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.
Highlights
The mesocorticolimbic dopamine system is involved in processing motivation, salience, and reward, with dopamine being a neuromodulator in brain areas that are involved in diverse cognitive processes
Among the inhibitors of dopamine reuptake, cocaine produces an accumulation of dopamine in the synaptic cleft, whereas amphetamines operate as substrates for dopamine transporter (DAT) to enter the presynaptic bouton, switching the activity of DAT, resulting in the efflux of dopamine
We examined the in vivo electrophysiological effects of (S)-CE-123 and R-modafinil on putative pyraWmeidexalamneiunreodntshreeicnorvdivedo efrloecmtrothpehIyLs/iPorloLgciocartleexffoefctasnoefst(hSe)-tCizEe-d12ra3tasn(FdigRu-mreo1dCa)fi. nCiul monuplautitvateivi.ev. paydrmaminidisatrlanteiounro(n1.s2r5e–c1o0rdmegd/kfrgo)mofth(Se)-ICL/EP-r1L23coprrtoedxuocfeadnaesdthoeseti-zdeedpreantdse(nFtigduercere1aCs)e
Summary
The mesocorticolimbic dopamine system is involved in processing motivation, salience, and reward, with dopamine being a neuromodulator in brain areas that are involved in diverse cognitive processes. The dopamine transporter (DAT) is located in the presynaptic plasma membrane, where it spatially and temporally produces an accumulation of dopamine [1]. Given its multifaceted role, increasing dopamine levels by inhibition of DAT provides the opportunity to target diverse neuropsychiatric conditions. Among the inhibitors of dopamine reuptake, cocaine produces an accumulation of dopamine in the synaptic cleft, whereas amphetamines operate as substrates for DAT to enter the presynaptic bouton, switching the activity of DAT, resulting in the efflux of dopamine. Modafinil is being clinically tested in ADHD, depression, schizophrenia, and mood disorders [4,5,6,7,8,9]. Modafinil is considered as a potential therapy against substance abuse disorders at different stages [2,10], in particular against psychostimulant abuse and withdrawal [11,12,13,14,15], as well as against alcohol dependence [16]
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