Females develop features of an addiction-like phenotype sooner during withdrawal than males.

Abstract

RATIONALE\nWomen meet criteria for substance use disorder after fewer years of drug use than men; this accelerated time course, or telescoping effect, has been observed for multiple drugs, including cocaine. Preclinical findings similarly indicate an enhanced vulnerability in females to developing an addiction-like phenotype; however, it is not yet known if this phenotype develops faster in females versus males.\n\n\nOBJECTIVES\nThe goal of this study was to determine using a rat model whether two key features of addiction in humans, an enhanced motivation for cocaine and compulsive use, emerge sooner during withdrawal from extended access cocaine self-administration in females versus males.\n\n\nMETHODS\nMotivation for cocaine, as assessed under a progressive-ratio reinforcement schedule, was determined prior to and following extended access cocaine self-administration (24\xa0h/day, 96 infusions/day, 10\xa0days) and after 7, 14, or 60\xa0days of withdrawal. Compulsive use, or use despite punishment, was evaluated once progressive-ratio responding stabilized by adding histamine, an aversive stimulus, to the cocaine solutions.\n\n\nRESULTS\nMotivation for cocaine increased from baseline sooner during withdrawal in females than males (at 7 versus 14\xa0days); motivation was also highest in the 60-day group. Histamine decreased progressive-ratio responding for cocaine in both sexes, although effects were greatest in males in the 7-day withdrawal group; males reached the female-level of resistance to histamine punishment by 14\xa0days of withdrawal.\n\n\nCONCLUSIONS\nFemale rats developed addition-like features sooner during withdrawal than male rats indicating that the telescoping effect observed in humans is biologically based. Additionally, like drug-seeking/craving, motivation for cocaine and measures of compulsive use incubate over withdrawal.