Neuronal calcium sensor-1 deletion in the mouse decreases motivation and dopamine release in the nucleus accumbens

•Neuronal calcium sensor-1 knockout mice were characterized.•Knockout mice are less willing to work for food.•Knockout brain slices show lower nucleus accumbens core dopamine release.•Food preference, Pavlovian incentive learning and sensory-specific satiety are normal.•Locomotion, amphetamine-induced hyperlocomotion and sensitization are normal. Calcium sensors detect intracellular calcium changes and interact with downstream targets to regulate many functions. Neuronal Calcium Sensor-1 (NCS-1) or Frequenin is widely expressed in the nervous system, and involved in neurotransmission, synaptic plasticity and learning. NCS-1 interacts with and regulates dopamine D2 receptor (D2R) internalization and is implicated in disorders like schizophrenia and substance abuse. However, the role of NCS-1 in behaviors dependent on dopamine signaling in the striatum, where D2R is most highly expressed, is unknown. We show that Ncs-1 deletion in the mouse decreases willingness to work for food. Moreover, Ncs-1 knockout mice have significantly lower activity-dependent dopamine release in the nucleus accumbens core in acute slice recordings. In contrast, food preference, responding for conditioned reinforcement, ability to represent changes in reward value, and locomotor response to amphetamine are not impaired. These studies identify novel roles for NCS-1 in regulating activity-dependent striatal dopamine release and aspects of motivated behavior.