A Quantitative Model of a Substitution Therapy Using Cocaine Self-Administration Behavior in Rats

Abstract ID 94483 Poster Board 106 According to a 2021 national survey on drug use and health, approximately 1.4 million people aged 12 or older had a cocaine disorder and about 4.8 million people among that demographic had reported using cocaine in the past 12 months. There are currently no approved pharmacotherapies for cocaine use disorder (CUD). Self-administration behavior in rats is a useful model of CUD in humans. A pharmacological theory of cocaine self-administration behavior states that cocaine induces lever pressing behavior only when cocaine levels are below the satiety threshold and above the priming/remission threshold, a range termed the compulsion zone. It was demonstrated that a continuous infusion of cocaine that maintains steady state levels at or above the satiety threshold stopped cocaine self-administration behavior. The cocaine analogue, WIN 35428, is also self-administered by rats that self-administer cocaine but at a rate approximately 43-fold lower than cocaine. The lower self-administration rate of WIN 35428 is the product of a 6-fold longer elimination half-life and 7-fold lower satiety threshold (higher pharmacodynamic potency) than that of cocaine. We hypothesized that a continuous infusion of WIN 35428 that produces a steady-state level above the WIN 35428 satiety threshold will stop self-administration of cocaine. Rats were trained to self-administer cocaine intravenously on a fixed ratio 1 schedule. A Y-catheter was inserted into the surgically implanted portal where one arm was connected to the lever operated self-administration pump and the other arm was connected to an operator controlled continuous infusion pump. Rats self-administered cocaine at regular inter-injection intervals at a unit dose of 0.75 μmol/kg for an average of 82.8 ± 3.7 minutes. A continuous infusion of cocaine at an average rate of 1128 ± 103.9 nmol kg⁻¹min⁻¹ commenced. Cocaine self-administration behavior stopped for the duration of the infusion. Self-administration behavior resumed when the infusion was ended. In separate sessions, the same rats self-administered cocaine under the same conditions and a loading dose of WIN 35428 (800 nmol/kg IV) was administered immediately before a continuous infusion of WIN 35428 commenced at an average rate of 21.3 ± 2.4 nmol kg⁻¹min⁻1, approximately 50-fold lower than the previous infusion of cocaine. Cocaine self-administration behavior stopped for the duration of the WIN 35428 infusion. After the infusion stopped, self-administration of cocaine resumed but initially at longer inter-injection intervals that gradually approached baseline over several hours. This provides a rational basis for designing a substitution therapy to mitigate the use of cocaine. Whether continuous use of stimulants in humans is safe has yet to be elucidated. Supported by NIDA grant U01DA050330 to ABN.