An intravenous self-administration procedure for assessing the reinforcing effects of hallucinogens in nonhuman primates

Background Cebranopadol, a mixed nociceptin/opioid receptor full agonist, can effectively relieve pain in rodents and humans. However, it is unclear to what degree different opioid receptor subtypes contribute to its antinociception and whether cebranopadol lacks acute opioid-associated side effects in primates. The authors hypothesized that coactivation of nociceptin receptors and μ receptors produces analgesia with reduced side effects in nonhuman primates. Methods The antinociceptive, reinforcing, respiratory-depressant, and pruritic effects of cebranopadol in adult rhesus monkeys (n = 22) were compared with μ receptor agonists fentanyl and morphine using assays, including acute thermal nociception, IV drug self-administration, telemetric measurement of respiratory function, and itch-scratching responses. Results Subcutaneous cebranopadol (ED50, 2.9 [95% CI, 1.8 to 4.6] μg/kg) potently produced antinociception compared to fentanyl (15.8 [14.6 to 17.1] μg/kg). Pretreatment with antagonists selective for nociceptin and μ receptors, but not δ and κ receptor antagonists, caused rightward shifts of the antinociceptive dose–response curve of cebranopadol with dose ratios of 2 and 9, respectively. Cebranopadol produced reinforcing effects comparable to fentanyl, but with decreased reinforcing strength, i.e., cebranopadol (mean ± SD, 7 ± 3 injections) versus fentanyl (12 ± 3 injections) determined by a progressive-ratio schedule of reinforcement. Unlike fentanyl (8 ± 2 breaths/min), systemic cebranopadol at higher doses did not decrease the respiratory rate (17 ± 2 breaths/min). Intrathecal cebranopadol (1 μg) exerted full antinociception with minimal scratching responses (231 ± 137 scratches) in contrast to intrathecal morphine (30 μg; 3,009 ± 1,474 scratches). Conclusions In nonhuman primates, the μ receptor mainly contributed to cebranopadol-induced antinociception. Similar to nociceptin/μ receptor partial agonists, cebranopadol displayed reduced side effects, such as a lack of respiratory depression and pruritus. Although cebranopadol showed reduced reinforcing strength, its detectable reinforcing effects and strength warrant caution, which is critical for the development and clinical use of cebranopadol. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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Faculty Opinions recommendation of The active heroin metabolite 6-acetylmorphine has robust reinforcing effects as assessed by self-administration in the rat.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.734678533.793555031 ◽

2019 ◽

Author(s):

M Foster Olive

Keyword(s):

Self Administration ◽

Reinforcing Effects

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A drug-vs-food “choice” self-administration procedure in rats to investigate pharmacological and environmental mechanisms of substance use disorders

Journal of Neuroscience Methods ◽

10.1016/j.jneumeth.2021.109110 ◽

2021 ◽

Vol 354 ◽

pp. 109110

Author(s):

E. Andrew Townsend ◽

Kathryn L. Schwienteck ◽

Hannah L. Robinson ◽

Stephen T. Lawson ◽

Matthew L. Banks

Keyword(s):

Substance Use ◽

Substance Use Disorders ◽

Food Choice ◽

Self Administration ◽

Administration Procedure

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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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