The rate of dasotraline brain entry is slow following intravenous administration

Robert Lew,Daniel Holden,Richard E Carson,Seth C Hopkins,Gerald Galluppi,Kenneth S Koblan,Vincent Carroll,Cristian C Constantinescu

doi:10.1007/s00213-020-05623-8

Abstract

RationaleDrugs that rapidly increase dopamine levels have an increased risk of abuse. Dasotraline (DAS) is a dopamine and norepinephrine reuptake inhibitor characterized by slow oral absorption with low potential for abuse. However, it remains unclear whether intravenous (i.v.) administration would facilitate the rapid elevation of dopamine levels associated with stimulant drugs.ObjectiveTo assess the kinetics of DAS across the blood-brain barrier and time to onset of dopamine transporters (DAT) inhibition.MethodsWe compared the onset of DAT occupancy and the associated elevation of synaptic dopamine levels in rhesus monkey following i.v. administration of DAS or methylphenidate (MPH) using positron emission tomography (PET). Brain entry times were estimated by reductions in [18F]-FE-PE2I binding to DAT in rhesus monkeys. Elevations of synaptic dopamine were estimated by reductions in [11C]-Raclopride binding to D2 receptors.ResultsIntravenous administration of DAS (0.1 and 0.2 mg/kg) resulted in striatal DAT occupancies of 54% and 68%, respectively; i.v. administered MPH (0.1 and 0.5 mg/kg) achieved occupancies of 69% and 88% respectively. Brain entry times of DAS (22 and 15 min, respectively) were longer than for MPH (3 and 2 min). Elevations in synaptic dopamine were similar for both DAS and MPH however the time for half-maximal displacement by MPH (t = 23 min) was 4-fold more rapid than for DAS (t = 88 min).ConclusionsThese results demonstrate that the pharmacodynamics effects of DAS on DAT occupancy and synaptic dopamine levels are more gradual in onset than those of MPH even with i.v. administration that is favored by recreational drug abusers.

Highlights

The risk of recreational abuse of psychostimulant drugs is associated with drug administration that yields rapid and large increases in synaptic dopamine concentrations in key brain areas, the ventral striatum
The present study assesses the kinetics of DAS and MPH respectively across the blood-brain barrier by measuring the time it takes from drug administration until 50% of maximal tracer displacement is reached
This measurement is the result of both blood-brain barrier (BBB) penetration and rate of binding of DAS to dopamine transporters (DAT)

Summary

Introduction

The risk of recreational abuse of psychostimulant drugs is associated with drug administration that yields rapid and large increases in synaptic dopamine concentrations in key brain areas, the ventral striatum. P.O. Box 208048, New Haven, CT 06520, USA delivery of drugs to the brain to induce multiple “highs.” Drug liking and abuse potential are higher when drugs such as cocaine or heroin are administered intravenously compared with other rapid modes of delivery such as insufflation (Resnick et al 1977; Comer et al 1999). Drugs that increase synaptic dopamine levels with fast onset kinetics are associated with drug liking and have a greater likelihood of stimulant effects and abuse. Drugs with a slow onset of effect typically have reduced abuse potential (Busto and Sellers 1986; Farré and Camí 1991; Volkow et al 1995; Volkow and Swanson 2003)

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