Pharmacological and non-pharmacological factors that regulate the acquisition of ketamine self-administration in rats

Recreational ketamine use may be modulated by factors such as ketamine infusion patterns, associated conditioned stimuli and spatial-temporal contexts. Our aim was to study the pharmacological and non-pharmacological factors that regulate the acquisition of ketamine use. In experiment 1, four groups of male rats were trained to self-administer ketamine during nine 1-h daily sessions, under four reinforcement schedules: i) pre-session ketamine priming (Priming-[KET]), ii) conditioned stimulus (CS) paired to the ketamine infusions ([KET + CS]), iii) neither priming nor CS ([KET]), iv) combination of both (Priming-[KET + CS]). In experiment 2, two groups of male rats were trained to self-administer ketamine during nine 1-h daily or weekly sessions, under the Priming-[KET + CS] schedule. Lever pressing was then extinguished by saline substitution for ketamine infusion. Afterwards, ketamine was made available again upon responding under the same schedule. The Priming-[KET + CS] schedule of reinforcement showed a significant increase in the number of ketamine reinforcements and a significant discrimination between active vs. inactive levers. The same schedule allowed the establishment of ketamine self-administration on a weekly basis. During the extinction phase, rate of responding significantly dropped in both weekly and daily groups although it was twofold longer in the former, which showed a lack of reacquisition. Both pre-session ketamine priming and a conditioned stimulus paired to the ketamine infusions are required for the acquisition of ketamine self-administration. The longer extinction and the lack of reacquisition in the weekly group could be due to changes in temporal context that might affect the conditioning process.