A partial trace amine-associated receptor 1 agonist exhibits properties consistent with a methamphetamine substitution treatment

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Abstract

Recent evidence suggests that the trace amine-associated receptor 1 (TAAR1) plays a pivotal role in the regulation of dopamine (DA) transmission and psychostimulant action. Several selective TAAR1 agonists have previously shown efficacy in models of cocaine addiction. However, the effects of TAAR1 activation on methamphetamine (METH)-induced behaviours are less well understood, as indeed are the underlying neurochemical mechanisms mediating potential interactions between TAAR1 and METH. Here, in a progressive ratio schedule of reinforcement the partial TAAR1 agonist, RO5263397, reduced the break-point for METH self-administration, while significantly increasing responding maintained by food reward. Following self-administration and extinction training, RO5263397 completely blocked METH-primed reinstatement of METH seeking. Moreover, when used as a substitute, unlike a low dose of METH, which sustained vigorous responding when substituting for the training dose of METH, RO5263397 was not self-administered at any dose, thus exhibiting no apparent abuse liability. Fast-scan cyclic voltammetry experiments showed that RO5263397 prevented METH-induced DA overflow in slices of the nucleus accumbens, while having no effect on DA transmission in its own right. Collectively, the present observations demonstrate that partial TAAR1 activation decreases the motivation to self-administer METH, blocks METH-primed reinstatement of METH seeking and prevents METH-induced DA elevations in the nucleus accumbens, and strongly support the candidacy of TAAR1-based medications as potential substitute treatment in METH addiction.

The trace amine-associated receptor 1 (TAAR1) has been proposed as a candidate for the development of new medications for stimulant addiction. The present experiments showed that the partial TAAR1 agonist, RO5263397, did not sustain self-administration, decreased the motivation to self-administer methamphetamine, blocked methamphetamine-primed reinstatement of methamphetamine seeking and attenuated methamphetamine-induced elevations in dopamine transmission in the nucleus accumbens. Taking together, these findings warrant further investigation of TAAR1 as a target for novel pharmacotherapeutics in stimulant addiction.

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