Neurophysiological and Neurochemical Effects of the Putative Cognitive Enhancer (S)-CE-123 on Mesocorticolimbic Dopamine System

Abstract

Treatments for cognitive impairments associated with neuropsychiatric disorders, such as attention deficit hyperactivity disorder or narcolepsy, aim at modulating extracellular dopamine levels in the brain. CE-123 (5-((benzhydrylsulfinyl)methyl) thiazole) is a novel modafinil analog with improved specificity and efficacy for dopamine transporter inhibition that improves cognitive and motivational processes in experimental animals. We studied the neuropharmacological and behavioral effects of the S-enantiomer of CE-123 ((S)-CE-123) and R-modafinil in cognitive- and reward-related brain areas of adult male rats. In vivo single unit recordings in anesthetized animals showed that (S)-CE-123, but not R-modafinil, dose-dependently (1.25 to 10 mg/kg i.v.) reduced firing of pyramidal neurons in the infralimbic/prelimbic (IL/PrL) cortex. Neither compound the affected firing activity of ventral tegmental area dopamine cells. In freely moving animals, (S)-CE-123 (10 mg/kg i.p.) increased extracellular dopamine levels in the IL/PrL, with different patterns when compared to R-modafinil (10 mg/kg i.p.); in the nucleus accumbens shell, a low and transitory increase of dopamine was observed only after (S)-CE-123. Neither (S)-CE-123 nor R-modafinil initiated the emission of 50-kHz ultrasonic vocalizations, a behavioral marker of positive affect and drug-mediated reward. Our data support previous reports of the procognitive effects of (S)-CE-123, and show a minor impact on reward-related dopaminergic areas.

Early Adolescence Prefrontal Cortex Alterations in Female Rats Lacking Dopamine Transporter

“…The functional state of DAT has been proven to affect neuronal plasticity and control of cognitive function in the PFC [ 56 , 57 ], where pharmacological inhibition has shown to induce pro-cognitive effects [ 58 ]. DA function in the PFC controls several processes including working memory, attention, flexibility in behavior and action planning [ 59 ].…”

“…The ensemble of behavioral phenotypes observed in DAT−/− rats [ 10 , 11 , 12 , 29 , 30 ] depends primarily on the different roles that DA neurotransmission plays in the mesocortical system and in the PFC [ 58 , 65 ], and it is ascribable to alterations in the cross-talk with glutamatergic neurotransmission [ 23 , 24 , 25 ]. Disruption of these pathways has been widely linked to psychiatric disorders [ 26 ] including autism, schizophrenia [ 27 ] and ADHD [ 28 ].…”

Repeated exposure to JWH‐018 induces adaptive changes in the mesolimbic and mesocortical dopaminergic pathways, glial cells alterations, and behavioural correlates

“…Animals were assigned randomly to different experimental groups for behavioural, electrophysiological, neurochemical, and molecular evaluation at different time points (1 h, 24 h, or 7 days) after drug discontinuation (Figure 1 ). The experimental group sizes ( n ≥ 5) were chosen based on our previous experimental protocols (Castelli et al, 2014 ; Sagheddu et al, 2020 ; Zanda et al, 2017 ) and are shown in the figure legends. Due to technical issues (e.g., catheter or dialysis probe obstruction), some animals were excluded from statistical analysis, thus reducing the group size in few cases.…”

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

“…( S )-MK-26, synthetized following previously described protocols [ 41 ], has structural similarities to the very well-characterized nootropic modafinil [ 42 ], with the carboxamide replaced with thiazole (five-membered heterocycle attached through position 5) and with a chlorine atom added in the meta position on both phenyl rings, thus also being a close structural analogue of the previously described compounds ( S , S )-CE-158 and ( S )-CE-123 [ 39 , 41 , 42 , 43 ] ( Figure 1 ).…”