The effect of modafinil on the rat dopamine transporter and dopamine receptors D1–D3 paralleling cognitive enhancement in the radial arm maze

Abstract

A series of drugs have been reported to increase memory performance modulating the dopaminergic system and herein modafinil was tested for its working memory (WM) enhancing properties. Reuptake inhibition of dopamine, serotonin (SERT) and norepinephrine (NET) by modafinil was tested. Sixty male Sprague–Dawley rats were divided into six groups (modafinil-treated 1–5–10 mg/kg body weight, trained and untrained and vehicle treated trained and untrained rats; daily injected intraperitoneally for a period of 10 days) and tested in a radial arm maze (RAM), a paradigm for testing spatial WM. Hippocampi were taken 6 h following the last day of training and complexes containing the unphosphorylated or phosphorylated dopamine transporter (DAT-CC and pDAT-CC) and complexes containing the D1–3 dopamine receptor subunits (D1–D3-CC) were determined. Modafinil was binding to the DAT but insignificantly to SERT or NET and dopamine reuptake was blocked specifically (IC50 = 11.11 μM; SERT 1547 μM; NET 182 μM). From day 8 (day 9 for 1 mg/kg body weight) modafinil was decreasing WM errors (WMEs) in the RAM significantly and remarkably at all doses tested as compared to the vehicle controls. WMEs were linked to the D2R-CC and the pDAT-CC. pDAT and D1–D3-CC levels were modulated significantly and modafinil was shown to enhance spatial WM in the rat in a well-documented paradigm at all the three doses and dopamine reuptake inhibition with subsequent modulation of D1–3-CC is proposed as a possible mechanism of action.

Pharmacological profile of methylphenidate-based designer drugs

“…Modafinil was a moderate and relatively selective DAT inhibitor, with an IC 50 value of 11 µM. This finding is consistent with previous in vitro studies that reported IC 50 values of 4-13 µM (Karabacak et al, 2015;Loland et al, 2012;Madras et al, 2006;Zolkowska et al, 2009). The interaction between modafinil and DAT is also thought to modulate the pharmacological effects of the drug (Wisor, 2013).…”

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

“…Multiple neurotransmitter systems have been implicated in modafinil activity [10,58], as several studies have reported significant occupancy of NET, beside activity at DAT [59]. Hence, in cells expressing human DAT, R-modafinil inhibits DAT (IC 50 6.4-13 µM) and NET activity (IC 50 35.6-182 µM), albeit with lower potency in the case of the latter [34,60,61]. On the other hand, (S)-CE-123 shows negligible activity at NET or SERT, and blocks DAT (IC 50 = 4.6 µM) without acting as a substrate [24].…”

<p>Knowledge and Attitudes of Ethiopian Nursing Staff Regarding Post-Operative Pain Management: A Cross-Sectional Multicenter Study</p>

“…Since pain relief has been recognized as a human right17 and considered as the “fifth” vital sign to be routinely assessed, nurses should give great attention to control postoperative pain 18. Nurses working in the surgical unit should have an adequate level of knowledge regarding different treatment modalities and their technique of administration 19. They should also consider patients’ self-report of pain which is the best to evaluate pain perceptions and cognitive response 20.…”