Incentive and dopamine sensitization produced by intermittent but not long access cocaine self‐administration

Abstract

The temporal pattern of drug use (pharmacokinetics) has a profound effect on the ability of self‐administered cocaine to produce addiction‐like behavior in rodents, and to change the brain. To further address this issue, we compared the effects of long access (LgA) cocaine self‐administration, which is widely used to model the transition to addiction, with intermittent access (IntA), which is thought to better reflect the pattern of drug use in humans, on the ability of a single, self‐administered injection of cocaine to increase dopamine (DA) overflow in the core of the nucleus accumbens (using in vivo microdialysis), and to produce addiction‐like behavior. IntA experience was more effective than LgA in producing addiction‐like behavior—a drug experience‐dependent increase in motivation for cocaine assessed using behavioral economic procedures, and cue‐induced reinstatement—despite much less total drug consumption. There were no group differences in basal levels of DA in dialysate [DA], but a single self‐administered IV injection of cocaine increased [DA] in the core of the nucleus accumbens to a greater extent in rats with prior IntA experience than those with LgA or limited access experience, and the latter two groups did not differ. Furthermore, high motivation for cocaine was associated with a high [DA] response. Thus, IntA, but not LgA, produced both incentive and DA sensitization. This is consistent with the notion that a hyper‐responsive dopaminergic system may contribute to the transition from casual patterns of drug use to the problematic patterns that define addiction.

Understanding Addiction Using Animal Models

“…While rats trained to self-administer cocaine using LgA procedures consume more drug, rats trained using IntA show greater motivation to work for cocaine compared to rats in LgA or ShA training (Zimmer et al, 2012). Rats also show greater cue-induced drug-seeking behavior following IntA training compared to LgA or ShA (Kawa et al, 2016, 2019). IntA results in greater dopamine concentrations within the NAc core following a single infusion of cocaine compared to LgA training, and dopamine levels correlated with several measures of motivation for cocaine (Kawa et al, 2019).…”

“…Rats also show greater cue-induced drug-seeking behavior following IntA training compared to LgA or ShA (Kawa et al, 2016, 2019). IntA results in greater dopamine concentrations within the NAc core following a single infusion of cocaine compared to LgA training, and dopamine levels correlated with several measures of motivation for cocaine (Kawa et al, 2019). IntA training, but not LgA or ShA, using psychostimulants also results in sensitization of NAc dopamine transports (Calipari et al, 2013, 2014).…”

Dopamine “Ups and Downs” in Addiction Revisited

“…As few as 3 IntA cocaine sessions sensitize cocaine's effects at the DAT, and after one week of abstinence, both cocaine potency and stimulated DA release are increased even further [54]. Using in vivo microdialysis in freely moving rats, it has recently been reported that IntA, but not LgA, sensitizes cocaine-induced overflow in the NAc core [51]. Furthermore, IntA cocaine experience enhances amphetamine and methylphenidate's effects at the DAT [29], and IntA methylphenidate experience produces sensitization-related effects similar to those produced by cocaine [55].…”

Interruption of continuous opioid exposure exacerbates drug-evoked adaptations in the mesolimbic dopamine system

“…Different patterns of drug exposure produce diverse effects on mesolimbic dopamine function and addiction-related behavior (e.g., refs. [ 14 – 25 ]). Decreased sensitivity (i.e., tolerance) is typically reported after relatively continuous patterns of opioid administration, whereas increased sensitivity (i.e., sensitization) is commonly observed after more intermittent patterns of opioid exposure [ 26 – 28 ].…”