Dopamine signalling inhibits Akt, leading to activation of GSK3b

It appears that dopaminergic signalling inactivates Akt protein, which in turn removes inhibition of GSK3b. That leads to reduced activation of Nrf2 and consequent increase of oxidative stress in the neuron.

Here, we used a pharmacogenetic approach to show that DA can exert its behavioral effects by acting on a lithium-sensitive signaling cascade involving Akt/PKB and glycogen synthase kinase 3 (GSK-3). In the mouse striatum, increased DA neurotransmission arising either from administration of amphetamine or from the lack of the DA transporter results in inactivation of Akt and concomitant activation of GSK-3α and GSK-3β.

These biochemical changes are not affected by activation of the cAMP pathway but are effectively reversed either by inhibition of DA synthesis, D2 receptor blockade, or administration of lithium salts. Furthermore, pharmacological or genetic inhibition of GSK-3 significantly reduces DA-dependent locomotor behaviors.

These data support the involvement of GSK-3 as an important mediator of DA and lithium action in vivo and suggest that modulation of the Akt/GSK-3 pathway might be relevant to DA-related disorders, such as attention deficit hyperactivity disorder and schizophrenia.

My comment

With that paper in mind, I suggest, that it’s the weak Akt signalling and/or stronger GSK3b activation that is related to the end result: tics and abnormal behavior, OCD.

Something about Akt / GSK3b. Maybe the root cause is directly related to them, or it’s about something that has influence of that pair of proteins (e.g. could be phospholipid composition of the membrane).