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 g/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 druginduced reinstatement of cocaine-seeking behavior.

The potent psychomotor, rewarding and reinforcing properties of 3‐fluoromethamphetamine in rodents

“…70 Several studies have shown that priming injection of psychostimulants such as METH and cocaine reinstate drug-seeking behaviors. [32][33][34][35] Consistent with these findings, the present study demonstrates that a priming injection of 3-FMA after extinction training reinstated drug-seeking behavior in 3-FMA self-administered rats.…”

TA1 agonists attenuate extended‐access cocaine self‐administration and yohimbine‐induced reinstatement of cocaine‐seeking

“…TA 1 is a well‐characterized GPCR that modulates the dopaminergic system (Revel et al, 2011). In rodents and humans, TA 1 is expressed in the dopaminergic system extensively including the ventral tegmental area (VTA) and its projecting areas such as dorsal and ventral striatum and prefrontal cortex (PFC) (Borowsky et al, 2001; Liu et al, 2017). Indeed, our previous study showed that TA 1 in the VTA, nucleus accumbens (NAc) and PFC all contribute to cue‐ and drug‐induced reinstatement of cocaine‐seeking (Liu et al, 2017).…”

“…In rodents and humans, TA 1 is expressed in the dopaminergic system extensively including the ventral tegmental area (VTA) and its projecting areas such as dorsal and ventral striatum and prefrontal cortex (PFC) (Borowsky et al, 2001; Liu et al, 2017). Indeed, our previous study showed that TA 1 in the VTA, nucleus accumbens (NAc) and PFC all contribute to cue‐ and drug‐induced reinstatement of cocaine‐seeking (Liu et al, 2017). A growing number of mechanistic studies have indicated a critical role of TA 1 in dopamine transmission (Borowsky et al, 2001; Gainetdinov et al, 2018; Revel et al, 2011).…”

“…A growing number of studies have suggested an inhibitory role of the TA 1 system in regulating dopamine neurotransmission (Revel et al, 2011) and the potential of TA 1 agonists for treating cocaine use disorder (Liu, Siemian, Seaman, Zhang, & Li, 2017; Thorn et al, 2014). Using a short‐access cocaine self‐administration model, in which animals maintain a stable cocaine intake pattern, earlier work showed that TA 1 agonists reduced cocaine intake and cocaine relapse (Pei et al, 2014; Revel, Moreau, et al, 2012; Thorn et al, 2014).…”

Trace Amines and Their Receptors

“…Furthermore, TAAR1 activation causes a downward shift in dose-response curves for cocaine reward efficacy, confirming lesser rewarding properties. Again, effects appear to be focused on TAAR1 activation within the nucleus accumbens as well as the VTA and prelimbic cortex (Liu et al, 2017b).…”