Motivational symptoms related to behavioral activation and exertion of
effort are among the most debilitating and commonly reported psychiatric
symptoms in general medicine. This cluster of symptoms is seen across
many psychological disorders including major depressive disorder (MDD)
and schizophrenia, and can include fatigue, anergia, avolition, reduced
exertion of effort, and psychomotor retardation. Effort-related symptoms
have proven to be crippling to quality of life and can be resistant to the
most commonly used psychotherapies for treatment of MDD, such as
selective serotonin reuptake inhibitors (SSRIs). Atypical antipsychotics
have a history of being used as an adjunctive therapy for MDD in
combination with SSRIs. Aripiprazole (Abilify) is part of a new class of
atypical antipsychotics that exerts partial agonism at the dopamine (DA)
D2/D3 receptors and was the first atypical agent to be FDA approved for
use as an augmentation agent in MDD. Despite its reported success in
open label clinical trials, aripiprazole has not been evaluated for its effects
specifically for effort-related symptoms.
The present studies used animal models of effort-based decision-making,
including the fixed ratio 5 (FR5)/chow feeding choice task and the
progressive ratio (PROG)/chow feeding choice task, to test aripiprazole
(0.625-5.0 mg/kg IP) for its ability to reverse the effects of the vesicular
monoamine transport-2 inhibitor tetrabenazine (TBZ) and to increase the
selection of the high effort behavior. With these tasks, rats had the choice
of working to obtain a preferred food (high carbohydrate Bio-serv pellets)
by lever pressing, vs. approaching and consuming a concurrently available
but less preferred food (lab chow). The results showed that aripiprazole
was unable to reverse the behavioral effects of TBZ, and, in fact, induced
a shift to a low-effort bias (i.e., decreased lever pressing and increased chow intake) when tested alone on the FR5/chow feeding choice task.
Additionally, aripiprazole failed to increase the selection of the high effort
option in rats responding on the PROG/chow feeding choice task. Despite
this, aripiprazole-treated rats still consumed laboratory chow during their
operant sessions and, when tested on a free feeding and preference task,
they still preferred and consumed high-carbohydrate pellets. Importantly, at
the lowest doses that produced very robust shifts in effort-based choice
(0.625 and 1.25 mg/kg), aripiprazole tended to slightly increase preference
for the preferred pellets in the free feeding task, suggesting that
aripiprazole did not impair primary food motivation at these low doses.
These results indicate that the shift in choice seen in the effort-based tasks
at low doses of aripiprazole is the result of a reduction in the selection of
the high effort alternative, and not due to a reduction of intake of or
preference for the high carbohydrate pellets. The present study also
investigated neural responses to administration of aripiprazole using the
immediate early gene product c-Fos as a cellular marker of signal
transduction activity in the nucleus accumbens core and neostriatum.
Results showed that, after administration of 5.0 mg/kg of aripiprazole, there
was an increase in c-Fos expression in both regions of interest.
The behavioral and neurochemical results of these studies suggest that,
while aripiprazole is characterized as a partial agonist, it is acting as a
functional DA antagonist on the effort-based tasks. While aripiprazole is
used to treat aspects of depression in combination with SSRIs, and can
reduce negative as well as positive symptoms of schizophrenia, this drug
did not enhance selection of physical effort in the choice tasks used. Thus,
these findings indicate that effort-based motivational dysfunctions may be
dissociable from other clinical symptoms seen in psychopathology.
