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

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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.

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Acknowledgements

Dr. Jayanthi and Dr. Ramamoorthy declare that the funding for this research was provided in part by NIH grants DA039451 and MH083928 as well as by Virginia Commonwealth University. Dr. Mannangatti gratefully acknowledges post-doctoral support from the department of Pharmacology and Toxicology at Virginia Commonwealth University.

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  1. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Padmanabhan Mannangatti, Santhanalakshmi Sundaramurthy, Sammanda Ramamoorthy & Lankupalle D. Jayanthi

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  1. Padmanabhan Mannangatti
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  2. Santhanalakshmi Sundaramurthy
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  3. Sammanda Ramamoorthy
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  4. Lankupalle D. Jayanthi
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Correspondence to Lankupalle D. Jayanthi.

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All animal procedures were approved by the Virginia Commonwealth University Institutional Animal Care and Use Committee and were in accordance with the National Institutes of Health guide (NIH) guidelines published in the National Research Council (2011) Guide for the Care and Use of Laboratory animals, 8th edition, National Academies Press, Washington, DC.

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Mannangatti, P., Sundaramurthy, S., Ramamoorthy, S. et al. Differential effects of aprepitant, a clinically used neurokinin-1 receptor antagonist on the expression of conditioned psychostimulant versus opioid reward. Psychopharmacology 234, 695–705 (2017). https://doi.org/10.1007/s00213-016-4504-6

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