Dopamine antagonist effects of the D2/D3 receptor partial agonist aripiprazole on effort-based choice tasks in male and female rats.

Dopamine (DA) D2 receptor family partial agonists, such as aripiprazole (Abilify), are third-generation antipsychotic drugs approved for treating schizophrenia, and as augmentation agents in depression. Partial agonists induce moderate-to-low levels of intrinsic activity at receptors and thus can have agonist or antagonist properties, depending on neurotransmitter tone and other factors. Previous research has shown that D2 receptor antagonists, such as haloperidol and eticlopride, produce a low-effort bias in rodents tested on effort-based choice. The present studies were undertaken to determine whether aripiprazole would produce effects that resemble D2 antagonists or alternatively would show signs of agonist activity when DA tone was low. Male and female Sprague-Dawley rats were tested across multiple effort-based choice tasks that offered rats the option of lever pressing for high-carbohydrate food pellets on fixed or progressive ratio schedules vs. approaching and consuming concurrently available laboratory chow. Similar to D2 receptor antagonists, aripiprazole (0.65-5 mg/kg IP) produced a low-effort bias, decreasing lever pressing and increasing chow intake. These shifts in choice behavior occurred at low doses that were not marked by decreases in food intake or preference in parallel free-feeding preference tests. Furthermore, when DA tone was reduced by administration of the DA storage inhibitor tetrabenazine, aripiprazole did not increase lever pressing, instead producing a further decrease in male rats. Overall, aripiprazole was more potent in male rats compared with female rats. Aripiprazole also increased c-Fos immunoreactivity in nucleus accumbens. These results indicate that aripiprazole acts as a D2 family functional antagonist on rat models of effort-based choice.