Droxidopa alters dopamine neuron and prefrontal cortex activity and improves attention-deficit/hyperactivity disorder-like behaviors in rats

Authors

Ike Dela Peña, Department of Pharmaceutical and Administrative Sciences, Loma Linda University School of Pharmacy, Loma Linda, CA, 92350, USA.Follow
Guofang Shen, Department of Pharmaceutical and Administrative Sciences, Loma Linda University School of Pharmacy, Loma Linda, CA, 92350, USA.
Wei-Xing Shi, Department of Pharmaceutical and Administrative Sciences, Loma Linda University School of Pharmacy, Loma Linda, CA, 92350, USA; Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA.Follow

Document Type

Article

Publication Date

2-5-2021

Publication Title

European journal of pharmacology

E-ISSN

1879-0712

Abstract

Finding alternative treatments for attention-deficit/hyperactivity disorder (ADHD) is crucial given the safety and efficacy problems of current ADHD medications. Droxidopa, also known as L-threo-dihydroxyphenylserine (L-DOPS), is a norepinephrine prodrug that enhances brain norepinephrine and dopamine levels. In this study, we used electrophysiological tests to examine effects of L-DOPS on the prefrontal cortex (PFC) and dopamine neurons in the ventral tegmental area. We also conducted behavioral tests to assess L-DOPS' effects on ADHD-like behaviors in rats. In chloral hydrate-anesthetized rats, PFC local field potentials oscillated between the active, depolarized UP state and the hyperpolarized DOWN state. Mimicking the effect of d-amphetamine, L-DOPS, given after the peripheral amino acid decarboxylase inhibitor, benserazide (BZ), increased the amount of time the PFC spent in the UP state, indicating an excitatory effect of L-DOPS on PFC neurons. Like d-amphetamine, L-DOPS also inhibited dopamine neurons, an effect significantly reversed by the D2-like receptor antagonist raclopride. In the behavioral tests, BZ + L-DOPS improved hyperactivity, inattention and impulsive action of the adolescent spontaneously hypertensive rat (SHR/NCrl), well-validated animal model of the combined type of ADHD. BZ + L-DOPS also reduced impulsive choice and impulsive action of Wistar rats, but did not ameliorate the inattentiveness of Wistar Kyoto rats (WKY/NCrl), proposed model of the ADHD-predominantly inattentive type. In conclusion, L-DOPS produced effects on the PFC and dopamine neurons characteristic of drugs used to treat ADHD. BZ + L-DOPS ameliorated ADHD-like behaviors in rats suggesting its potential as an alternative ADHD treatment.

Volume

892

First Page

173826

DOI

10.1016/j.ejphar.2020.173826

PubMed ID

33347825

Recommended Citation

Dela Peña, Ike; Shen, Guofang; and Shi, Wei-Xing, "Droxidopa alters dopamine neuron and prefrontal cortex activity and improves attention-deficit/hyperactivity disorder-like behaviors in rats" (2021). Loma Linda University Faculty Publications. 407.
https://scholarsrepository.llu.edu/fac_pubs/407