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

2019 ◽  
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.

scholarly journals Contribution of Harman and Norharman to the Reinforcing Efficacy of Aqueous Tobacco Smoke Extract Self-Administered by Rats

2021 ◽  
Author(s):  
◽  
Alex John Crowther
Keyword(s):  
Tobacco Smoke ◽  
Fixed Ratio ◽  
Progressive Ratio ◽  
Sprague Dawley ◽  
Self Administration ◽  
Reinforcing Efficacy ◽  
Treatment Groups ◽  
Sprague Dawley Rats ◽  
Reinforcing Agent

<p>Background: Animal models of drug abuse treat nicotine as the primary reinforcing agent that promotes tobacco addiction. However, rodents demonstrate poor self-administration of nicotine despite evidence of tobacco's high abuse potential in humans. This discrepancy has been attributed to other constituents of tobacco smoke that facilitate the development of nicotine dependence. Objectives: This study aimed to determine whether rats would self-administer intravenous an aqueous tobacco smoke extract (TPM) to find evidence if it was more reinforcing than nicotine alone. The study also evaluated the role of tobacco smoke constituent’s harman and norharman in any differences observed. Methods: Firstly, male Sprague-Dawley rats (n=29) were assigned to treatment groups: nicotine (30.0μg/kg/infusion), TPM (containing 30.0μg/kg/infusion nicotine) or saline vehicle. Ability for each treatment to support intravenous self-administration was assessed using spontaneous acquisition of responding on gradually increasing fixed ratio schedules (FR1, FR2, FR5). Subsequent progressive ratio (PR) testing was employed to determine reinforcing efficacy of each treatment. Then a second group of rats (N = 56) were assigned to treatment groups: nicotine alone (30.0 or 75.0μg/kg/infusion) or nicotine combined with norharman (0, 0.4, 2.5 or 6.25μg/kg/infusion) and harman (0.0, 1.6 or 10.0μg/kg, IP), and tested using a similar protocol. Results: Animals readily acquired self-administration responding for TPM and produced higher PR breakpoints (BP) than rats treated with nicotine alone or vehicle. Rats trained to respond for a larger dose of nicotine demonstrated significantly greater response rates than those receiving the lower dose of nicotine. Finally, the addition of harman and norharman to nicotine significantly reduced BP at the lower unit dose of nicotine tested. Conclusions: These findings support the hypothesis that TPM is more reinforcing than nicotine alone. However, the increased reinforcing efficacy of TPM cannot be attributed to the actions of harman and norharman. The potential role of serotonin inhibition in tobacco reward processes is discussed.</p>

Cannabidiol treatment reduces the motivation to self-administer methamphetamine and methamphetamine-primed relapse in rats

2018 ◽  
Vol 32 (12) ◽  
pp. 1369-1378 ◽  
Author(s):  
Gracie L Hay ◽  
Sarah J Baracz ◽  
Nicholas A Everett ◽  
Jessica Roberts ◽  
Priscila A Costa ◽  
...  
Keyword(s):  
Lever Press ◽  
Jugular Vein ◽  
Fixed Ratio ◽  
Progressive Ratio ◽  
Preliminary Evidence ◽  
Sprague Dawley ◽  
Psychosocial Effects ◽  
Methamphetamine Dependence ◽  
Sprague Dawley Rats ◽  
Seeking Behavior

Background: Methamphetamine is an addictive stimulant that can cause many adverse physical, psychological and psychosocial effects. Preliminary evidence shows cannabidiol, a non-intoxicating constituent of the cannabis plant, may have efficacy in treating opioid and nicotine dependence. However, no study has yet examined whether cannabidiol treatment might impact on methamphetamine addiction. Aims: The current study investigated whether cannabidiol administration reduces the motivation to self-administer methamphetamine and relapse to methamphetamine-seeking behavior following abstinence. Methods: Thirty-two male Sprague Dawley rats with implanted jugular vein catheters were initially trained to self-administer methamphetamine via lever press during two-hour sessions on a fixed ratio 1 schedule of reinforcement. Rats in experiment 1 ( n=16) then advanced to a progressive ratio reinforcement schedule to examine the effects of cannabidiol (0, 20, 40, and 80 mg/kg intraperitoneal) on motivation to self-administer methamphetamine. Rats in experiment 2 ( n=16) were tested for cannabidiol effects on methamphetamine-primed reinstatement following extinction. Results: Cannabidiol (80 mg/kg, but not 40 mg/kg, or 20 mg/kg) reduced the motivation to self-administer methamphetamine and attenuated methamphetamine-primed relapse to methamphetamine-seeking behavior after extinction. Conclusion: This is the first demonstration that cannabidiol can reduce the motivation to seek and consume methamphetamine, and suggests that cannabidiol might be worth trialing as a novel pharmacotherapy for methamphetamine dependence.

scholarly journals Contribution of Harman and Norharman to the Reinforcing Efficacy of Aqueous Tobacco Smoke Extract Self-Administered by Rats

2021 ◽  
Author(s):  
◽  
Alex John Crowther
Keyword(s):  
Tobacco Smoke ◽  
Fixed Ratio ◽  
Progressive Ratio ◽  
Sprague Dawley ◽  
Self Administration ◽  
Reinforcing Efficacy ◽  
Treatment Groups ◽  
Sprague Dawley Rats ◽  
Reinforcing Agent

<p>Background: Animal models of drug abuse treat nicotine as the primary reinforcing agent that promotes tobacco addiction. However, rodents demonstrate poor self-administration of nicotine despite evidence of tobacco's high abuse potential in humans. This discrepancy has been attributed to other constituents of tobacco smoke that facilitate the development of nicotine dependence. Objectives: This study aimed to determine whether rats would self-administer intravenous an aqueous tobacco smoke extract (TPM) to find evidence if it was more reinforcing than nicotine alone. The study also evaluated the role of tobacco smoke constituent’s harman and norharman in any differences observed. Methods: Firstly, male Sprague-Dawley rats (n=29) were assigned to treatment groups: nicotine (30.0μg/kg/infusion), TPM (containing 30.0μg/kg/infusion nicotine) or saline vehicle. Ability for each treatment to support intravenous self-administration was assessed using spontaneous acquisition of responding on gradually increasing fixed ratio schedules (FR1, FR2, FR5). Subsequent progressive ratio (PR) testing was employed to determine reinforcing efficacy of each treatment. Then a second group of rats (N = 56) were assigned to treatment groups: nicotine alone (30.0 or 75.0μg/kg/infusion) or nicotine combined with norharman (0, 0.4, 2.5 or 6.25μg/kg/infusion) and harman (0.0, 1.6 or 10.0μg/kg, IP), and tested using a similar protocol. Results: Animals readily acquired self-administration responding for TPM and produced higher PR breakpoints (BP) than rats treated with nicotine alone or vehicle. Rats trained to respond for a larger dose of nicotine demonstrated significantly greater response rates than those receiving the lower dose of nicotine. Finally, the addition of harman and norharman to nicotine significantly reduced BP at the lower unit dose of nicotine tested. Conclusions: These findings support the hypothesis that TPM is more reinforcing than nicotine alone. However, the increased reinforcing efficacy of TPM cannot be attributed to the actions of harman and norharman. The potential role of serotonin inhibition in tobacco reward processes is discussed.</p>

scholarly journals 7,8-Dihydroxyflavone Enhances Cue-Conditioned Alcohol Reinstatement in Rats

2020 ◽  
Vol 10 (5) ◽  
pp. 270 ◽  
Author(s):  
Samuel J. Hogarth ◽  
Elvan Djouma ◽  
Maarten van den Buuse
Keyword(s):  
Body Weight ◽  
Progressive Ratio ◽  
Ethanol Exposure ◽  
Ethanol Solution ◽  
Female Rats ◽  
Male Rats ◽  
Sprague Dawley ◽  
Self Administration ◽  
Bdnf Expression ◽  
Sprague Dawley Rats

Alcohol use disorder (AUD) is a detrimental disease that develops through chronic ethanol exposure. Reduced brain-derived neurotrophic factor (BDNF) expression has been associated with AUD and alcohol addiction, however the effects of activation of BDNF signalling in the brain on voluntary alcohol intake reinstatement and relapse are unknown. We therefore trained male and female Sprague Dawley rats in operant chambers to self-administer a 10% ethanol solution. Following baseline acquisition and progressive ratio (PR) analysis, rats were split into drug and vehicle groups during alcohol lever extinction. The animals received two weeks of daily IP injection of either the BDNF receptor, TrkB, agonist, 7,8-dihydroxyflavone (7,8-DHF), or vehicle. During acquisition of alcohol self-administration, males had significantly higher absolute numbers of alcohol-paired lever presses and a higher PR breakpoint. However, after adjusting for body weight, the amount of ethanol was not different between the sexes and the PR breakpoint was higher in females than males. Following extinction, alcohol-primed reinstatement in male rats was not altered by pretreatment with 7,8-DHF when adjusted for body weight. In contrast, in female rats, the weight-adjusted potential amount of ethanol, but not absolute numbers of active lever presses, was significantly enhanced by 7,8-DHF treatment during reinstatement. Analysis of spontaneous locomotor activity in automated photocell cages suggested that the effect of 7,8-DHF was not associated with hyperactivity. These results suggest that stimulation of the TrkB receptor may contribute to reward craving and relapse in AUD, particularly in females.

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

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
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.

scholarly journals Knockdown of Hypocretin/Orexin Attenuates Extended-Access Cocaine Self-Administration in Rats

2017 ◽  
Author(s):  
Brooke E. Schmeichel ◽  
Alessandra Matzeu ◽  
Pascale Koebel ◽  
Leandro F. Vendruscolo ◽  
Brigitte L. Kieffer ◽  
...  
Keyword(s):  
Stress Responses ◽  
Viral Vector ◽  
Fixed Ratio ◽  
Progressive Ratio ◽  
Ratio Schedule ◽  
Self Administration ◽  
Adult Rats ◽  
Extended Access ◽  
Seeking Behavior ◽  
Melanin Concentrating Hormone

AbstractThe hypocretin/orexin (HCRT) neuropeptide system regulates feeding, arousal state, stress responses, and reward, especially under conditions of enhanced motivational relevance. In particular, HCRT neurotransmission facilitates drug-seeking behavior in circumstances that demand increased effort and/or motivation to take the drug. The present study used a shRNA-encoding adeno-associated viral vector to knockdown Hcrt expression throughout the dorsal hypothalamus in adult rats and determine the role of HCRT in cocaine self-administration. Longterm Hcrt silencing did not impact cocaine self-administration under short-access conditions, but robustly attenuated cocaine intake during extended self-administration access, a model that mimics key features of compulsive cocaine-taking. In addition, Hcrt silencing decreased motivation for both cocaine and palatable food (i.e., sweetened condensed milk; SCM) under a progressive ratio schedule of reinforcement, but did not alter responding for SCM under a fixed ratio schedule. Importantly, Hcrt silencing did not affect food or water consumption, and had no consequence to general measures of arousal-dependent behaviors. At the molecular level, longterm Hcrt knockdown moderately reduced the downstream expression of dynorphin (DYN) and melanin-concentrating hormone (MCH) in the dorsal hypothalamus. These original findings support the hypothesis that HCRT neurotransmission promotes operant responding for both drug and non-drug rewards, preferentially under conditions requiring a high degree of motivation. Furthermore, the current study provides compelling evidence for the involvement of the HCRT system in cocaine self-administration also under low-effort conditions in rats allowed extended access, possibly via functional interactions with DYN and MCH signaling.

Investigation of the reinforcing potential of samidorphan and naltrexone by fixed and progressive ratio intravenous self-administration testing in heroin-maintained rats

2019 ◽  
Vol 33 (3) ◽  
pp. 383-391
Author(s):  
Sharon L Smith ◽  
Reginald L Dean ◽  
Mark S Todtenkopf ◽  
David J Heal
Keyword(s):  
Positive Reinforcement ◽  
Plasma Concentrations ◽  
Fixed Ratio ◽  
Progressive Ratio ◽  
Abuse Liability ◽  
Opioid Antagonist ◽  
Intrinsic Activity ◽  
Self Administration ◽  
Positive Reinforcer ◽  
Break Points

Background: Samidorphan is a novel μ-opioid antagonist with low intrinsic activity at κ- and δ-opioid receptors. Aims: Because samidorphan is central nervous system-active, we investigated whether samidorphan (13.6, 40.8, 68 μg/kg/injection) served as a positive reinforcer in rats trained to self-administer heroin on a fixed ratio-5 schedule. Samidorphan’s relative reinforcing effect was evaluated by progressive ratio/break-point determination. Naltrexone (13.6, 40.8, 68 μg/kg/injection) and heroin (7.5, 15, 25 μg/kg/injection) were comparators. Results: All heroin doses maintained self-administration on fixed ratio-5 and progressive ratio/break-points at levels significantly greater than saline. Samidorphan and naltrexone had similar profiles on fixed ratio-5 with one samidorphan dose serving as a positive reinforcer and one naltrexone dose showing a strong trend ( p=0.053) for positive reinforcement. The numbers of injections of every samidorphan and naltrexone dose were significantly lower than all heroin doses. The numbers of self-administered samidorphan and naltrexone injections/session on fixed ratio-5 were not significantly different from one another. The mean inter-injection intervals for heroin were significantly shorter than for saline, whereas those of samidorphan and naltrexone were not. Progressive ratio break-points for samidorphan and naltrexone were not different from saline except for the highest dose of samidorphan. In addition, the progressive ratio break-points for samidorphan were not significantly different from those of naltrexone and were significantly lower than heroin. The samidorphan unit-doses evaluated in self-administration yielded plasma concentrations ranging between 25–109% and 10–45% of the maximum concentration values in humans. Conclusions: Overall, the profiles of samidorphan and naltrexone, which has no abuse liability, were similar in this model.

scholarly journals Reduced sensitivity to reinforcement in adolescent compared to adult Sprague-Dawley rats of both sexes

2017 ◽  
Author(s):  
Emily R. Hankosky ◽  
Sara Ruth Westbrook ◽  
Rachel M. Haake ◽  
Michela Marinelli ◽  
Joshua Michael Gulley
Keyword(s):  
Progressive Ratio ◽  
Schedules Of Reinforcement ◽  
Sprague Dawley ◽  
Self Administration ◽  
Adult Rats ◽  
Saccharin Intake ◽  
Sprague Dawley Rats ◽  
Brain And Behavior ◽  
Motivated Behaviors ◽  
And Behavior

RATIONALE: Adolescence is a period of considerable development of brain and behavior and is the time during which most drug use is initiated. OBJECTIVE: Age-dependent differences in motivated behaviors may be one of the factors that contribute to heightened vulnerability to developing substance use disorders, so we sought to compare age differences in methamphetamine (METH) and saccharin seeking. METHODS: Beginning during adolescence or adulthood, male and female Sprague-Dawley rats were trained to self-administer 0.1% saccharin (via liquid dipper cup) or intravenous METH at one of three doses (0.02, 0.05, 0.08 mg/kg/inf) under increasing fixed ratios schedules of reinforcement. Subsequently, responding for METH (0.02, 0.05, 0.08 or 0.1 mg/kg/inf) under progressive ratio response requirements was assessed in rats that acquired METH self-administration at the highest dose (0.08 mg/kg/inf). RESULTS: We found that adult-onset rats acquired METH self-administration more readily and exhibited higher motivation compared to adolescent-onset rats, although there were no differences in METH intake during acquisition. Adult rats also acquired saccharin self-administration more readily, but in contrast to METH, there were age and sex differences in saccharin intake driven by high levels of responding in adult females. CONCLUSIONS: These findings challenge the prevailing notion that adolescents are hypersensitive to reward and instead raise questions about the potential role of methodological factors on which rodent studies often differ.

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.

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