Local Regulation of Striatal Dopamine Release Shifts from Predominantly Cholinergic in Mice to GABAergic in Macaques

Dopamine critically regulates neuronal excitability and promotes synaptic plasticity in the striatum, thereby shaping network connectivity and influencing behavior. These functions establish dopamine as a key neuromodulator, whose release properties have been well studied in rodents but remain understudied in nonhuman primates. This study aims to close this gap by investigating the properties of dopamine release in macaque striatum and comparing/contrasting them to better-characterized mouse striatum, using ex vivo brain slices from male and female animals. Using combined electrochemical techniques and photometry with fluorescent dopamine sensors, we found that evoked dopamine signals have smaller amplitudes in macaques compared with those in mice. Interestingly, cholinergic-dependent dopamine release, which accounts for two-thirds of evoked dopamine release in mouse slices, is significantly reduced in macaques, providing a potential mechanistic underpinning for the observed species difference. In macaques, only nicotinic receptors with alpha-6 subunits contribute to evoked dopamine release, whereas in mice, both alpha-6 and non-alpha6-containing receptors are involved. We also identified robust potentiation of dopamine release in both species when GABA_A and GABA_B receptors were blocked. This potentiation was stronger in macaques, with an average increase of 50%, compared with 15% in mice. Together, these results suggest that dopamine release in macaque is under stronger GABA-mediated inhibition and that weaker cholinergic-mediated dopamine release may account for the smaller amplitude of evoked dopamine signals in macaque slices.