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

Abstract

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.

Keywords: TAAR1; cocaine; mesocorticolimbic regions; reinstatement; self-administration.

Figure 1.

TAAR1 mRNA in the subregions of the mesocorticolimbic system in rats and representative bands. Representative gel electrophoresis bands of RT-PCR products were for GAPDH and TAAR1 in the VTA. The expected GAPDH and TAAR1 bands were 191 and 127 bp, respectively.

Figure 2.

Experimental timeline and cocaine self-administration training and extinction of drug-reinforced responding. a, Experimental timeline. b, Cocaine self-administration data during training: number of infusions and active and inactive lever presses over the 12 d of 2 h daily sessions. c, Extinction data: number of nonreinforced active and inactive lever presses over the 7 d of 2 h daily extinction sessions. Data are mean ± SEM. Cocaine, n = 131; saline, n = 5.

Figure 3.

Microinjection of RO5166017 into the VTA, but not the SN, prevented both cue- and drug-induced reinstatement of cocaine-seeking behavior. a, e, The cocaine-vehicle group of rats that self-administrated cocaine showed higher active lever pressing compared with the saline-vehicle group during cue-induced reinstatement test. Microinjection of RO5166017 into the VTA, but not the SN, reduced active lever pressing in the cue-induced reinstatement of cocaine-seeking. b, f, No difference was found during re-extinction. c, g, Cocaine priming reinstated active lever pressing of the cocaine-vehicle group of rats. Microinjection of RO5166017 into the VTA, but not the SN, decreased active lever pressing in the drug-induced reinstatement of cocaine-seeking. d, h, Microinjection sites for the VTA and the SN. Data are mean ± SEM. ^#p < 0.05, different from the saline-vehicle group. *p < 0.05, different from the cocaine-vehicle group. n = 5–7 per group.

Figure 4.

Microinjection of RO5166017 into the NAc core and shell reduced cue- and drug-induced reinstatement of cocaine-seeking behavior, respectively. a, e, Microinjection of RO5166017 into the NAc core, but not shell, decreased cue-induced reinstatement of cocaine-seeking. b, f, No difference was found during re-extinction. c, g, Microinjection of RO5166017 into the NAc shell, but not core, decreased drug-induced reinstatement of cocaine-seeking. d, h, Microinjection sites for the NAc core and shell. Data are mean ± SEM. *p < 0.05, different from the vehicle group. n = 8 or 9 per group.

Figure 5.

Microinjection of RO5166017 into the PrL, but not the IL, of mPFC decreased cue- and drug-induced reinstatement of cocaine-seeking behavior. a, e, Microinjection of RO5166017 into the PrL, but not IL, decreased cue-induced reinstatement of cocaine-seeking. b, f, No difference was found during re-extinction. c, g, Microinjection of RO5166017 into the PrL, but not IL, decreased drug-induced reinstatement of cocaine-seeking. d, h, Microinjection sites for the PrL and the IL. Data are mean ± SEM. *p < 0.05, different from the vehicle group. n = 7–9 per group.

Figure 6.

Microinjection of RO5166017 into the BLA and the CeA had no effect on cue- and drug-induced reinstatement of cocaine-seeking behavior. a, e, Microinjection of RO5166017 into the BLA and the CeA had no effect on cue-induced reinstatement of cocaine-seeking. b, f, No difference was found during re-extinction. c, g, Microinjection of RO5166017 into the BLA and the CeA did not affect drug-induced reinstatement of cocaine-seeking. d, h, Microinjection sites for the BLA and the CeA. Data are mean ± SEM. *p < 0.05, different from the vehicle group. n = 8 per group.

Figure 7.

Microinjection of RO5166017 into the VTA, PrL, NAc core, or NAc shell had no effect on the response rate for a food reinforcer. a–d, After recovery from the stereotaxic surgery, rats were retrained to satisfy the criteria before tests. All rats received two tests. Before the first cycle of the first and second tests, rats received a single microinjection of vehicle and RO5166017, respectively. Microinjection of RO5166017 into the VTA, the PrL, the NAc core, or the NAc shell did not affect the response rate for a food reward. Data are mean ± SEM. n = 6–8 per group.