Abstract
The newly discovered trace amine-associated receptor 1 (TAAR1) has the ability to regulate both dopamine function and psychostimulant action. Here, we tested in rats the ability of RO5203648, a selective TAAR1 partial agonist, to modulate the physiological and behavioral effects of methamphetamine (METH). In experiment 1, RO5203468 dose- and time-dependently altered METH-induced locomotor activity, manifested as an early attenuation followed by a late potentiation of METH's stimulating effects. In experiment 2, rats received a 14-day treatment regimen during which RO5203648 was co-administered with METH. RO5203648 dose-dependently attenuated METH-stimulated hyperactivity, with the effects becoming more apparent as the treatments progressed. After chronic exposure and 3-day withdrawal, rats were tested for locomotor sensitization. RO5203648 administration during the sensitizing phase prevented the development of METH sensitization. However, RO5203648, at the high dose, cross-sensitized with METH. In experiment 3, RO5203648 dose-dependently blocked METH self-administration without affecting operant responding maintained by sucrose, and exhibited lack of reinforcing efficacy when tested as a METH's substitute. Neurochemical data showed that RO5203648 did not affect METH-mediated DA efflux and uptake inhibition in striatal synaptosomes. In vivo, however, RO5203648 was able to transiently inhibit METH-induced accumulation of extracellular DA levels in the nucleus accumbens. Taken together, these data highlight the significant potential of TAAR1 to modulate METH's neurochemical and behavioral effects.
Highlights
Methamphetamine (METH) is a widely abused and highly addictive psychostimulant drug
Our finding that repeated RO5203648 co-administered with METH blocked the development of METH sensitization suggests that trace amine-associated receptor 1 (TAAR1) is able to modulate the long-term neuroadaptations induced by chronic METH exposure
In line with these observations, it has been shown previously that mice lacking taar1 were hypersensitive to the motor-stimulating effects of METH (Achat-Mendes et al, 2012), suggesting that TAAR1 is either constitutively active or tonically activated by ambient ligands to suppress the dopaminergic response to METH
Summary
Methamphetamine (METH) is a widely abused and highly addictive psychostimulant drug. In the brain, METH elevates extracellular dopamine (DA) levels, an effect that is thought to underlie its potent motor and psychoactive actions (Fleckenstein et al, 2007). TAAR1 shares overlapping distribution in the brain with mesolimbic DA pathways (Borowsky et al, 2001; Lindemann et al, 2008), is co-localized with the DAT in a subset of DA neurons (Xie and Miller, 2007), and interacts with both the DAT and the D2 DA autoreceptor (D2R) to modulate DA transmission (Xie et al, 2007, 2008; Espinoza et al, 2011) These observations suggest that TAAR1 regulates DA activity and has the potential to serve as a pharmacological target to modulate DA dysregulation that results from chronic stimulant exposure
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