Irreversible antagonism of receptors accelerates rat cocaine self‐administration behavior (848.4)

Abstract

A pharmacological model of self‐administration can be explained by the equation T=ln(1+Du/Dst)/k, where T=time between self‐administrations, Du=unit dose, Dst=satiety threshold, and k=first order elimination rate constant, predicts that increasing the pharmacodynamic parameter Dst accelerates self‐administration. Competitive dopamine receptor antagonists temporarily increase cocaine intake implicating dopamine receptor fractional occupancy by dopamine as a mediator of the behavior. Competitive antagonists do not alter the number of receptors, so they cannot be used to study spare receptors or to differentiate between fractional occupancy of receptors and absolute numbers of receptors occupied. Rats that reliably self‐administered cocaine were injected with the non‐specific irreversible antagonist, N‐Ethoxycarbonyl‐2‐ethoxy‐1,2‐dihydroquinoline (1mg/kg i.v.). Attempts were made every 8 hours to reinstate self‐administration and once reinstated self‐administration was regular but was initially 2‐fold higher than baseline with a concomitant increase in the satiety threshold. Over 6 days the rate slowly declined and eventually returned to baseline presumably due to receptor repopulation. This indicates that satiety threshold corresponds to a specific number of receptors occupied. Changes in the number of dopamine receptors are key regulators of addictive behavior.Grant Funding Source: NIH Grant DP1DA031386