Candidate Review:

Amphetamine-fueled insights into dopaminergic diseases: the protein kinase Akt drives responses to psychostimulants

Michael Siuta

Neuroscience Graduate Program, Vanderbilt University School of Medicine, U1205 Medical Center North, Nashville, TN 37232, USA.
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Abstract | Full Text | PDF

Abstract | Amphetamine (AMPH) is a psychostimulant that exerts its behavioral effects, in part, through release of pre-synaptic dopamine (DA) via reversal of the dopamine transporter (DAT) at mesostriatal synapses. Due to the characteristic and robust release of DA in response to AMPH, this drug is often used to study animal models of diseases where DA dysfunction at mesostriatal synapses is implicated, namely schizophrenia, Parkinson’s disease, and drug addiction. Interestingly, the function of the protein kinase Akt (also known as protein kinase B) has recently been associated, in both human and animal studies, with both the pathogenesis and treatment of these DA-related diseases. Akt is stimulated by phosphotidylinositol 3-kinase (PI3K) signaling, which itself is activated by growth factors (such as brain derived neurotrophic factor) and hormones (such as insulin) through receptor tyrosine kinases (RTKs). Many of these growth factors and hormones also influence the actions of psychostimulants through cellular and molecular mechanisms that include promotion of DAT trafficking, increased axonal innervation of the striatum, and enhanced synthesis of pre-synaptic dopamine. Recent evidence suggests that many of these mechanisms may be profoundly regulated by Akt. Collectively, studies of the activation and inhibition of PI3K/Akt signaling, through pharmacologic, genetic, or viral manipulations, suggest a prominent role for Akt signaling in neuronal growth, neuronal migration, and regulation of DA neurotransmission. These findings hold promise for development of future strategies aimed at more directly influencing Akt signaling in the brain in order to treat dopaminergic diseases.