Self-administration is the gold-standard for assessing reinforcement. Self-administration studies assess voluntary consumption of a compound. Safety studies examine the ability of a novel compound to maintain operant responding for drug delivery compared to vehicle and a drug of abuse from the same class or therapeutic category. Efficacy studies evaluate whether a novel compound can reduce reinforcement of a known drug of abuse. Transpharmation offers oral and intravenous self-administration using a variety of schedules of reinforcement.
Aspects of self-administration:
Acquisition
Dose-response
Drug pretreatment
Progressive ratio (motivation)
Reinstatement (model of relapse)
Acquisition of IV reinforcers
Data presented: Subjects (n=16 Male Sprague-Dawley rats) acquired appropriate discrimination between active and inactive levers for all IV reinforcers tested during daily 1 hr sessions in an operant chamber.
Acquisition of 15% Ethanol Self-administration
Data presented: Male and female Wistar rats (n=16 per sex) acquired appropriate discrimination between active and inactive levers when responding for access to 15% EtOH with and without 2% sucrose during daily 45-min sessions in an operant chamber.
Dose-response of IV reinforcers
Data presented: Male Sprague-Dawley rats (n=16 per group) modulate their behaviour and intake depending on the intravenous dose per infusion they are responding for.
Time-course data for IV reinforcer dose-response
Data presented: Male Sprague-Dawley rats (n=16 per group) modulate their behaviour and intake depending on the intravenous dose per infusion they are responding for.
IV Self-administration: Drug Pretreatment
Data presented: The smoking cessation therapy, Varenicline (α4β2 nicotinic receptor partial agonist), dose-dependently reduced responding for, and intake of, IV nicotine on a fixed ratio 2 and progressive ratio schedule of reinforcement. The 5-HT2C agonist, Lorcaserin, dose-dependently reduced responding for, and intake of, IV cocaine on a fixed ratio 2 and progressive ratio schedule of reinforcement (n=16 male Sprague-Dawley rats per reinforcer). The fixed ratio 2 schedule assesses basic consumption, while the progressive ratio schedule assesses motivation to consume the IV reinforcer.
Drug pretreatment on Oral EtOH Self-administration
Data presented: There is emerging evidence in humans that the 5-HT receptor agonist and potent psychedelic, 5-MeO-DMT, could be effective in treating alcohol use disorder (AUD). However, this therapeutic effect hasn’t been reproduced or systematically studied in a preclinical model. Here, we established a preclinical model and found that 5-MeO-DMT dose-dependently reduced responding for, and intake of, EtOH (sweetened or unsweetened), along with associated blood ethanol concentration, without altering responding for or intake of 2% sucrose (n=16 male Wistar rats).
Self-administration: Reinstatement (model of relapse)
Data presented: Reinstatement is a model of relapse wherein subjects that previously self-administered IV drug (nicotine, d-amphetamine, cocaine, heroin) undergo extinction. During extinction (i.e., Ext), subjects respond for vehicle and responding diminishes over time. Drug-seeking can be instigated by presentation of drug-paired cues (i.e., Cue), or a drug prime prior to a session in an operant chamber where subjects respond for vehicle (i.e., Drug+Cue). Drug primes included nicotine (0.15 mg/kg, SC), d-amphetamine (0.5 mg/kg, SC), cocaine (10 mg/kg, IP), or heroin (0.25 mg/kg, SC).
Drug pretreatment on Reinstatement
Data presented: In subjects previously trained to self-administer IV nicotine, the smoking cessation therapy Varenicline dose-dependently blocked nicotine-induced reinstatement of nicotine-seeking (n=16 male Sprague-Dawley rats). In subjects previously trained to self-administer IV cocaine, the 5-HT2C agonist Lorcaserin blocked cocaine-induced reinstatement of cocaine-seeking (n=16 male Sprague-Dawley rats).
Drug pretreatment on Reinstatement
Data presented: Male and female Sprague-Dawley rats (n=16 per sex) that first self-administered IV heroin, extinguished responding during extinction, and then tested for reinstatement. Both drug-paired cues and a heroin drug prime (0.25 mg/kg, SC) significantly reinstated heroin-seeking responses, and this reinstatement was blocked by pretreatment with naltrexone.
