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. The gene discussed is HTR5A; the disease is major depressive disorder.