Reward-associated cues reduce H-current amplitude in midbrain dopamine neurons

Cocaine is a psychoactive substance that targets brain regions involved in motivation and reward learning. Lateral ventral tegmental area (VTA) dopamine (DA) neurons play a critical role in these processes, yet their intrinsic modulations during drug and non-drug self-administration or reward-associated cue learning remain poorly understood. This study employed an Intermittent Access (IntA) cocaine model, both contingent and non-contingent, to examine how reward delivery and associated cues modulate the hyperpolarization-activated cyclic nucleotide-gated (HCN) current (I_h), an intrinsic property regulating neuronal physiology. Male rats were divided into saline and cocaine IntA groups, with yoked controls receiving non-contingent cocaine infusions either paired (Yoked + cue) or unpaired (Yoked - cue) with a light cue to control for contingency and cue exposure. A parallel sucrose self-administration cohort served as a non-addictive reward control. Whole-cell patch-clamp recordings in lateral VTA DA neurons revealed reduced I_h amplitude in the cocaine IntA and Yoked-cocaine + cue groups, accompanied by a hyperpolarizing voltage shift in all cocaine-treated animals. Cocaine IntA enhanced input integration, whereas IntA animals also exhibited reduced membrane capacitance (C_m). Similar I_h reductions were observed in sucrose IntA and Yoked-sucrose + cue groups. These learning-associated changes may enhance DA neurons' ability to signal reward anticipation or saliency. We propose that I_h modulation in VTA DA neurons maintains intrinsic excitability, improves signal-to-noise ratio, and facilitates learning of reward-salient cues—processes essential for motivation toward drug and non-drug rewards. This hypothesis provides insight into how intrinsic plasticity in VTA DA neurons shapes reward learning.