Differential Effect of Fixed Ratio Magnitude on the Rate of Lever-Pressing and Interinjection Intervals of Cocaine Self-Administration in Rats.

Background: Many features of self-administration behavior may be explained by reference to the properties of schedules of reinforcement. Schedules alter the probability of a behavior being reinforced and thereby increase, or decrease, the frequency of the behavior and fixed ratio (FR) magnitude reportedly alters the rate of responding to cocaine. A pharmacokinetic/pharmacodynamic interaction theory states that lever-pressing behavior is induced only when cocaine levels in the body are above the priming/remission threshold and below the satiety threshold-a range termed the compulsion zone. This theory successfully explains cocaine self-administration in rats on a progressive ratio and the FR1 schedule. Objectives: To determine the effects of high FR magnitude on the rate of self-administration of cocaine and the rate of lever-pressing behavior when cocaine levels are within the compulsion zone. Methods: Rats acquired cocaine self-administration on an FR1 schedule and then were switched to sessions that started with FR1 and then FR 5, 10, 20, or 50. An only FR1 session was run each week between FR1/FR50 sessions and then only FR1 sessions were conducted for several weeks. Results: Interinjection intervals at a unit dose of 3 µmol/kg were regular at both FR1 and FR50 but were longer by the time required to complete the 50 presses. When responding by rats was maintained under an FR50 schedule of cocaine presentations, compared to baseline FR1 sessions, dramatic increases in the number of lever-presses were observed after access to cocaine was terminated, a previously unreported finding. However, lever-pressing occurred only when cocaine levels were in the compulsion zone, and this duration was unchanged. The increase in lever-pressing persisted for weeks. Interinjection intervals at FR1 were not altered after exposure to FR50. Conclusions: Although previously considered key to understanding the regulation of cocaine self-administration behavior, FR magnitude simply increased interinjection intervals by the time required to complete 50 lever-presses. The dramatic increase in the rate of lever-pressing was caused by the high FR schedule rather than cocaine. The utility of the schedule-induced increase in the rate of lever-pressing is unclear. The compulsion zone theory provides a rational pharmacological basis for understanding cocaine self-administration behavior.

SCH23390 and a humanized anti-cocaine mAb decrease the latency to cocaine-induced reinstatement of lever pressing behavior in rats that self-administer cocaine.

In rats that self-administer cocaine, the latency to the reinstatement of lever pressing behavior induced by a single dose of cocaine is due to the time taken for cocaine levels to fall to the satiety threshold. The D1 dopamine receptor antagonist SCH23390, and the recombinant humanized anti-cocaine mAb h2E2 increase the cocaine satiety threshold and would be expected to alter the latency to reinstatement. Male rats acquired cocaine self-administration behavior on an FR1 schedule. These rats received a single injection of cocaine (12 µmol/kg i.v.) after an i.v. injection of SCH23390 or an infusion of h2E2 or vehicle. The latency to, and the duration of, lever pressing was measured but the presses had no consequence. SCH23390 decreased the latency to lever pressing consistent with dose-dependent increases in satiety threshold. The duration of lever pressing behavior was inversely proportional to the SCH23390 dose suggesting that SCH23390 also increased the cocaine compulsion zone. The mAb h2E2 also produced a similar decrease in latency to responding that gradually reversed over 2 weeks. SCH23390 and h2E2 had an additive effect on the decreased latency to cocaine-induced lever pressing. The single cocaine dose reinstatement paradigm within the context of the compulsion zone theory is a useful pharmacological bioassay system to explore potential pharmacotherapies for relapse prevention in cocaine use disorder.

The cocaine compulsion zone theory explains the reinstatement of lever pressing behavior in rats in response to a single cocaine dose.

A single non-contingent dose of cocaine reinstates extinguished lever pressing behavior in rats trained to self-administer cocaine. This represents a model of relapse in cocaine use disorder and the number of lever presses has been the standard measure. Lever pressing behavior during self-administration occurs only when cocaine levels are below the satiety threshold and above the remission/priming threshold, a range termed the compulsion zone. Calculated cocaine levels at the time of each lever press during an FR1 self-administration session and following a single non-contingent dose of cocaine were compared. The mean latency to lever pressing behavior was dose dependent and ranged from 1 to 11 min after cocaine doses of 2 or 12 µmol/kg, respectively. This is consistent with higher cocaine doses producing levels above satiety threshold that take more time to fall back to that threshold. The level of cocaine when lever pressing occurred was similar whether cocaine was self-administered or after a single dose of cocaine. The number of lever presses after a single cocaine dose was variable and poorly dose dependent. The latency to the start of lever pressing behavior is a more reliable dependent measure than the number of lever presses. In addition, lever pressing behavior occurs only when cocaine levels are within the compulsion zone. The compulsion zone theory not only explains maintained cocaine self-administration behavior, but also explains the reinstatement of lever pressing behavior in response to a single non-contingent cocaine dose.

The ascending limb of the cocaine unit dose-response function in rats as an experimental artifact.

The cocaine unit dose-response function is an inverted U with the ascending and descending limbs representing the positive and rate limiting cocaine effects, respectively. Higher fixed ratio (FR) schedules and/or time-out periods make the ascending limb more prominent. Alternatively, a pharmacokinetic/pharmacodynamic interaction theory demonstrates that cocaine-induced lever pressing occurs only when cocaine levels are within a range termed the compulsion zone. The inter-injection intervals of self-administration increase with cocaine unit dose because of the longer time required to eliminate higher doses. However, this theory has not been applied to high FR schedules. Rats acquired cocaine self-administration on a FR1 schedule and then were changed to sessions that started with both FR1 and then FR50 over a range of unit doses with a set number of self-administrations allowed for each dose. On FR1, rats completed the maximum number of injections at all but the lowest unit dose. In contrast, on FR50 the proportion of the permitted injections increased as a function of unit dose. However, this ascending limb was the result of averaging data from sessions where rats completed or failed to complete the allowed number of injections. Rats completed all injections when cocaine levels were maintained in the compulsion zone. The FR50 schedule and low unit doses decreased this probability of maintaining cocaine levels in the compulsion zone when the rate of cocaine elimination exceeded the rate of cocaine input during the time required to complete the 50 presses. It is concluded that the ascending limb is an experimental artifact and that the entire dose-response function and the FR50-induced increase in inter-injection intervals are explained in terms of the compulsion zone theory of cocaine self-administration behavior.