¹Tokyo Metropolitan Institute of Medical Science, Addictive Substance Project, Tokyo, Japan, ²University of Maryland School of Medicine, Departments of Neurology and Pharmacology, Baltimore, United States, ³Kobe University Graduate School of Medicine, Department of Digital Psychiatry, Kobe, Japan, ⁴National Center of Neurology and Psychiatry, Department of Neuropsychopharmacology, Tokyo, Japan

Background: Behavioral addictions such as gambling disorder are characterized by persistent engagement in reward-seeking under conditions of uncertainty. One candidate mechanism is a bias toward rewards delivered at unpredictable points within a sequence of actions, even when the total amount of reward is matched to fixed schedules. However, the neurobiological basis of this “randomness preference” remains unclear. Dopamine transporter knockout (DAT-KO) mice exhibit chronically elevated extracellular dopamine and impulsive–compulsive phenotypes, providing a model to examine how dopaminergic hyperactivity shapes motivated behavior when the position of reinforced responses is randomized within fixed response requirements.

Aims & Objectives: We aimed to determine whether (1) dopaminergic hyperactivity selectively enhances persistence of intracranial self-stimulation (ICSS) responding when reward is delivered at random responses within fixed response blocks, and (2) chronic psychostimulant exposure in wild-type (WT) mice can mimic this phenotype.

Method: Brain reward function and motivated responding were assessed using lateral hypothalamic ICSS (lhICSS) in mice. We compared a fixed progressive ratio (PR) schedule with a progressive variable ratio (PVR) schedule. In both schedules, the number of nosepokes required per reinforcement increased across blocks (1, 2, 4, 8, 16, 32, 64). In PR, electrical stimulation was delivered on the first response of each block. In PVR, stimulation was delivered on one response chosen pseudo-randomly within each block, so that the number of possible reinforcers per block was fixed and only the position of the reinforced response within the block was randomized. Drug-free WT and DAT-KO mice were first tested under PR and PVR. In a pharmacological model, WT mice received chronic low-dose methamphetamine (0.03 mg/kg, i.p., 5 days), a regimen previously without acute effects on PR performance. Frequency–rate functions were normalized to each animal’s maximum control rate.

Results: Under baseline conditions, WT mice showed no systematic difference between PR and PVR frequency–rate curves. In contrast, DAT-KO mice exhibited a robust rightward/upward shift under PVR relative to PR, indicating enhanced persistence of lhICSS responding when reinforcement occurred at random responses within fixed blocks. Chronic low-dose methamphetamine in WT mice reproduced this pattern: PR curves remained unchanged, whereas PVR curves shifted rightward, indicating increased persistence specifically under conditions of randomly positioned reinforcement.

Discussion & Conclusions: Dopaminergic hyperactivity selectively amplifies motivated responding when reward is delivered at random responses within fixed response blocks, without uniformly increasing responding under fixed-position schedules. The convergence between DAT-KO mice and chronically methamphetamine-treated WT mice indicates that elevated dopaminergic tone is sufficient to promote persistence toward randomly positioned rewards even when overall reward availability is unchanged. This “randomness-biased” motivation may represent a preclinical analogue of human behavioral addictions in which the unpredictability of which action is rewarded, rather than reward magnitude alone, plays a critical role.