Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations

Abstract

Background and purpose:There is increasing evidence that not only the monoaminergic but also the glutamatergic system is involved in the pathophysiology of attention-deficit hyperactivity disorder (ADHD). Hyperactivity of glutamate metabolism might be causally related to a hypoactive state in the dopaminergic system. Atomoxetine, a selective noradrenaline reuptake inhibitor, is the first non-stimulant approved for the treatment of this disorder. Here we have evaluated the effects of atomoxetine on glutamate receptors in vitro. Experimental approach: The whole-cell configuration of the patch-clamp technique was used to analyse the effect of atomoxetine on N-methyl-D-aspartate (NMDA) receptors in cultured rodent cortical and hippocampal neurons as well as on NMDA receptors heterologously expressed in human TsA cells. Key results: Atomoxetine blocked NMDA-induced membrane currents. Half-maximal inhibition emerged at about 3 mM which is in the range of clinically relevant concentrations found in plasma of patients treated with this drug. The inhibition was voltage-dependent, indicating an open-channel blocking mechanism. Furthermore, the inhibitory potency of atomoxetine did not vary when measured on NMDA receptors from different brain regions or with different subunit compositions. Conclusions and implications:The effective NMDA receptor antagonism by atomoxetine at low micromolar concentrations may be relevant to its clinical effects in the treatment of ADHD. Our data provide further evidence that altered glutamatergic transmission might play a role in ADHD pathophysiology.

Attention-Deficit Hyperactivity Disorder and Pharmacotherapy—Past, Present, and Future: A Review of the Changing Landscape of Drug Therapy

“…It also an NMDA receptor antagonist, thereby altering glutamatergic transmission 40 . Unlike stimulants, atomoxetine is not strongly associated with striatal effects, and is less likely to be abused (full effect also takes 4–6 weeks).…”

Developmental and Functional Nature of Human iPSC Derived Motoneurons

“…Electrophysiological experiments were performed as previously described [105,118]. Briefly, hiPSC derived motoneurons were used for experimentation after differentiation for 3-6 weeks.…”

Differential roles for cortical versus sub-cortical noradrenaline and modulation of impulsivity in the rat

“…Although selective for the NAT, neurochemical studies suggest that atomoxetine also has effects on cortical dopamine as a result of the relatively low expression of DAT in the prefrontal cortex (PFC) and the role of NAT in terminating the effects of dopamine in this region (Bymaster et al 2002). As well as effects on the catecholamine transmitters, atomoxetine also has a reasonable affinity for the NMDA receptor and may interact with this receptor at therapeutic doses (Di Miceli and Gronier 2015; Ludolph et al 2010). Atomoxetine has also been shown to increase levels of acetylcholine at doses as low as 0.3 mg/kg (Tzavara et al 2006).…”