The compulsion zone theory of cocaine self-administration behavior in rats explains the effects of fixed ratio magnitude on inter-injection intervals

Abstract

<b>Abstract ID 17002</b> <b>Poster Board 464</b> Cocaine self-administration paradigm in rats is an established animal model of cocaine use disorder and is integral to medication development. Since the inception of the field, self-administration schedules have been used as a measure of “reinforcing efficacy” under the belief that altering schedules modifies the reinforcement magnitude of cocaine. This approach has failed to predict the clinical effectiveness of any medications. Cocaine is a drug and would be expected to elicit its effects according to the principles of pharmacology. It activates dopaminergic mechanisms underlying stereotypy. The compulsion zone theory of acquired cocaine self-administration behavior states that cocaine induces stereotypic lever-pressing behavior only when cocaine levels are below the satiety threshold and above the priming/remission threshold. This theory explains both Progressive Ratio and Fixed Ratio (FR) 1 schedules of cocaine delivery and was applied to different magnitude FR schedules. Eight Male Sprague-Dawley rats were trained to acquire cocaine self-administration behavior on an FR1 schedule at different unit doses (i.v). Next, they were trained to self-administer cocaine on other FR schedules. Daily sessions began with 4 contingent cocaine priming injections of 1.5 μmol/kg followed by 15 injections on FR1 and then switched to 15 injections of FR5, 10, 20 or 50 schedules at a unit dose of 3 μmol/kg, ending with unloading where lever presses had no consequences. The inter-injection intervals were regular at all FR values, but the mean values were significantly longer at FR50 (7.7 min) compared to FR1 (5.7 min). The 34% increase in inter-injection intervals could be accounted for by the additional time that it took to complete the 50 presses (approximately 2.3 min). The mean calculated cocaine level at the time of injection was 31% lower at FR50 relative to FR1, again because it took longer to complete the 50 presses. However, the concentration of cocaine at the time of the first lever press in the sequence of 50 was similar to the concentration at the time of injection at FR1 suggesting that satiety threshold is not altered by increased FR value. Once rats perform the first lever press at the satiety threshold on FR50, the 50 lever presses occur at a high rate (20.8 presses/min) within the compulsion zone until the last press results in an injection. All lever pressing behavior, regardless of FR value, occurred at or below the satiety threshold in accordance with the compulsion zone theory. There is no reason to assume that the FR value alters the reinforcing efficacy of cocaine. Increased rate of lever pressing at FR50 occurs only because rats are compelled to press the lever when cocaine levels are below the satiety threshold, and lever pressing behavior does not stop until it results in an injection that raises cocaine levels above the satiety threshold. A higher FR value does not affect how cocaine induces lever pressing behavior and does not convey any different information than FR1. It simply acts as a time-out period and adds noise to maintained cocaine-self administration. Thus, the compulsion zone theory appears to provide a unified theory of schedules of cocaine delivery and provide a rational basis for advancing medications development. Supported by NIDA grant U01DA50330 (to ABN).