We found that reduced 5-HT transmission leads to reduced motivation through 2 distinct processes: increased cost sensitivity exclusively via 5-HT1AR and reduced incentive via 5-HT1AR and 5-HT1BR. Our findings shed light on the mechanistic role of 5-HT in different aspects of motivational regulation and their relevance to different aspects of medications used to treat depression. Here, HTR5A is linked to depressive symptom measurement.