Compulsion zone theory of the self‐administration paradigm explains different drug durations of extinction responding with different cocaine analogues.
Authors: Zinani Dakota B. , Wetzel Hanna N. , Tsibulsky Vladimir L. , Norman Andrew B. 
Published: April 2020

The compulsion zone theory of cocaine self‐administration states that lever‐pressing behavior is a drug‐induced behavior that is induced only when drug concentrations are between the priming and satiety thresholds. This explains responding after the termination of access to cocaine (the extinction phase of each session). Therefore, self‐administered drugs with longer durations of action would be expected to induce protracted extinction responding.To test this hypothesis, extinction responding was measured in rats after self‐administering 3 indirect dopamine agonists: cocaine (n = 11 rats) or the cocaine‐mimetic drugs, RTI‐55 (n = 7 rats), and bupropion (n = 7 rats). These drugs are known to have different half‐lives, with a rank order of RTI‐55, bupropion, and cocaine from longest to shortest. Across these drugs, we observed the number of lever‐presses correlated with the rank order, there were, on average, 20 presses for cocaine, 35 bupropion presses 53 RTI‐55 lever presses after the termination of access to each drug, respectively. However, lever‐pressing behavior would extinguish on an average of 18 minutes with cocaine, and 27 minutes with bupropion, while responding induced by RTI‐55 persisted for several hours, extinguishing within an average of 288 minutes. These durations were significantly different from one another (p < 0.01, t‐test) and correlated with the established rank order of the half‐life of each drug.Additionally, we tested apomorphine (n=12 rats) a direct dopamine receptor agonist that is reliably self‐administered and has a short half‐life. Apomorphine‐induced responding extinguished in an average of 7 minutes. Apomorphine showed comparable lever presses to cocaine with an average of 23 per extinction. This indicates the extinction lever‐pressing is a method of measurement not limited to dopamine reuptake inhibitors but can be observed in direct‐acting agonists.These data provide further evidence that the lever‐pressing behavior after the termination of drug access is a drug‐induced response drug‐induced. The different durations of extinction responding, and numbers of extinction presses are not consistent with the idea that extinction occurs because animals learn that the drug is no longer available. Importantly, the compulsion zone theory applies to both self‐administered dopamine reuptake inhibitors other than cocaine, as well as direct‐acting dopamine receptor agonists. Thus, drugs with a longer half‐life take longer to transit the compulsion zone and induce lever‐pressing behavior for a correspondingly longer time. Further study into extinction responding may yield more information on the pharmacokinetic characteristics of self‐administered drugs.Support or Funding InformationSupported by NIDA grant U01DA039550Percent of active extinction sessions over time, with the cut‐off criteria data. Active sessions were grouped into 10‐minute bins. We see a rightward shift in extinction sessions of drugs with longer t1/2.Figure 1Durations of normalized sessions with the criteria applied. These durations were significantly different relative to the half‐life of each drug after the criteria are applied.*indicates significance (p < 0.01, t‐test)Figure 2