CENTRAL KISSPEPTIN-8 INHIBITS SPONTANEOUS LOCOMOTION VIA NEUROCHEMICAL MODULATION OF THE VENTRAL TEGMENTAL AREA – NUCLEUS ACCUMBENS CIRCUIT IN RATS

In our previous studies, intracerebroventricular (icv.) kisspeptin-8 (Kp-8) reduced exploratory locomotion, increased GABA release, and caused a downregulation of D1 and D2 dopamine receptors in the nucleus accumbens (NAc). We aimed to investigate the effect of icv. Kp-8 on spontaneous locomotion with a Kiss1 receptor antagonist (Kp-234) pretreatment to assess the mechanism of action. Furthermore, in the NAc and ventral tegmental area (VTA), receptor expressions were determined, and GABA and dopamine metabolites were measured after icv. Kp-8 treatment.
Following icv. cannulation, male Wistar rats were implanted with an E-mitter, then spontaneous locomotion was recorded by telemetry, with daily icv. treatment (0.1; 0.5; 1 or 2 µg Kp-8; or 0.1 µg Kp-234 followed by 0.1 or 1 µg Kp-8). The expression of Kiss1R, Npff1R and Npffr2 were determined in the NAc and VTA using immunohistochemistry. GABA and dopamine metabolites were measured 4 hours after icv. Kp-8 treatment using UHPLC-MS/MS.
In the telemetry study, Kp-8 induced a dose-dependent hypolocomotion, which was abolished by Kp-234 pretreatment. Kiss1R, Npff1R and Npff2R expression were detected both in the VTA and NAc. In the VTA, Kp-8 increased dopamine synthesis and metabolism without significantly affecting turnover, whereas dopamine turnover and GABA levels rose in the NAc.
To conclude, Kp-8 dose-dependently reduced spontaneous locomotion, possibly via Kiss1R. Although dopamine levels rose in the VTA, increased dopamine turnover and GABA levels in the NAc, accompanied by dopamine receptor downregulation, may lead to a net inhibitory effect of Kp-8 on the VTA-NAc dopaminergic circuit.
Funding: SZAOK-KKA-SZGYA: 2024.02.01-2026.01.31.; SZAOK-KKA-PKP: 2025.02.01-2027.01.31.; EFOP-3.6.2-16-2017-00006