Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1

Abstract

The trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that is functionally activated by amphetamine-based psychostimulants, including amphetamine, methamphetamine and MDMA. Previous studies have shown that in transgenic mice lacking the TAAR1 gene (TAAR1 knockout; KO) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild-type (WT) mice. Further, the psychostimulant effects of cocaine can be diminished by selective activation of TAAR1. These findings suggest that TAAR1 might be implicated in the rewarding properties of psychostimulants. To investigate the role of TAAR1 in the rewarding effects of drugs of abuse, the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and TAAR1 KO mice. In locomotor activity studies, both single and repeated exposure to d-amphetamine or methamphetamine generated significantly higher levels of total distance traveled in TAAR1 KO mice compared to WT mice. In conditioned place preference (CPP) studies, TAAR1 KO mice acquired methamphetamine-induced CPP earlier than WT mice and retained CPP longer during extinction training. In morphine-induced CPP, both WT and KO genotypes displayed similar levels of CPP. Results from locomotor activity studies suggest that TAAR1 may have a modulatory role in the behavioral sensitization to amphetamine-based psychostimulants. That methamphetamine-but not morphine-induced CPP was augmented in TAAR1 KO mice suggests a selective role of TAAR1 in the conditioned reinforcing effects of methamphetamine. Collectively, these findings provide support for a regulatory role of TAAR1 in methamphetamine signaling.

Figure 1

Total distance travelled during a 60-min period immediately following d-amphetamine or methamphetamine (1, 3 or 5 mg/kg; n=15 per dose, per genotype) or saline (n=20 per genotype) injections; ** p < 0.01, * p < 0.05 comparing WT vs. TAAR1 KO mice.

Figure 2

Total distance travelled during a 60-min period following administration of escalating doses of d-amphetamine or methamphetamine (0.5 to 6 mg/kg; n=4-5 per dose, per genotype). *** p < 0.001, * p < 0.05 comparing WT vs. TAAR1 KO mice.

Figure 3

a) Methamphetamine dose-response curve showing the magnitude of CPP following place conditioning with methamphetamine (0.3 – 3.0 mg/kg; n = 9-12 per dose, per genotype). CPP score is the difference in time spent between the drug- and saline-paired compartments. Points above “Veh” represent data from control subjects that were administered saline during each conditioning session. b) Time spent in compartments during the preconditioning test for the group of mice that received the intermediate methamphetamine dose (1.0 mg/kg). # p < 0.05: Saline vs. methamphetamine conditioning.

Figure 4

CPP tests following conditioning with methamphetamine (1.0 mg/kg; n=15-16 per genotype) or saline (n=8 per genotype) a) After only 2 methamphetamine conditioning sessions: Post-conditioning test 1 and b) After 4 methamphetamine conditioning sessions: Postconditioning test 2; c) Extinction of methamphetamine-induced CPP achieved by exposure to compartments in the absence of methamphetamine or saline injections and reinstatement to place preference in response to a priming injection of methamphetamine (0.56 mg/kg; i.m.).* p <0.05; WT vs. TAAR1 KO; # p < 0.05: Saline vs. methamphetamine conditioning.

Figure 5

CPP induced by morphine 5 and 15 mg/kg (n=9 per dose, per genotype) after A) 2 saline and 2 morphine conditioning sessions and B) 4 saline and 4 morphine conditioning sessions. # p <0.05: Saline vs. morphine conditioning.