PHARMACOLOGICAL DOPAMINE MANIPULATIONS IN DOPAMINE DEFICIENT AK MICE: IMPACT ON PREFERENCE FOR ACTIVE REINFORCERS

The transcription factor Pitx3 is essential for both the function of midbrain dopaminergic neurons. Aphakia (Ak) mice carry a Pitx3 mutation that leads to a marked loss of dopaminergic projections to the ventral striatum, including the nucleus accumbens (NAcb). Because dopamine (DA) signaling in the NAcb is critical for the modulation of the activational component of motivation, we investigated spontaneous effort-based choice using the 3-choice-T-maze task and the voluntary running wheel (RW) task in Ak and wild-type (WT) mice.
Compared to Ak mice, WT animals displayed significantly greater levels of vigorous locomotor activity in the RW. In the 3-choice-T-maze paradigm offering three reinforcers with different effort demands (RW, sucrose pellets, and a floral odor), WT mice predominantly engaged in running. Although Ak mice also preferred the RW, they showed reduced running compared to WT mice, but consumed more palatable food. Ak mice treated with tetrabenazine (TBZ; 2–6 mg/kg), a VMAT-2 inhibitor that depletes DA by disrupting vesicular storage, further reduced RW engagement without altering food intake. Repeated treatment with L-Dopa which increases DA levels, increased voluntary running in both genotypes and restored Ak mice to WT baseline levels. Importantly, neither TBZ nor L-Dopa changed overall preference patterns in the effort-based decision-making task.
Together, these results indicate that DA tone regulates the energizing aspects of motivated behavior. The Ak mouse model therefore offers a useful framework for studying fatigue-related mechanisms and their pharmacological modulation through DA alterations.
Grant support: Ministerio de Ciencia e Innovación. PID2021-125977OB-I00