Obesity is a primary healthcare challenge of the 21st century. Medications increasing the bioavailability of the neurotransmitter serotonin (5-hydroxytriptamine; 5-HT) have historically been used for obesity treatment. 5-HT primarily influences appetite via action at the 5-HT2C receptor (5-HT2CR); the clinical significance of which has recently been realized with the launch of the 5-HT2CR agonist lorcaserin for obesity treatment in the USA. Efforts to delineate the underpinnings of 5-HT2CR appetite suppression have largely focused upon action within the hypothalamus, a crucial brain region modulating energy homeostasis. However, another neuroanatomical population of 5-HT2CRs is located within the ventral tegmental area (VTA), a primary node within reward circuits. To examine the physiological significance of 5-HT2CRs within the VTA, we utilized designer receptors exclusively activated by designer drugs (DREADD) technology to probe the discrete function of VTA 5-HT2CRs in the reward value of food. Designer Gq receptor (AAV8-hSyn-DIO-hM3Dq-mCherry) was bilaterally injected into the VTA of 5-HT2CR-Cre mice producing 5-HT2CR-Cre:hM3Dq-expressing neurons exclusively within the VTA. The selective activation of these neurons by designer drug clozapine-N-oxide (CNO) significantly suppressed home cage laboratory chow intake. Further analysis indicated that this was related to a reduction in food reward. Specifically, discrete simulation of 5-HT2CRs within the VTA significantly suppressed operant responding for food reward (chocolate pellets), both when mice were motivated to eat through food restriction and in the free feeding condition. To evaluate the translational significance of this finding, we next examined whether human obesity medication 5-HT2CR agonist lorcaserin influences the reward value of food. The same concentrations of lorcaserin that reduced ad libitum home cage food intake also significantly reduced operant responding for food reward. Thereby, these data suggest that a component of lorcaserin-induced appetite suppression is due to a reduction in food reward and identify that the little studied population of VTA 5-HT2CRs are sufficient to mediate this effect.
28 - 31 May 2016
European Society of Endocrinology