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 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 Ethanol-Related Behaviors in Mouse Lines Selectively Bred for Drinking to Intoxication

2021 ◽  
Vol 11 (2) ◽  
pp. 189
Author(s):  
Bryan E. Jensen ◽  
Kayla G. Townsley ◽  
Kolter B. Grigsby ◽  
Pamela Metten ◽  
Meher Chand ◽  
...  
Keyword(s):  
Drinking Behavior ◽  
Effective Means ◽  
Fixed Ratio ◽  
Progressive Ratio ◽  
Blood Alcohol ◽  
Drinking Patterns ◽  
Self Administration ◽  
Blood Alcohol Levels ◽  
Drinking In The Dark ◽  
Mouse Lines

Alcohol use disorder (AUD) is a devastating psychiatric disorder that has significant wide-reaching effects on individuals and society. Selectively bred mouse lines are an effective means of exploring the genetic and neuronal mechanisms underlying AUD and such studies are translationally important for identifying treatment options. Here, we report on behavioral characterization of two replicate lines of mice that drink to intoxication, the High Drinking in the Dark (HDID)-1 and -2 mice, which have been selectively bred (20+ generations) for the primary phenotype of reaching high blood alcohol levels (BALs) during the drinking in the dark (DID) task, a binge-like drinking assay. Along with their genetically heterogenous progenitor line, Hs/Npt, we tested these mice on: DID and drinking in the light (DIL); temporal drinking patterns; ethanol sensitivity, through loss of righting reflex (LORR); and operant self-administration, including fixed ratio (FR1), fixed ratio 3:1 (FR3), extinction/reinstatement, and progressive ratio (PR). All mice consumed more ethanol during the dark than the light and both HDID lines consumed more ethanol than Hs/Npt during DIL and DID. In the dark, we found that the HDID lines achieved high blood alcohol levels early into a drinking session, suggesting that they exhibit front loading like drinking behavior in the absence of the chronicity usually required for such behavior. Surprisingly, HDID-1 (female and male) and HDID-2 (male) mice were more sensitive to the intoxicating effects of ethanol during the dark (as determined by LORR), while Hs/Npt (female and male) and HDID-2 (female) mice appeared less sensitive. We observed lower HDID-1 ethanol intake compared to either HDID-2 or Hs/Npt during operant ethanol self-administration. There were no genotype differences for either progressive ratio responding, or cue-induced ethanol reinstatement, though the latter is complicated by a lack of extinguished responding behavior. Taken together, these findings suggest that genes affecting one AUD-related behavior do not necessarily affect other AUD-related behaviors. Moreover, these findings highlight that alcohol-related behaviors can also differ between lines selectively bred for the same phenotype, and even between sexes within those same line.

scholarly journals Dramatic increase in lever-pressing activity in rats after training on the progressive ratio schedule of cocaine self-administration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Vladimir L. Tsibulsky ◽  
Andrew B. Norman
Keyword(s):  
Fixed Ratio ◽  
Progressive Ratio ◽  
Ratio Schedule ◽  
Self Administration ◽  
The Press ◽  
Second Mode ◽  
Before And After ◽  
Lever Pressing ◽  
Remission Phase ◽  
Definition Of

AbstractTransition from the highest rate of lever-pressing activity during the unloading (extinction) phase of a cocaine self-administration session to an extremely low activity rate during the remission phase is in many cases gradual. This makes it difficult to assess the duration of the unloading phase after a fixed ratio 1 (FR1) or breakpoint after a progressive-ratio (PR) self-administration session. In addition, 3–5 days of training under the PR schedule results in a dramatic and persistent increase in the rate of presses during PR sessions and in the unloading phase following FR1 self-administration sessions. The goals of this study were to find the definition of the last press demarcating the border between the unloading and remission phases of the session and to determine if this border was also affected by PR training. Rats were trained to self-administer cocaine under the FR1 schedule and then under the PR schedule of drug delivery. Distributions of inter-press intervals (IPIs) during the unloading phase in sessions before and after PR training were compared. It was found that the distribution of cocaine-induced IPIs during the unloading phase was lognormal, bimodal, and independent of previously injected cocaine unit doses. The first mode represented intervals within the short bouts of stereotypic presses and the second mode represented intervals between bouts. The two modes were approximately 0.7 s and 21 s during unloading prior to and 0.6 s and 1.5 s after PR self-administration training. The total number of presses per unloading phase increased eightfold. When the FR1 schedule was restored, the intervals between bouts remained very short for at least 7–10 days and only then started a gradual increase towards baseline levels. The last unloading press was defined as the press followed by the IPI longer than the defined criterion. PR training resulted in a substantial and long-lasting increase in lever-pressing activity during unloading. The duration of the unloading phase did not depend on the rate of lever-pressing activity.

The dopamine β-hydroxylase inhibitor, nepicastat, suppresses chocolate self-administration and reinstatement of chocolate seeking in rats

2013 ◽  
Vol 110 (8) ◽  
pp. 1524-1533 ◽  
Author(s):  
Alessandro Zaru ◽  
Paola Maccioni ◽  
Giancarlo Colombo ◽  
Gian Luigi Gessa
Keyword(s):  
Fixed Ratio ◽  
Progressive Ratio ◽  
Schedules Of Reinforcement ◽  
Self Administration ◽  
Pharmacological Agents ◽  
New Class ◽  
Cocaine Seeking ◽  
Reinforcement Measures ◽  
Food Seeking ◽  
Prevention Of Relapse

Craving for chocolate is a common phenomenon, which may evolve to an addictive-like behaviour and contribute to obesity. Nepicastat is a selective dopamine β-hydroxylase (DBH) inhibitor that suppresses cocaine-primed reinstatement of cocaine seeking in rats. We verified whether nepicastat was able to modify the reinforcing and motivational properties of a chocolate solution and to prevent the reinstatement of chocolate seeking in rats. Nepicastat (25, 50 and 100 mg/kg, intraperitoneal) produced a dose-related inhibition of operant self-administration of the chocolate solution in rats under fixed-ratio 10 (FR10) and progressive-ratio schedules of reinforcement, measures of the reinforcing and motivational properties of the chocolate solution, respectively. The effect of nepicastat on the reinstatement of chocolate seeking was studied in rats in which lever-responding had been extinguished by removing the chocolate solution for approximately 8 d. Nepicastat dose-dependently suppressed the reinstatement of lever-responding triggered by a ‘priming’ of the chocolate solution together with cues previously associated with the availability of the reward. In a separate group of food-restricted rats trained to lever-respond for regular food pellets, nepicastat reduced FR10 lever-responding with the same potency as for the chocolate solution. Spontaneous locomotor activity was not modified by nepicastat doses that reduced self-administration of the chocolate solution and regular food pellets and suppressed the reinstatement of chocolate seeking. The results indicate that nepicastat reduces motivation to food consumption sustained by appetite or palatability. Moreover, the results suggest that DBH inhibitors may be a new class of pharmacological agents potentially useful in the prevention of relapse to food seeking in human dieters.

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.

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