Shifts in the neurobiological mechanisms motivating cocaine use with the development of an addiction-like phenotype in male rats.

Rationale: The development of addiction is accompanied by a shift in the mechanisms motivating cocaine use from nucleus accumbens (NAc) dopamine D receptor (DR) signaling to glutamate AMPA-kainate receptor (AMPA-R) signaling.

Objective: Here, we determined whether similar shifts occur for NAc-DR signaling and following systemic manipulation of DR, DR, and AMPA-R signaling.

Methods: Male rats were given short-access (20 infusions/day) or extended-access to cocaine (24 h/day, 96 infusions/day, 10 days). Motivation for cocaine was assessed following 14 days of abstinence using a progressive-ratio schedule. Once responding stabilized, the effects of NAc-DR antagonism (eticlopride; 0-10.0 μg/side) and systemic DR (SCH-23390; 0-1.0 mg/kg), DR (eticlopride; 0-0.1 mg/kg), and AMPA-R (CNQX; 0-1.5 mg/kg) antagonism, and NAc-dopamine-R gene expression (Drd1/2/3) were examined.

Results: Motivation for cocaine was markedly higher in the extended- versus short-access group confirming the development of an addiction-like phenotype in the extended-access group. NAc-infused eticlopride decreased motivation for cocaine in both the short- and extended-access groups although low doses (0.1-0.3 μg) were more effective in the short-access group and high doses (3-10 μg/side) tended to be more effective in the extended-access group. Systemic administration of eticlopride (0.1 mg/kg) was more effective in the extended-access group, and systemic administration of CNQX was effective in the extended- but not short-access group. NAc-Drd2 expression was decreased in both the short- and extended-access groups.

Conclusion: These findings indicate that in contrast to NAc-DR, DR remain critical for motivating cocaine use with the development of an addiction-like phenotype. These findings also indicate that shifts in the mechanisms motivating cocaine use impact the response to both site-specific and systemic pharmacological treatment.