Most animal self-administration models to date have sessions for only 1 or 2 hour per day with no access for longer periods of time, such as 6 to 24 hours, which would more closely mimic the human condition. Also, the doses per injection allowed in animals are usually low to extremely low, with the presumed scientific purpose of minimally altering neurobiological systems to elucidate threshold effects with the practical reason of preventing accidental animal overdose. Neither of these constraints pertain to humans; heroin addicts administer maximal doses monetarily affordable and within the limits of physiologic tolerance to prevent accidental opiate overdose (although this sometimes does occur on the street with surges in purity of heroin). Cocaine addicts similarly self-administer cocaine to the extent of funds available at the time within the limits of tolerable side effects, primarily jitteriness, nervousness, dysphoria, and depression.
The Koob and Kreek groups have created new models that more closely mimic the human condition. In the Koob group, extended-access models have been developed for long-term self-exposure, extinction, reexposure, and relapse and have included very long-term studies for each of several drugs of abuse (30
). In the Kreek group, even longer sessions of extended access have been used for short-term through long-term exposure, and some studies have involved acquisition, extinction, and rechallenge (34
). High and moderate doses of cocaine and morphine have been used in addition to the more usual low and very low doses per injection. Extended access to drugs of abuse produces dramatic increases in drug intake over time that mirror the human condition and that at a neurobiological level more clearly mimic the investigator-administered binge pattern.
To explore the possibility that differential access to intravenous cocaine self-administration in rats may produce different patterns of drug intake (the Koob group), rats were allowed access to intravenous self-administration of cocaine for 1 hour and 6 hours per day (30
) (). With 1 hour of access (short access) to cocaine per session through intravenous self-administration, drug intake remained low and stable, not changing from day to day as observed previously. In contrast, with 6-hour access (long access) to cocaine, drug intake gradually escalated over days (30
) (). In the escalation group, there was increased early intake, sustained intake over the session, and an upward shift in the dose-effect function, suggesting an increase in the hedonic set point.
Maximum (mean) Drug Dose Attained in Animal Models of Escalated Drug Intake
FIGURE 1 Effect of Drug Availability on Cocaine Intakea
In a similar 10-hour extended-access model (the Kreek group), intravenous cocaine was self-administered by randomly assigned rats allowed to self-administer 0.25, 0.50, 1.00, or 2.00 mg/kg per infusion intravenously in a continuous schedule of cocaine reinforcement during five consecutive daily 10-hour sessions (34
) (). When data from the animals self-administering any dose of cocaine were collapsed as a single group, the mean amount of self-administered cocaine exceeded 60 mg/kg per day, significantly greater than in our investigator-administered binge administration with 3×15 mg/kg cocaine per day (for a total of 45 mg/kg per day). In addition, when data from animals were analyzed by their randomly assigned group, the total daily dose administered by animals allowed to self-administer the highest and intermediate doses of cocaine (2.00 and 1.00 mg/kg, respectively) had a much steeper incremental daily total amount of cocaine self-administered than did low and very low dose groups. Animals allowed access to the highest (2.00 mg/kg per injection) dose were administering over 100 mg/kg by the end of the 5-day period. The slope of this acquisition was much steeper in the moderate and high-dose groups than in the animals allowed to self-administer very low (0.25 mg/kg) or low (0.50 mg/kg) doses of cocaine (34
FIGURE 2 Escalation of Cocaine Intake as a Function of Dosea
In further studies of the escalation in drug intake with extended access, rats were randomly assigned to short-access and long-access groups (36
) (). The short-access animals were tested daily for multidose self-administration for 3 hours. The long-access animals were tested initially with multidose self-administration over 3 hours. Over the next 7 hours, the animals were allowed to self-administer a relatively high dose of cocaine (2.0 mg/kg). After 14 days, lever pressing was extinguished in 10 consecutive 3.5-hour extinction sessions. Following extinction, the ability of a single non contingent investigator-administered infusion of cocaine at 0, 0.50, or 2.00 mg/kg to reinstate extinguished lever pressing was studied. Self-administration was not altered over time in the short-access rats. However, a general escalation of cocaine intake was found in the long-access, high-dose rats, which showed an increased susceptibility to reinstatement.
Similar changes in the self-administration of heroin and alcohol have been observed in animals with more prolonged access (31
) or a history of dependence (39
). In related work, prolonged access to escalating doses of morphine in a rat self-administration model in which the animals self-regulated the dose of drug showed that repeated intake of opioids is associated with significant escalation in intake. Rats self-administered one of three doses of morphine (0.30, 1.00, or 3.00 mg/kg per infusion) during 7 daily 4-hour (short-access) sessions. In a second experiment, all animals were allowed 18-hour sessions of self-administration for 7 consecutive days and were randomly assigned to a self-escalation, individual-choice group or a fixed morphine dose group (38
) (). For the short-access 4-hour sessions, the dose of 0.30 mg/kg morphine per injection did not adequately support stable self-administration, but higher doses did. The animals who had 18-hour extended access in the self-escalation model even on day 1 administered more morphine than the fixed-dose group. The total daily consumption from day 1 was approximately 45 mg/kg and with escalation reached significance by day 4 and continued through day 7. By day 7, the animals were self-administering an average of 165 mg/kg per day of morphine. These results dramatically demonstrate escalation in morphine intake, consistent with studies of escalation in heroin intake described by heroin addicts (38
) (). Similar results were obtained with 23-hour access to heroin, in which rats reached daily levels of up to 3.0 mg/kg per day and showed significant changes in circadian patterns that paralleled the escalation in intake (40
Ethanol-dependent rats will self-administer significantly more ethanol during acute withdrawal than rats in a nondependent state. In these studies, Wistar rats are trained with a sweet solution fadeout procedure to self-administer ethanol in a two-lever operant situation in which one lever delivers 0.1 ml of 10% ethanol and the other lever delivers 0.1 ml of water. Nondependent animals typically self-administer doses of ethanol sufficient to produce blood alcohol levels averaging 25–30 mg % at the end of a 30-minute session, but rats made dependent on ethanol with ethanol vapor chambers self-administer three to four times as much ethanol (). With unlimited access to ethanol during a full 12 hours of withdrawal, the animals will maintain blood alcohol levels above 100 mg % (39
). When the animals were subjected to repeated withdrawals and ethanol intake was charted over repeated abstinence, operant responding was enhanced by 30%–100% for up to 4–8 weeks postwithdrawal. Similar but even more dramatic results have been obtained with intermittent access to ethanol vapors (14 hours on, 10 hours off) (41
). These results suggest an increase in ethanol self-administration in animals with a history of dependence that is not observed in animals maintained on limited access to ethanol of 30 minutes/day. The increase in responding has been hypothesized to be linked to changes in reward set point that invoke the theoretical concepts of tolerance or allostasis.