Vulnerability to ethanol sensitization predicts higher intake and motivation to self-administer ethanol: Proof of the incentive salience sensitization theory?

Abstract

Ethanol-induced behavioral sensitization (EIBS) is thought to play a key role in addiction. However, whether EIBS is linked to an increase in the motivation to self-administerethanol in an operant paradigm has never been demonstrated, and thus, the motivational sensitization theory (increase in drug wanting) has not been yet confirmed. We investigated using the operant ethanol self-administrationparadigm if the motivation to self-administerethanol (breakpoint) is increased in female mice prone to develop EIBS. Outbred female Swiss mice were treated once a day with 2.5-g ethanol per kilogram during 10 days and challenged with the same dose of ethanol 7 days later. EIBS-pronegroup was characterized by a significant increase in locomotion between the challenge day and day 1. When the difference was not significant, mice were considered as the "EIBS-resistant"group. Mice were then trained to nose poke for a 20% ethanol solution reinforcer under a FR1 and then a FR-2schedule of reinforcement. Motivation was assessed more directly with a progressive ratio schedule. Our results show that there is a positive correlation between EIBS and both the level of intake and motivation. Interestingly, acquisition of ethanol self-administrationwas faster in sensitized mice that also display a quick and long-lastingincrease in ethanol intake together with a lack of effect of alcohol challenge on c-Fosexpression restricted to the dorsolateral striatum. These results further support that EIBS vulnerability is crucial in the development of addictive behaviors and suggest a potential link with habit learning processes.