Assessment of reward responsiveness in the response bias probabilistic reward task in rats: implications for cross-species translational research

Abstract

Mood disorders, such as major depressive disorder, are characterized by abnormal reward responsiveness. The Response Bias Probabilistic Reward Task (hereafter referred to as probabilistic reward task (PRT)) quantifies reward responsiveness in human subjects, and an equivalent animal assessment is needed to facilitate preclinical translational research. Thus, the goals of the present studies were to develop, validate and characterize a rat analog of the PRT. Adult male Wistar and Long-Evans rats were trained in operant testing chambers to discriminate between two tone stimuli that varied in duration (0.5 and 2 s). During a subsequent test session consisting of 100 trials, the two tones were made ambiguous (0.9 and 1.6 s) and correct identification of one tone was reinforced with a food pellet three times more frequently than the other tone. In subsequent experiments, Wistar rats were administered either a low dose of the dopamine D2/D3 receptor agonist pramipexole (0.1 mg kg(-1), subcutaneous) or the psychostimulant amphetamine (0.5 mg kg(-1), intraperitoneal) before the test session. Similar to human subjects, both rat strains developed a response bias toward the more frequently reinforced stimulus, reflecting robust reward responsiveness. Mirroring prior findings in humans, a low dose of pramipexole blunted response bias. Moreover, in rats, amphetamine potentiated response bias. These results indicate that in rats, reward responsiveness can be quantified and bidirectionally modulated by pharmacological manipulations that alter striatal dopamine transmission. Thus, this new procedure in rats, which is conceptually and procedurally analogous to the one used in humans, provides a reverse translational platform to investigate abnormal reward responsiveness across species.

Figure 1

Response bias, discriminability, accuracy and reaction time in Wistar and Long–Evans rats. (a) Response bias gradually increased across blocks in Wistar rats (n=12) and Long–Evans rats (n=11; **P<0.01, significant difference between blocks). (b) Discriminability was consistent across blocks in both rat strains, indicating that the change in response bias was not a function of a change in the ability to differentiate the two ambiguous tone durations but rather a function of reinforcement history. The increased response bias was reflected by greater accuracy for the rich stimulus compared with the lean stimulus across blocks in both (c) Wistar and (d) Long–Evans rats (*P<0.05, **P<0.01 and ***P<0.001, significant difference between rich and lean stimuli). Consistent with the differential reinforcement schedule, across rat strains, rich accuracy increased from block 1 to block 2 (t₂₂=2.39, P<0.05) and block 3 (t₂₂=2.00, P=0.058), whereas lean accuracy decreased from block 1 to block 2 (t₂₂=−2.06, P=0.051) and block 3 (t₂₂=−2.29, P<0.05). Reaction times decreased for the rich stimulus compared with the lean stimulus in (e) Wistar, but not (f) Long–Evans, rats (**P<0.01, significant difference between rich and lean stimuli).

Figure 2

Effects of pramipexole on reward responsiveness. Relative to saline, pramipexole administration reduced (a) response bias and (b) discriminability (n=16; *P<0.05, significantly different from saline). (c, d) The pramipexole-induced attenuation of response bias was reflected by greater accuracy for the rich stimulus in saline-treated rats compared with pramipexole-treated rats (***P<0.001, significantly greater than saline/lean; ^#P<0.05, significantly greater than pramipexole/rich).

Figure 3

Effects of amphetamine on reward responsiveness. Relative to saline, amphetamine administration (a) potentiated response bias (n=22; *P<0.05, significantly greater than saline) (b) without affecting discriminability (*P<0.05, significant difference between blocks). (c, d) The amphetamine-induced potentiation of response bias was reflected by greater accuracy for the rich stimulus in amphetamine-treated rats compared with saline-treated rats (*P<0.05, significantly greater than saline/lean; ***P<0.001, significantly greater than amphetamine/lean; ^#P<0.05, significantly greater than saline/rich).