Cholecystokinin released somatodendritically from dopamine neurons broadly alters synaptic strength across the...

Neuropeptides are found in nearly every brain neuron, and can modulate behaviors by regulating neuronal excitability, synaptic transmission, and plasticity. In contrast to the canonical view of neuropeptide release from nerve terminals, we previously reported the somatodendritic release of cholecystokinin (CCK) from ventral tegmental area (VTA) dopamine (DA) neurons. Release of CCK occurs during modest depolarization of VTA DA cells, and by activating CCK2Rs, potentiates synaptic transmission from GABAergic afferents. Here, recording from dopamine neurons in acute midbrain slices from male and female mice, we examined how somatodendritic release of CCK regulates synaptic plasticity and the extent of its influence. Depolarization of a dopamine neuron induced long-term potentiation (LTP) at GABAergic synapses, and in parallel somatodendritic CCK release produced long-term depression (LTD) at glutamatergic synapses. CCK-induced LTP persisted when postsynaptic G protein signaling in dopamine neurons was blocked, suggesting that CCK likely acts at GABAergic presynaptic terminals. Activation of kappa opioid receptors prevented CCK-dependent LTP of GABAergic synapses, indicating interaction between these two neuromodulatory signaling pathways in VTA. Surprisingly, depolarization of one dopamine neuron potentiated synapses onto both the depolarized neuron and neighboring dopamine neurons located up to ∼100 µm away, indicating substantial spread of CCK signaling and synaptic modulation within the VTA region. Taken together, our findings demonstrate that somatodendritic CCK release bidirectionally coordinates synaptic strength across dopamine neurons, identifying a peptide-mediated feedback mechanism that shapes VTA circuit function.Significance Statement Dopamine neurons in the ventral tegmental area (VTA) play central roles in reward, motivation, stress responses, and feeding behavior. While fast synaptic inputs regulate dopamine neuron firing on fast timescales, less is known about how slower neuromodulatory signals shape these circuits. We show that somatodendritic release of the neuropeptide cholecystokinin from dopamine neurons coordinately alters both inhibitory and excitatory synaptic strength and influences neighboring neurons within the VTA. This peptide-mediated feedback mechanism operates over a broader spatial scale than classical synaptic transmission and is regulated by kappa opioid signaling. These findings reveal how local peptide release can reshape dopamine circuit function and may contribute to changes in reward processing and feeding behavior.