2AR by shA2AR did not affect the acquisition of propofol self-administration behavior, but enhance cue-induced reinstatement of propofol self-administration compared with the AAV-shCTRLgroup. Pharmacological activation of the A2AR by CGS21680 (≥ 5.0 ng/site) attenuated cue-induced reinstatement of propofol self-administration behavior. Similarly, pharmacological blockade of D2R by eticlopride (0.75–3.0 μg/site) attenuated propofol seeking behavior. These effects were reversed by the administration of MSX-3 (5.0–20.0 μg/site). The A2AR- and D2R-mediated effects on propofol relapse were not confounded by the learning process, and motor activity as the sucrose self-administration and locomotor activity were not affected by all the treatments. This study provides genetic and pharmacological evidence that NAc A2AR activation suppresses cue-induced propofol relapse in rats, possibly by interacting with D2R.

scholarly journals Sex Differences in Escalated Methamphetamine Self-Administration and Altered Gene Expression Associated With Incubation of Methamphetamine Seeking

2019 ◽  
Vol 22 (11) ◽  
pp. 710-723 ◽  
Author(s):  
Atul P Daiwile ◽  
Subramaniam Jayanthi ◽  
Bruce Ladenheim ◽  
Michael T McCoy ◽  
Christie Brannock ◽  
...  
Keyword(s):  
Sex Differences ◽  
Nucleus Accumbens ◽  
Fixed Ratio ◽  
Female Rats ◽  
Male Rats ◽  
Mrna Levels ◽  
Self Administration ◽  
Male And Female ◽  
Orexin Receptors ◽  
Male And Female Rats

Abstract Background Methamphetamine (METH) use disorder is prevalent worldwide. There are reports of sex differences in quantities of drug used and relapses to drug use among individuals with METH use disorder. However, the molecular neurobiology of these potential sex differences remains unknown. Methods We trained rats to self-administer METH (0. 1 mg/kg/infusion, i.v.) on an fixed-ratio-1 schedule for 20 days using two 3-hour daily METH sessions separated by 30-minute breaks. At the end of self-administration training, rats underwent tests of cue-induced METH seeking on withdrawal days 3 and 30. Twenty-four hours later, nucleus accumbens was dissected and then used to measure neuropeptide mRNA levels. Results Behavioral results show that male rats increased the number of METH infusions earlier during self-administration training and took more METH than females. Both male and female rats could be further divided into 2 phenotypes labeled high and low takers based on the degree of escalation that they exhibited during the course of the METH self-administration experiment. Both males and females exhibited incubation of METH seeking after 30 days of forced withdrawal. Females had higher basal mRNA levels of dynorphin and hypocretin/orexin receptors than males, whereas males expressed higher vasopressin mRNA levels than females under saline and METH conditions. Unexpectedly, only males showed increased expression of nucleus accumbens dynorphin after METH self-administration. Moreover, there were significant correlations between nucleus accumbens Hcrtr1, Hcrtr2, Crhr2, and Avpr1b mRNA levels and cue-induced METH seeking only in female rats. Conclusion Our results identify some behavioral and molecular differences between male and female rats that had self-administered METH. Sexual dimorphism in responses to METH exposure should be considered when developing potential therapeutic agents against METH use disorder.

scholarly journals Concentration-Dependent Antioxidant/Pro-Oxidant Activity of Ascorbic Acid in Chickens

2012 ◽  
Vol 66 (6) ◽  
pp. 256-260
Author(s):  
Nadežda Berzina ◽  
Jurijs Markovs ◽  
Mirdza Apsīte ◽  
Svetlana Vasiļjeva ◽  
Galina Smirnova ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ascorbic Acid ◽  
Cadmium Concentration ◽  
Dehydroascorbic Acid ◽  
Cadmium Accumulation ◽  
Suppressive Effect ◽  
High Dose ◽  
Dependent Manner ◽  
Treatment Groups ◽  
Liver And Kidney

The effects of ascorbic acid supplementation on biomarkers of oxidative stress, cadmium accumulation in organs, immune system activity and kidney function in chickens were investigated. The treatment groups of chickens were fed either plain diet or diet supplemented with ascorbic acid at 100, 500, 1000 and 2000 mg/kg for four weeks. Liver and kidney tissues were assayed for cadmium concentration, and the hepatic levels of ascorbic acid and dehydroascorbic acid (DHAA; the oxidised form), malondialdehyde, glutathione, activity of glutathione peroxidase, blood serum uric acid, creatinine, lysozyme and circulating immune complexes were measured. Supplementation with a high dose of ascorbic acid (1000 and 2000 mg/kg in the diet) caused an imbalance between pro-oxidative and antioxidative activities, and induced a suppressive effect on innate immunity. The results suggest that oxidative stress compromises renal function. We observed that ascorbic acid increased cadmium accumulation in a dose-dependent manner.

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