Effects of Pair Housing on Patency of Jugular Catheters in Rats (Rattus norvegicus)

Chronic vascular access devices are widely used in a variety of species for repeated blood sampling or substance administration. Jugular catheters are commonly used for studying addiction-related behaviors in rats. Rats with catheters have historically been individually housed for the duration of the study to prevent cage mates from damaging the catheter. The 2 goals of this study were to determine 1) the effects of pair housing on catheter patency and 2) the effects of pair housing on catheter patency of rats in a study of opioid self-administration and cue-induced reinstatement of opioid-seeking behavior. The latter study also represented an opportunity for experimental refinement as it evaluated the temporary use of a barrier that allowed for pair-housed rats to be physically separated. Male Heterogeneous Stock (HS; n = 24) and Sprague–Dawley(SD; n = 121) rats were allocated to either single- or pair-housed condition. To assess the effect of social housing on catheter patency, rats (HS, n = 24; SD, n = 36) were monitored in their assigned housing condition for one month, with scheduled evaluation of catheter patency and structural damage. To examine the effect of social housing on catheter patency during a study of opioid self-administration and cue-induced reinstatement of opioid-seeking behavior, rats (SD, n = 85) were monitored in their assigned housing condition with similar routine patency evaluations. Catheter patency rates between single- and pairhoused rats were not statistically different in the first experiment, and pair-housed animals were successfully maintained on an infusion study in the second experiment. The use of a barrier between pair-housed rats after surgery allowed continued social contact with no observed adverse effects. These results suggest that, pair housing is a viable option for rats with chronicvascular implants, and may improve their wellbeing by allowing them to display species-typical social behaviors.

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Electroacupuncture Suppresses Discrete Cue-Evoked Heroin-Seeking and Fos Protein Expression in the Nucleus Accumbens Core in Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/286404 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

Sheng Liu ◽

Fenglei Zhu ◽

Miaojun Lai ◽

Limin Sun ◽

Yijun Liu ◽

...

Keyword(s):

Nucleus Accumbens ◽

Therapeutic Benefit ◽

Sprague Dawley ◽

Contextual Cues ◽

Self Administration ◽

Nucleus Accumbens Core ◽

Beneficial Effects ◽

Fos Protein ◽

Sprague Dawley Rats ◽

Seeking Behavior

Relapse to drug seeking was studied using a rodent model of reinstatement induced by exposure to drug-related cues. Here, we used intravenous drug self-administration procedures in rats to further investigate the beneficial effects of electroacupuncture (EA) on heroin-seeking behavior in a reinstatement model of relapse. We trained Sprague-Dawley rats to nose-poke for i.v. heroin either daily for 4 h or 25 infusions for 14 consecutive days. Then the rats were abstinent from heroin for two weeks. 2 Hz EA stimulation was conducted once daily for 14 days during heroin abstinence. We tested these animals for contextual and discrete cue-induced reinstatement of active responses. We also applied immunohistochemistry to detect Fos-positive nuclei in the nucleus accumbens (NACc) core and shell after reinstatement test. We found that active responses elicited by both contextual cues and discrete cues were high in the rats trained with heroin than in saline controls. EA treatment significantly reduced active responses elicited by discrete cues. EA stimulation attenuated Fos expression in the core but not the shell of the NACc. Altogether, these results highlight the therapeutic benefit of EA in preventing relapse to drug addiction.

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Vaporized cannabis extracts have reinforcing properties and support conditioned drug-seeking behavior in rats

10.1101/791319 ◽

2019 ◽

Cited By ~ 1

Author(s):

Timothy G. Freels ◽

Lydia N. Baxter-Potter ◽

Janelle M. Lugo ◽

Nicholas C. Glodosky ◽

Hayden R. Wright ◽

...

Keyword(s):

Fixed Ratio ◽

Progressive Ratio ◽

Sprague Dawley ◽

Self Administration ◽

Daily Food ◽

Sprague Dawley Rats ◽

Seeking Behavior ◽

Break Points ◽

Bona Fide ◽

Novel Method

ABSTRACTRecent trends in cannabis legalization have increased the necessity to better understand the effects of cannabis use. Animal models involving traditional cannabinoid self-administration approaches have been notoriously difficult to establish and differences in the drug employed and its route of administration have limited the translational value of preclinical studies. To address this challenge in the field, we have developed a novel method of cannabis self-administration using response-contingent delivery of vaporized Δ9-tetrahydrocannabinol-rich (CANTHC) or cannabidiol-rich (CANCBD) complete cannabis extracts. Male Sprague Dawley rats were trained to nosepoke for discrete puffs of CANTHC, CANCBD, or vehicle (VEH) in daily one-hour sessions. Cannabis vapor reinforcement resulted in strong discrimination between active and inactive operanda. CANTHC maintained higher response rates under fixed ratio schedules and higher break points under progressive ratio schedules compared to CANCBD or VEH, and the number of vapor deliveries positively correlated with plasma THC concentrations. Moreover, metabolic phenotyping studies revealed alterations in locomotor activity, energy expenditure, and daily food intake that are consistent with effects in human cannabis users. Furthermore, both cannabis regimens produced ecologically relevant brain concentrations of THC and CBD and CANTHC administration decreased hippocampal CB1 receptor binding. Removal of CANTHC reinforcement (but not CANCBD) resulted in a robust extinction burst and an increase in cue-induced cannabis-seeking behavior relative to VEH. These data indicate that volitional exposure to THC-rich cannabis vapor has bona fide reinforcing properties and collectively support the utility of the vapor self-administration model for the preclinical assessment of volitional cannabis intake and cannabis-seeking behaviors.

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Role of GABRD Gene Methylation in the Nucleus Accumbens in Heroin-Seeking Behavior in Rats

Frontiers in Pharmacology ◽

10.3389/fphar.2020.612200 ◽

2021 ◽

Vol 11 ◽

Author(s):

Qingxiao Hong ◽

Wenjin Xu ◽

Zi Lin ◽

Jing Liu ◽

Weisheng Chen ◽

...

Keyword(s):

Dna Methylation ◽

Nucleus Accumbens ◽

Dna Methyltransferase ◽

Opposite Effect ◽

Heroin Addiction ◽

Gamma Aminobutyric Acid ◽

Sprague Dawley ◽

Self Administration ◽

Drug Induced ◽

Seeking Behavior

Epigenetic modifications such as DNA methylation play important roles in regulating gene expression and may mediate neuroplasticity and lead to drug-induced aberrant behaviors. Although several brain regions and neurobiological mechanisms have been suggested to be involved in these processes, there is remarkably little known about the effects of DNA methylation on heroin-seeking behavior. Using a Sprague-Dawley rat model, we show that heroin self-administration resulted in gamma-aminobutyric acid type A receptor subunit delta (GABRD) gene hypomethylation, which was associated with transcriptional upregulation of GABRD in the nucleus accumbens (NAc). Systemic l-methionine (MET) administration significantly strengthened the reinstatement of heroin-seeking behavior induced by heroin priming, whereas intra-NAc injections of the DNA methyltransferase (DNMT) inhibitor 5-aza-2′-deoxycytidine (5-Aza-dC) had the opposite effect on heroin-seeking. Meanwhile, 5-Aza-dC treatment decreased DNA methylation and upregulated the expression of GABRD in the NAc, whereas MET had the opposite effect. Our results also reveal that 5-Aza-dC might alter the methylation landscape of the GABRD gene by directly repressing DNMT1 and DNMT3A expression. Furthermore, reinstatement of heroin-seeking behavior was significantly inhibited by directly overexpressing GABRD and remarkably reinforced by GABRD gene silencing in the NAc. Collectively, these results suggest that targeting the GABRD gene and its methylation might represent a novel pharmacological strategy for treating heroin addiction and relapse.

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Glucagon-like peptide-1 receptor agonist, exendin-4, reduces reinstatement of heroin seeking behavior in rats

10.1101/730408 ◽

2019 ◽

Cited By ~ 1

Author(s):

Joaquin E. Douton ◽

Corinne Augusto ◽

Brooke A Stultzfus ◽

Nurgul Carkaci-Salli ◽

Kent E. Vrana ◽

...

Keyword(s):

Phase 1 ◽

Phase 2 ◽

Sprague Dawley ◽

Nucleus Accumbens Shell ◽

Self Administration ◽

Phase 3 ◽

Drug Induced ◽

Seeking Behavior ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

AbstractBackgroundStudies have shown that ‘satiety’ agents such as exendin-4 (a glucagon-like peptide-1 analog) reduce responding for addictive drugs (e.g., cocaine, nicotine, alcohol). In this study we tested the effect of exendin-4 on cue-induced and drug-induced reinstatement of heroin seeking behavior in rats.MethodsThis study consisted of three phases: In Phase 1, 55 male Sprague-Dawley rats had 15 daily pairings of saccharin with heroin self-administration. In Phase 2, rats experienced a 16-day home cage abstinence period and daily treatment with vehicle or exendin-4. On day 17, an extinction/reinstatement test was performed to assess drug seeking. In Phase 3, rats experienced 9 days of extinction followed by a reinstatement only test. Finally, expression of mRNA for various receptors in the nucleus accumbens shell (NAcS) was measured using RTqPCR.ResultsIn Phase 1, rats that avoided intake of the heroin-paired saccharin cue exhibited shorter latency to obtain the first infusion. In Phase 2, treatment with exendin-4 decreased cue-induced, but not drug-induced heroin seeking. In Phase 3, saccharin avoiders previously treated with exendin-4 increased acceptance of saccharin, and 1-hour pretreatment with Exendin-4 abolished drug-induced heroin seeking. Finally, exendin-4 treatment increased expression of mRNA for the Orexin 1 receptor (OX1) in the NAcS, but did not affect expression of dopamine D2 receptors, GLP-1 receptors, or leptin receptors in this same structure.ConclusionExendin-4 reduced cue- and drug-induced heroin seeking and increased acceptance of the drug-associated saccharin cue. These changes in behavior were accompanied by an increase in the expression of the OX1 receptor in the NAcS.

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Social Interaction With Relapsed Partner Facilitates Cocaine Relapse in Rats

Frontiers in Pharmacology ◽

10.3389/fphar.2021.750397 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shiqiu Meng ◽

Wei Yan ◽

Xiaoxing Liu ◽

Yimiao Gong ◽

Shanshan Tian ◽

...

Keyword(s):

Social Interaction ◽

Social Factors ◽

Sprague Dawley ◽

Self Administration ◽

Facilitation Effect ◽

Drug Seeking ◽

Cocaine Seeking ◽

Social Partners ◽

Seeking Behavior ◽

Drug Relapse

Social factors strongly contribute to drug use and relapse, and epidemiological studies have found that members of peer groups influence each other to use drugs. However, previous animal models mostly failed to incorporate social factors and demonstrate the effects of social partners on drug addiction and relapse. In the present study, we investigated the transfer of relapse to cocaine seeking between drug-addicted partners in rats. Male Sprague–Dawley rats were pair-housed and subjected to training and extinction of cocaine self-administration and conditioned place preference (CPP). 24 h after extinction test, the targeted rats interacted with a cocaine-primed (relapsed) partner or stranger, or saline-injected (unrelapsed) partner for 30 min, after which the targeted rats were tested for drug seeking behavior. We found that social interaction with a relapsed partner increased drug seeking behavior in cocaine self-administration and CPP models in rats, while social interaction with an unrelapsed partner or relapsed stranger had no effect on cocaine seeking. Moreover, the effect of social interaction on cocaine seeking could last for at least 1 day. Our findings demonstrate a facilitation effect of relapsed social partners on drug relapse in rats and provide a novel animal model for social transfer of drug relapse.

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

Neurochemical Research ◽

10.1007/s11064-021-03238-9 ◽

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.

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Proximal tubule microvilli remodeling and albuminuria in the Ren2 transgenic rat

AJP Renal Physiology ◽

10.1152/ajprenal.00252.2006 ◽

2007 ◽

Vol 292 (2) ◽

pp. F861-F867 ◽

Cited By ~ 17

Author(s):

Melvin R. Hayden ◽

Nazif A. Chowdhury ◽

Shawna A. Cooper ◽

Adam Whaley-Connell ◽

Javad Habibi ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Systolic Blood Pressure ◽

Proximal Tubule ◽

Structural Damage ◽

Kidney Tissue ◽

Proximal Tubule Cell ◽

Ang Ii ◽

Sprague Dawley ◽

Sprague Dawley Rats

TG(mRen2)27 (Ren2) transgenic rats overexpress the mouse renin gene, with subsequent elevated tissue ANG II, hypertension, and nephropathy. The proximal tubule cell (PTC) is responsible for the reabsorption of 5–8 g of glomerular filtered albumin each day. Excess filtered albumin may contribute to PTC damage and tubulointerstitial disease. This investigation examined the role of ANG II-induced oxidative stress in PTC structural remodeling: whether such changes could be modified with in vivo treatment with ANG type 1 receptor (AT1R) blockade (valsartan) or SOD/catalase mimetic (tempol). Male Ren2 (6–7 wk old) and age-matched Sprague-Dawley rats were treated with valsartan (30 mg/kg), tempol (1 mmol/l), or placebo for 3 wk. Systolic blood pressure, albuminuria, N-acetyl-β-d-glucosaminidase, and kidney tissue malondialdehyde (MDA) were measured, and ×60,000 transmission electron microscopy images were used to assess PTC microvilli structure. There were significant differences in systolic blood pressure, albuminuria, lipid peroxidation (MDA and nitrotyrosine staining), and PTC structure in Ren2 vs. Sprague-Dawley rats (each P < 0.05). Increased mean diameter of PTC microvilli in the placebo-treated Ren2 rats ( P < 0.05) correlated strongly with albuminuria ( r2 = 0.83) and moderately with MDA ( r2 = 0.49), and there was an increase in the ratio of abnormal forms of microvilli in placebo-treated Ren2 rats compared with Sprague-Dawley control rats ( P < 0.05). AT1R blockade, but not tempol treatment, abrogated albuminuria and N-acetyl-β-d-glucosaminidase; both therapies corrected abnormalities in oxidative stress and PTC microvilli remodeling. These data indicate that PTC structural damage in the Ren2 rat is related to the oxidative stress response to ANG II and/or albuminuria.

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Effects of adolescent caffeine consumption on cocaine self-administration and reinstatement of cocaine seeking

Journal of Psychopharmacology ◽

10.1177/0269881118812098 ◽

2018 ◽

Vol 33 (1) ◽

pp. 132-144

Author(s):

Tracey A Larson ◽

Casey E O’Neill ◽

Michaela P Palumbo ◽

Ryan K Bachtell

Keyword(s):

Dose Response ◽

Extinction Training ◽

Schedules Of Reinforcement ◽

Sprague Dawley ◽

Self Administration ◽

Caffeine Consumption ◽

Adult Rats ◽

Sprague Dawley Rats ◽

Cocaine Seeking ◽

Administration Procedure

Background: Caffeine consumption by children and adolescents has risen dramatically in recent years, yet the lasting effects of caffeine consumption during adolescence remain poorly understood. Aim: These experiments explore the effects of adolescent caffeine consumption on cocaine self-administration and seeking using a rodent model. Methods: Sprague-Dawley rats consumed caffeine for 28 days during the adolescent period. Following the caffeine consumption period, the caffeine solution was replaced with water for the remainder of the experiment. Age-matched control rats received water for the duration of the study. Behavioral testing in a cocaine self-administration procedure occurred during adulthood (postnatal days 62–82) to evaluate how adolescent caffeine exposure influenced the reinforcing properties of cocaine. Cocaine seeking was also tested during extinction training and reinstatement tests following cocaine self-administration. Results: Adolescent caffeine consumption increased the acquisition of cocaine self-administration and increased performance on different schedules of reinforcement. Consumption of caffeine in adult rats did not produce similar enhancements in cocaine self-administration. Adolescent caffeine consumption also produced an upward shift in the U-shaped dose response curve on cocaine self-administration maintained on a within-session dose-response procedure. Adolescent caffeine consumption had no effect on cocaine seeking during extinction training or reinstatement of cocaine seeking by cues or cocaine. Conclusions: These findings suggest that caffeine consumption during adolescence may enhance the reinforcing properties of cocaine, leading to enhanced acquisition that may contribute to increased addiction vulnerability.

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Impact of Morphine Dependence and Withdrawal on the Reinforcing Effectiveness of Fentanyl, Cocaine, and Methamphetamine in Rats

Frontiers in Pharmacology ◽

10.3389/fphar.2021.691700 ◽

2021 ◽

Vol 12 ◽

Author(s):

Robert W. Seaman Jr ◽

Gregory T. Collins

Keyword(s):

Opioid Dependence ◽

Progressive Ratio ◽

Morphine Dependence ◽

Sprague Dawley ◽

Self Administration ◽

Stimulant Use ◽

Concurrent Use ◽

Reinforcing Effects ◽

The Individual ◽

The Impact

Recent estimates suggest increased popularity of the concurrent use of opioids and stimulants, with over 50% of treatment-seeking opioid users reporting regular stimulant use. The goal of the current study was to determine how opioid dependence and withdrawal affect the reinforcing effects of fentanyl, cocaine, and methamphetamine. Male Sprague-Dawley rats were allowed to self-administer fentanyl under a progressive ratio (PR) schedule of reinforcement. Baseline evaluations of reinforcing effectiveness of fentanyl, cocaine, and methamphetamine were determined. Opioid dependence was then established by administering escalating doses of morphine (10–40 mg/kg) twice-daily for four days and subsequently maintained by once-daily injections of 40 mg/kg morphine. To evaluate the impact of opioid dependence and withdrawal on the self-administration of fentanyl, cocaine, and methamphetamine, sessions occurred either 12 or 20 h after the morphine, respectively. During opioid withdrawal, the fentanyl dose-response curve was shifted rightward with an increase in maximal effectiveness, whereas it was shifted rightward with a reduction in maximal effectiveness when evaluated in rats currently dependent on opioids, relative to baseline. The reinforcing effects of cocaine and methamphetamine were unchanged by either condition. The current studies provide direct evidence that the reinforcing effects of fentanyl are increased in opioid-withdrawn rats and reduced in opioid-dependent rats, relative to rats that are not physically dependent on opioids. These findings suggest that motivations to use opioids are dependent on the state of the individual whereas stimulants retain their reinforcing effects regardless of whether the individual is in an opioid-dependent or withdrawn state.

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Ibogaine Modifies GDNF, BDNF and NGF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits

10.26434/chemrxiv.7261559 ◽

2018 ◽

Author(s):

Soledad Marton ◽

Bruno González ◽

Sebastián Rodríguez ◽

Ernesto Miquel ◽

Laura Martínez Palma ◽

...

Keyword(s):

Neurotrophic Factor ◽

Dopaminergic Neurons ◽

Brain Regions ◽

Dopamine Neurons ◽

Acute Administration ◽

Dependent Manner ◽

Self Administration ◽

Seeking Behavior ◽

A Site ◽

Dose Dependent

Ibogaine is a psychedelic alkaloid which has been subject of intense scientific research due to its reported ability to attenuate drug-seeking behavior. Recent work suggested that ibogaine effects on alcohol self-administration in rats was related to the release of Glial Cell Derived Neurotrophic Factor (GDNF) in the Ventral Tegmental Area (VTA), a mesencephalic region which hosts soma of dopamine neurons. It is well known that neurotrophic factors (NFs) mediate the neuroadaptations induced in the mesocorticolimbic dopaminergic system by repeated exposure to drugs. Although previous reports have shown ibogaine´s ability to induce GDNF expression in rat midbrain, there are no studies addressing its effect on the expression of GDNF, Brain Derived Neurotrophic Factor (BDNF) or Nerve Growth Factor (NGF) in distinct regions containing dopaminergic neurons. In this work, we examined the effect of ibogaine acute administration on the expression of these NFs in the VTA, Prefrontal Cortex (PFC), Nucleus Accumbens (NAcc) and the Substantia Nigra (SN). Thus, rats were i.p. treated with ibogaine 20 mg/kg (I20), 40 mg/kg (I40) or vehicle, and NFs expression was analyzed after 3 and 24 hours. Only at 24 h an increase of the expression for the three NFs were observed in a site and dose dependent manner. Results for GDNF showed that only I40 selectively upregulated its expression in the VTA and SN. Both doses of ibogaine elicited a large increase in the expression of BDNF in the NAcc, SN and PFC, while a significant effect was found in the VTA only for I40. Finally, NGF was found to be upregulated in all regions after I40, while a selective upregulation was found in PFC and VTA for the I20 treatment. An increase in the content of mature GDNF was observed in the VTA but no significant increase in the mature BDNF protein content was found in all the studied areas. Interestingly, an increase in the content of proBDNF was detected in the NAcc for both treatments. Further research is needed to understand the neurochemical bases of these changes, and to confirm their contribution to the anti-addictive properties of ibogaine.

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