Thyrotropin-releasing hormone and dopaminergic systems interact in the ventral tegmental area to regulate food intake...

Dopamine neurons in the ventral tegmental area (VTA^DA) projecting to the nucleus accumbens (Acb) modulate food intake and play a critical role in energy balance. Although a range of signaling agents are known to control the activity of VTA^DA and regulate food intake, the underlying microcircuitry is poorly understood. Since VTA expresses thyrotropin-releasing hormone (TRH) receptors, we try to dissect the role of TRH-dopamine (DA) interaction within the VTA in controlling food intake in adult, male Sprague-Dawley rats. TRH-ir axons were seen throughout VTA-subdivisions, inclusive of interfascicular (IF), rostral and caudal linear, paranigral (PN), and parabrachial pigmented nuclei. Among these, the IF and PN showed particularly dense TRH innervation. The TRH-fiber density in the VTA was significantly increased in fasted rats, while refeeding abolished the response. Double-immunofluorescence showed that VTA^DA-neurons were contacted by TRH-fiber terminals. Intra-VTA TRH microinjection in fasted rats significantly reduced food intake at 2 h post-injection and increased DA/DA-metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) turnover in Acb. Ex vivo treatment of midbrain slices from fasted rats with TRH significantly augmented tyrosine hydroxylase-immunoreactivity in VTA. While the retrograde tracer iontophoresed into the VTA retrogradely labelled TRH-neurons in the dorsal raphe nucleus (DRN), hypothalamic TRH-ergic populations showed no labeling. Further, Trh-mRNA levels in DRN-containing tissues were significantly elevated during fasting compared with fed controls and returned to baseline following refeeding. Electrically stimulating DRN during fasting significantly reduced TRH-ir but increased TH-ir in the VTA. We suggest that TRH, probably received from DRN, may directly target the VTA→Acb DAergic pathway to suppress food intake.