Table 1.

Summary of Findings Regarding Sex Differences in Drug Self-Administration Paradigms

Paradigma	Description	Considerations for studying sex differences
Home-cage access	Drug solutions are provided in the home cage. Most commonly employed with alcohol, although other solutions (e.g., opioids or nicotine) are also used. Drug may be presented alone or alongside a bottle of drinking water.	Consumption is generally higher in females versus males. Drug preference (vs. water) is less often influenced by sex but sometimes higher in females versus males.
Chronic, continuous access	Drug solutions are provided without interruption. Consumption is typically measured every 24 or 48 hr.	Consumption is often higher in females versus males.
Intermittent access	Drug solutions are provided in 24-hr blocks separated by drug-free periods. Typically, drug is offered for three 24-hr sessions/week.	Produces escalation in males and females. Escalation is sometimes greater in females.
Limited access (e.g., “drinking in the dark”)	Drug solutions are provided during select hours of the day, typically for 1, 2, or 4 hr. Access during the dark phase of the light cycle can increase consumption.	For alcohol, consumption is higher in females versus males.
Aversion-resistant drinking	Drug solutions are mixed with an aversive, bitter-tasting compound (e.g., quinine).	Resistance to aversion is sometimes greater in females, depending on the access model/drug used.
Operant responding	Rodents respond for access to drug using a lever or at a nose-poke hole. Drug may be delivered orally or intravenously.	Females generally respond more for drug.
Fixed-ratio (FR) schedules	Rodents respond for drug during daily access sessions (varying from 30 min to 6 hr). The response requirement is fixed and does not vary within a session. Used to assess acquisition and escalation of drug intake.	Females often acquire responding sooner and maintain higher levels of intake.
Progressive-ratio (PR) schedules	Typically following training on an FR schedule, the response requirement is set to progressively increase following successful completion of the previous ratio.	PR responding and breakpoints are often higher in females versus males.
Extinction and reinstatement	During extinction, responding no longer results in drug delivery. Reinstatement behavior is assessed by delivering priming injections of the drug, cues previously paired with drug delivery, or exposure to a stressor.	Responding during reinstatement is often higher in females versus males.
Choice procedures	Rodents respond for drug versus access to an alternative reinforcer, such as food, sucrose, or social interaction.	Limited data suggest no sex differences.
Punishment procedures	Responding for drug is paired with probability of punishment, typically footshock. For oral paradigms, drug solutions may also be mixed with an aversive, bitter compound.	Limited data suggest female vulnerability.

^aWhen sex differences in drug self-administration are observed, females tend to be more vulnerable than males. Female rodents typically consume more across home-cage access paradigms and sometimes prefer drug (vs. water) more than males as well. In the operant chamber, females acquire self-administration behavior more readily and will often respond for and/or consume drug at higher rates. Measures such as reinstatement and progressive-ratio responding have also been observed to be greater in female versus male animals. Some paradigms, such as those presenting drug versus the choice of an alternative reinforce, have not yet been widely tested in female rodents.