A Novel and Selective Dopamine Transporter Inhibitor, (S)-MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions

Abstract

Dopamine (DA), the most abundant human brain catecholaminergic neurotransmitter, modulates key behavioral and neurological processes in young and senescent brains, including motricity, sleep, attention, emotion, learning and memory, and social and reward-seeking behaviors. The DA transporter (DAT) regulates transsynaptic DA levels, influencing all these processes. Compounds targeting DAT (e.g., cocaine and amphetamines) were historically used to shape mood and cognition, but these substances typically lead to severe negative side effects (tolerance, abuse, addiction, and dependence). DA/DAT signaling dysfunctions are associated with neuropsychiatric and progressive brain disorders, including Parkinson’s and Alzheimer diseases, drug addiction and dementia, resulting in devastating personal and familial concerns and high socioeconomic costs worldwide. The development of low-side-effect, new/selective medicaments with reduced abuse-liability and which ameliorate DA/DAT-related dysfunctions is therefore crucial in the fields of medicine and healthcare. Using the rat as experimental animal model, the present work describes the synthesis and pharmacological profile of (S)-MK-26, a new modafinil analogue with markedly improved potency and selectivity for DAT over parent drug. Ex vivo electrophysiology revealed significantly augmented hippocampal long-term synaptic potentiation upon acute, intraperitoneally delivered (S)-MK-26 treatment, whereas in vivo experiments in the hole-board test showed only lesser effects on reference memory performance in aged rats. However, in effort-related FR5/chow and PROG/chow feeding choice experiments, (S)-MK-26 treatment reversed the depression-like behavior induced by the dopamine-depleting drug tetrabenazine (TBZ) and increased the selection of high-effort alternatives. Moreover, in in vivo microdialysis experiments, (S)-MK-26 significantly increased extracellular DA levels in the prefrontal cortex and in nucleus accumbens core and shell. These studies highlight (S)-MK-26 as a potent enhancer of transsynaptic DA and promoter of synaptic plasticity, with predominant beneficial effects on effort-related behaviors, thus proposing therapeutic potentials for (S)-MK-26 in the treatment of low-effort exertion and motivational dysfunctions characteristic of depression and aging-related disorders.

Cognitive performance in aged rats is associated with differences in distinctive neuronal populations in the ventral tegmental area and altered synaptic plasticity in the hippocampus

“…Reduced dopamine function is consistent with exacerbation of neuropsychiatric symptoms during lifespan, ranging from depressive states to substance use disorders ( Skoog, 2011 ; Alexopoulos, 2019 ; Tampi et al, 2022 ). Further, these data are consistent with beneficial electrophysiological and behavioral effects of dopamine enhancement through selective reuptake inhibition in aged rats, including compromised aged rats ( Sagheddu et al, 2020 ; Lubec et al, 2021 ; Kouhnavardi et al, 2022 ). To the best of our knowledge, this is the first extensive in vivo investigation of non-dopaminergic neurons in the VTA of aged rats.…”

“…Indeed, understanding age-related mechanisms in the VTA and limbic projections could provide novel preventive and/or therapeutic approaches ( Cordella et al, 2018 ; La Barbera et al, 2021 ; Spoleti et al, 2022 ), a major goal to counteract age-related cognitive decline as well as dementia and AD ( Scheltens et al, 2021 ). Accordingly, our previous findings indicate that modulation of the dopamine system by the selective dopamine transporter (DAT) inhibition could prove beneficial to restoring several brain alterations associated with aging and age-related cognitive decline ( Sagheddu et al, 2020 ; Lubec et al, 2021 ; Kouhnavardi et al, 2022 ; Lubec et al, 2023 ; Sagheddu et al, 2023 ).…”

Electroacupuncture alleviated depression‐like behaviors in ventromedial prefrontal cortex of chronic unpredictable mild stress‐induced rats: Increasing synaptic transmission and phosphorylating dopamine transporter

“…Taken together, our results suggest that CUMS induces the pathogenesis of depression by suppressing the excitatory synaptic transmission in vmPFC, and EA ameliorates the depression‐like phenotypes most likely by reversing the declined excitatory synaptic transmission in vmPFC. DA‐induced synaptic plasticity was associated with DAT 45 and proven to act in depression with mPFC involved 46 . Therefore, we probed into the DAT‐related changes for further studying the relationship between the DA system and depressive‐like behaviors.…”

Chirality Matters: Fine-Tuning of Novel Monoamine Reuptake Inhibitors Selectivity through Manipulation of Stereochemistry

“…Activity-dependent synaptic plasticity, particularly long-term potentiation (LTP), is considered a possible cellular correlate of learning and memory. Aged rats have previously been used as plausible models to test the learning- and memory-enhancing effects of DAT inhibitors [ 26 , 37 ]. Therefore, we used aged (22–23 months) rats to examine the effect of 8h on basal synaptic transmission and synaptic plasticity at Schaffer collateral (SC)-CA1 synapses ( Figure 2 c 1 ).…”