Revisiting long-access versus short-access cocaine self-administration in rats: intermittent intake promotes addiction symptoms independent of session length.

In rats, continuous cocaine access during long self-administration sessions (6 versus 1-2 hours) promotes the development of behavioral symptoms of addiction. This has led to the assumption that taking large amounts of drug during extended daily bouts is necessary to develop an addiction phenotype. Recent work shows that within-session intermittent access (IntA) to cocaine produces much less drug intake than continuous-access procedures (i.e. long-access sessions) but evokes addiction symptoms more effectively. IntA-sessions are also long, typically lasting 6 hours. It is not known whether IntA-sessions must be extended to promote addiction-relevant changes in drug use over time. Here, we determined the influence of IntA-session length on patterns of cocaine use relevant to addiction. Two groups of male Wistar rats self-administered cocaine (0.25 mg/kg/injection, injected over 5 seconds) during 18 daily IntA-sessions. One group had long 6-hour sessions (Long-IntA), the other group had shorter, 2-hour sessions (Short-IntA). Only Long-IntA rats escalated their cocaine intake over sessions, but both groups developed a burst-like pattern of drug use over time and similar levels of psychomotor sensitization. The two groups also showed robust and similar levels of both responding for cocaine under a progressive ratio schedule of reinforcement and cocaine-induced reinstatement of extinguished drug-seeking behavior. In summary, long IntA-sessions lead to greater cocaine intake than shorter IntA-sessions, but the two conditions are equally effective in evoking the patterns of drug-taking and drug-seeking that define addiction. This suggests that chronic intermittent cocaine use, even during short daily bouts, is sufficient to promote addiction symptoms.

Prenatal ethanol exposure increases risk of psychostimulant addiction.

Prenatal ethanol exposure (PE) causes many cognitive and behavioral deficits including increased drug addiction risk, demonstrated by enhanced ethanol intake and behavioral phenotypes associated with addiction risk. Additionally, preclinical studies show that PE persistently changes the function of dopaminergic neurons in the ventral tegmental area, a major neural substrate for addiction, and alters these neurons' responses to psychostimulants. Accordingly, PE could also lead to increased risk of addiction to drugs of abuse, other than ethanol. In the present study, addiction risk was examined utilizing paradigms of amphetamine conditioned place preference (CPP) and intravenous self-administration. Ethanol was administered to pregnant dams via intragastric gavage (6 g/kg, during gestational days 8-20). Behavioral tests were conducted in adult male offspring. Amphetamine at a low dose (0.3 mg/kg, i.p.) induced CPP in PE but not control rats, whereas at a higher dose (0.6 mg/kg, i.p.) both groups acquired CPP. There was no group difference in amphetamine-induced CPP reinstatement. Furthermore, PE rats self-administered more amphetamine at a low dose (0.02 mg/kg/infusion) than controls, while no group differences were observed at a higher dose (0.1 mg/kg/infusion). Rats with PE also exhibited greater reactivity to contextual drug cues after extended abstinence and amphetamine-induced reinstatement of drug seeking. These results support that PE persistently leads to increased psychostimulant addiction risk later in life, manifested in many elements of addictive behavior following limited psychostimulant exposure. The observations provide insights into prevention strategies for drug addiction in individuals with fetal alcohol spectrum disorders.