Optimizing cognitive enhancement through dopamine transporter modulation

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ABSTRACT

psychostimulants, such as R-modafinil, enhance cognitive performance without inducing significant euphoria or addiction, making them promising lead candidates for clinical application ()

R-modafinil analogs with extended residence time at DAT (i.e., slow koff) would enhance cognitive function more effectively ()

evaluated a series of R-modafinil analogs using in vitro equilibrium and non-equilibrium measurements, in vivo fast-scan cyclic voltammetry, and highly translational cognitive assays in both healthy and scopolamine-treated rats modelling cognitive impairment ()

Scopolamine blocks acetylcholine from binding to muscarinic receptor.

It is a competitive antagonist.

This results in impaired memory and attention.

prolonging DAT occupancy improves dopamine signalling and leads to more robust enhancements in cognitive flexibility ()

S-MK-26 and (S,S)-CE158—produced the strongest cognitive effects ()

1. Introduction

(DAT) is a key protein in spatially and temporally shaping the dopaminergic signal ()

DAT reuptakes the dopamine (DA) released by exocytosis from the extracellular space and moves it back into the presynaptic terminals ()

Exocytosis: process of releasing molecules outside.

Dopamine molecules are stored inside tiny membrane-bound sacs called vesicles.

single-point mutations altering DAT function are associated with a variety of psychiatric disorders ()

inhibitors if they bind to the transporter and prevent neurotransmitter uptake (2)

Cocaine, Modafinil, Benztropine.

releasers if they act as substrates and reverse the normal direction of transporter flux (2)

Methamphetamine.

inhibitors or releasers, many compounds interacting with DAT stimulate different brain functions and are normally classified as psychostimulants (2)

Drugs that act more potently with DAT compared to the serotonin transporter (SERT) are typically associated with higher psychostimulant and abuse potential (2)

DAT inhibitors, such as cocaine, despite showing an unselective DAT/SERT profile, still show pronounced psychostimulant effects and high abuse liability (2)

benztropine possesses high DAT selectivity but lacks pronounced reinforcing properties (2)

benztropines stabilize the inward-facing conformation of DAT, which differs from the typical binding mode of classical DAT inhibitors such as cocaine (2)

modafinil or (S)-amphetamine, promote wakefulness without producing marked euphoria (2)

weak interaction with DAT and the existence of related analogs with even lower DAT affinity and more powerful eugeroics properties made questioning the importance of DAT in the cognitive enhancing properties elicited by eugeroics (2)

Eugeroics: Wakefulness promoting drugs.

new modafinil analog (S,S)-CE-158 was shown to lack off-target effects (2)

promnestic effects (2)

Memory enhancing.

DAT as the central and clinically relevant target responsible for the cognitive effects (2)

faster is the DA increase induced by a given psychostimulant, the stronger is the high perceived, and therefore the risk of misuse (2)

lower is the koff of psychostimulants at DAT (i.e. the longer the psychostimulant stay bound to DAT) the longer is the behavioral effect (2)

electrophysiological protocol (Niello et al., 2023) for quantifying the koff of different modafinil analogs designed for cognitive enhancement (2)

more effective cognitive enhancers display a higher affinity for DAT and that the increased affinity is associated with a slower koff (2)

high affinity DAT inhibitors impact DA dynamics in anhestetized rats (2)

2. Experimental procedures

2.1. Animals

European Community Council Directive (2010/63/EU) and approved by the 1st Local Ethics Committee for Animal Experimentation in Warsaw (ethics permits no. 1085/2020, 1237/2021 and 1526/2023) (2)

2.2. Cell culture

human embryonic kidney 293 cells (HEK293 cells) (2)

Dulbecco's Modified Eagle Medium (DMEM) (2)

fetal calf serum (FCS) (2)

HEK293 cells with DAT/SERT/NET plasmid with polyethylenimine (Santa Cruz) at a ratio of 1:3 (w/w) in serum-free DMEM (2)

Geneticin (2)

cells were seeded the day before the experiment onto poly-D-lysine (PDL) coated 96-well plates (2)

2.3. Drugs

Kolliphor EL (2)

2.4. Radiotracer assay

Krebs-HEPES buffer (3)