Differential effects of aprepitant, a clinically used neurokinin-1 receptor antagonist on the expression of conditioned psychostimulant versus opioid reward

Abstract

Rationale: Neurokinin-1 receptor (NK1R) signaling modulates behaviors associated with psychostimulants and opioids. Psychostimulants, such as amphetamine (AMPH) and cocaine, bind to monoamine transporters and alter their functions. Both dopamine and norepinephrine transporters are regulated by NK1R activation suggesting a role for NK1R mediated catecholamine transporter regulation in psychostimulant-mediated behaviors.

Objectives: The effect of in vivo administration of aprepitant (10 mg/kg) on the expression of AMPH (0.5 and 2 mg/kg) and cocaine (5 and 20 mg/kg)-induced conditioned place preference (CPP) as well as locomotor activation was examined in C57BL/6J mice. The effect of aprepitant on morphine (1 and 5 mg/kg)-induced CPP was also examined to identify the specific actions of aprepitant on psychostimulant versus opioid-induced behaviors.

Results: Aprepitant administration significantly attenuated the CPP expression and locomotor activation produced by AMPH and cocaine. In contrast, aprepitant significantly enhanced the expression of CPP produced by morphine while significantly suppressing the locomotor activity of the mice conditioned with morphine. Aprepitant by itself did not induce significant CPP or conditioned place aversion or locomotor activation or suppression.

Conclusions: Attenuation of AMPH or cocaine-induced CPP and locomotor activation by aprepitant suggests a role for NK1R signaling in psychostimulant-mediated behaviors. Stimulation of morphine-induced CPP expression and suppression of locomotor activity of morphine-conditioned mice suggest differential effects of NK1R antagonism on conditioned psychostimulant versus opioid reward. Collectively, these findings indicate that clinically used NK1R antagonist, aprepitant may serve as a potential therapeutic agent in the treatment of psychostimulant abuse.

Keywords: Amphetamine; Antagonist; Aprepitant; Cocaine; Conditioned place preference; Drug abuse; Morphine; Neurokinin-1 receptor; Opioids; Psychostimulants.

Figure 1

CPP scores recorded during postconditioning testing, given as means ± SEM, show significant CPP in mice conditioned with AMPH (A) 0.5 mg/kg (n=11) or (B) 2 mg/kg (n=11) compared to mice conditioned with saline (n=11). Treatment with aprepitant (10 mg/kg) significantly reduced AMPH CPP. ** and **** indicate significant effect by AMPH (p < 0.005 & p < 0.0001 respectively) and ^ indicates significant effect by aprepitant treatment in the AMPH group (p < 0.05). Movement counts recorded simultaneously during postconditioning testing, given as means ± SEM, show significant locomotor activation in mice conditioned with AMPH (C) 0.5 mg/kg or (D) 2 mg/kg compared to mice conditioned with saline. Treatment with aprepitant (10 mg/kg) significantly reduced AMPH induced locomotor activity. **, *** and **** indicate significant effect by AMPH (p < 0.005, p < 0.0003, p < 0.0001) and ^ indicates significant effect by aprepitant treatment in the AMPH group (p < 0.05).

Figure 2

CPP scores recorded during postconditioning testing, given as means ± SEM, show significant CPP in mice conditioned with cocaine (A) 5 mg/kg (n=11) or (B) 20 mg/kg (n=11) compared to mice conditioned with saline (n=11). Treatment with aprepitant (10 mg/kg) significantly reduced cocaine CPP. * and **** indicate significant effect by cocaine (p < 0.05 & p < 0.0001 respectively) and ^ and ^^ indicate significant effect by aprepitant treatment in the cocaine group (p < 0.005 & p < 0.05 respectively). Movement counts recorded simultaneously during postconditioning testing, given as means ± SEM, show significant locomotor activation in mice conditioned with cocaine (C) 5 mg/kg (n=11) or (D) 20 mg/kg (n=11) compared to mice conditioned with saline (n=11). Treatment with aprepitant (10 mg/kg) significantly reduced cocaine induced locomotor activity. *, **, *** and **** indicate significant effect by cocaine (p < 0.05, p < 0.005, p < 0.0003 & p < 0.0001) and ^^ indicates significant effect by aprepitant treatment in the cocaine group (p < 0.005).

Figure 3

CPP scores recorded during postconditioning testing, given as means ± SEM, show significant CPP in mice conditioned with morphine (A) 1 mg/kg (n=8) or (B) 5 mg/kg (n=11) compared to mice conditioned with saline (n=19). Treatment with aprepitant (10 mg/kg) significantly reduced morphine CPP. ** *** and **** indicate significant effect by morphine (p < 0.005, p < 0.0003 & p < 0.0001 respectively) and ^^ indicates significant effect by aprepitant treatment in the morphine group (p < 0.005). Movement counts recorded simultaneously during postconditioning testing, given as means ± SEM, show significant locomotor activation in mice conditioned with morphine (C) 1 mg/kg (n=8) or (D) 5 mg/kg (n=11) compared to mice conditioned with saline (n=19). Treatment with aprepitant (10 mg/kg) significantly reduced locomotor activity of morphine conditioned mice. ** indicates significant effect by morphine (p < 0.005) and ^ indicates significant effect by aprepitant treatment in the morphine group (p < 0.05).

Figure 4

(A) CPP scores recorded during post-conditioning testing shows no CPP in mice conditioned with Aprepitant (10 mg/kg i.p. daily for 3 days) compared to vehicle conditioned mice. Data represent means ± SEM. (B) Locomotor activity of mice recorded simultaneously as movement counts during postconditioning testing shows no significant difference between vehicle conditioned mice and aprepitant conditioned mice. Data represent means ± SEM.