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Link to original content: https://pubmed.ncbi.nlm.nih.gov/25762894/
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. 2015 Feb 13:9:39.
doi: 10.3389/fnins.2015.00039. eCollection 2015.

The trace amine-associated receptor 1 modulates methamphetamine's neurochemical and behavioral effects

Rachel Cotter  1 , Yue Pei  2 , Liudmila Mus  3 , Anja Harmeier  4 , Raul R Gainetdinov  5 , Marius C Hoener  4 , Juan J Canales  6
Affiliations

The trace amine-associated receptor 1 modulates methamphetamine's neurochemical and behavioral effects

Rachel Cotter et al. Front Neurosci. .

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.

Keywords: methamphetamine; microdialysis; self-administration; sensitization; synaptosomes; trace amine-associated receptor.

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Figures

Figure 1
Figure 1
Modulation of METH-induced locomotor activity and sensitization by TAAR1. (A) Chronic exposure to methamphetamine gradually increased locomotor activity. Low and moderate doses of RO5203648 attenuated METH-induced locomotor activity and blocked the progressive increment induced by repeated exposure to METH. (B) Following withdrawal from chronic METH exposure, a challenge with a low dose of METH produced sensitized locomotor responsiveness. The long-term expression of locomotor sensitization was prevented in rats that had received concurrent treatment with RO5203648 (at either low or moderate doses) and METH. Treatment with the high dose of RO5203648 alone during the sensitization phase enhanced the subsequent long-term response to METH. (C) METH produced robust increases in locomotor activity compared with control treatment in a 3-h activity test. RO5203648 produced an early attenuation and a late potentiation of METH-stimulated locomotor activity. φp < 0.01, different from acute METH (day 1); #p < 0.01, different from chronic METH (day 7), *p < 0.01 different from METH (after chronic control treatment), ϕp < 0.01 different from METH (after chronic METH exposure). RO = RO5203648, MA = methamphetamine.
Figure 2
Figure 2
RO5203648 decreases METH S-A and exhibits reduced abuse liability in a substitution test. (A) Rats were trained on METH S-A until consistent performance was attained. (B) RO5203648 dose-dependently reduced METH S-A but did not affect sucrose S-A (C). (D) In a substitution procedure, varying concentrations of RO5203648 did not sustain S-A behavior over and above control values, whereas a concentration of METH three times lower than that used during training generated strong responding. *p < 0.01, different from control values; #p < 0.01, different from METH. RO = RO5203648, MA = methamphetamine.
Figure 3
Figure 3
RO5203648 transiently attenuated DA overflow in the NAc in vivo but not in striatal synaptosomes. (A) In striatal synaptosomes the efflux of [3H]DA induced by varying concentrations of METH was not affected by co-application of RO5203648, as was the uptake of [3H]DA (B) In the 3-h long in vivo microdialysis experiment RO5203648 delayed the strong increases in extracellular DA accumulation induced by METH treatment in the NAc, producing a marked transient inhibition of the DA response (C) please note that a pure control cannot be included in the uptake experiments (B) because no efflux or release can be measured after vehicle treatment. #p < 0.01, different from METH. RO = RO5203648, MA = methamphetamine.
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