Role of TAAR1 within the Subregions of the Mesocorticolimbic Dopaminergic System in Cocaine-Seeking Behavior.

Unlabelled: A novel G-protein coupled receptor, trace amine-associated receptor 1 (TAAR1), has been shown to be a promising target to prevent stimulant relapse. Our recent studies showed that systemic administration of TAAR1 agonists decreased abuse-related behaviors of cocaine. However, the role of TAAR1 in specific subregions of the reward system in drug addiction is unknown. Here, using a local pharmacological activation method, we assessed the role of TAAR1 within the subregions of the mesocorticolimbic system: that is, the VTA, the prelimbic cortex (PrL), and infralimbic cortex of medial prefrontal cortex, the core and shell of NAc, BLA, and CeA, on cue- and drug-induced cocaine-seeking in the rat cocaine reinstatement model. We first showed that TAAR1 mRNA was expressed throughout these brain regions. Rats underwent cocaine self-administration, followed by extinction training. RO5166017 (1.5 or 5.0 μg/side) or vehicle was microinjected into each brain region immediately before cue- and drug-induced reinstatement of cocaine-seeking. The results showed that microinjection of RO5166017 into the VTA and PrL decreased both cue- and drug priming-induced cocaine-seeking. Microinjection of RO5166017 into the NAc core and shell inhibited cue- and drug-induced cocaine-seeking, respectively. Locomotor activity or food reinforced operant responding was unaffected by microinjection of RO5166017 into these brain regions. Cocaine-seeking behaviors were not affected by RO5166017 when microinjected into the substantia nigra, infralimbic cortex, BLA, and CeA. Together, these results indicate that TAAR1 in different subregions of the mesocorticolimbic system distinctly contributes to cue- and drug-induced reinstatement of cocaine-seeking behavior.

Significance Statement: TAAR1 has been indicated as a modulator of the dopaminergic system. Previous research showed that systemic administration of TAAR1 agonists could attenuate cocaine-related behaviors, suggesting that TAAR1 may be a promising drug target for the treatment of cocaine addiction. However, the specific role of TAAR1 in subregions of the mesocorticolimbic system in drug addiction is unknown. Here, we first showed that TAAR1 mRNA is expressed throughout the subregions of the mesocorticolimbic system. Then, by using a local pharmacological activation method, we demonstrated that TAAR1 in different subregions of the mesocorticolimbic system distinctly contributes to cue- and drug-induced reinstatement of cocaine-seeking behavior.