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 to 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 to 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. Dopamine plays a vital role in striatal function, influencing both essential physiological processes and the development of debilitating brain disorders. Most of our current understanding of dopamine release and regulation stems from rodent studies. Investigating the similarities and differences between rodent and primate dopamine systems will improve translatability of findings from rodents to humans. This comparative study identified differences in the local regulation of dopamine release within the striatum of macaques and mice. The modulation by acetylcholine was weaker while the modulation by GABA was stronger in macaques.