Trafficking of dopamine transporters in psychostimulant actions

Abstract

Brain dopamine (DA) plays a pivotal role in drug addiction. Since the plasma membrane DA transporter (DAT) is critical for terminating DA neurotransmission, it is important to understand how DATs are regulated and this regulation impacts drug addiction. The number of cell surface DATs is controlled by constitutive and regulated endocytic trafficking. Psychostimulants impact this trafficking. Amphetamines, DAT substrates, cause rapid up-regulation and slower down-regulation of DAT whereas cocaine, a DAT inhibitor, increases surface DATs. Recent reports have begun to elucidate the molecular mechanisms of these psychostimulant effects and link changes in DAT trafficking to psychostimulant-induced reward/reinforcement in animal models.

Anticipatory postural adjustments stabilise the whole upper-limb prior to a gentle index finger tap

“…Our findings are consistent with an upregulation of noradrenaline reuptake in the LC area, which is well compatible with enhanced noradrenaline release [19,20].…”

“…Despite the higher affinity of FP-CIT for DATs, it is unlikely that the higher binding observed in the LC area is due to an enhanced dopaminergic, rather than noradrenergic, transporter for two main reasons: (i) in LC, DAT represent a minor and inconsistent component of the midbrain-derived dopaminergic terminals which degenerates in PD, along with other dopaminergic projections, [4] and (ii) in the LC a major NET component is synthesized in the cell body of pigmented neurons and exposed on their membrane to be transferred toward axonal terminals, [20] with a less Data are reported as median and range (brackets). Age at SPECT, age at motor symptoms onset and disease duration are in years.…”

Postendocytic Sorting of Constitutively Internalized Dopamine Transporter in Cell Lines and Dopaminergic Neurons

“…The sustained DAT down-regulation in response to PKC activation is believed mainly to be a result of DAT endocytosis through a clathrin-dependent mechanism (6,7,9,10). In addition, DAT trafficking is regulated by other protein kinases, such as MAPK and Akt (14,15), as well as by substrates and inhibitors (16).…”

Cyclin-Dependent Kinase 5 Inhibitors: Inhibition of Dopamine Transporter Activity

“…This is accomplished by the active removal of extracellular DA through functional DAT molecules, which are located on the cell surface of DA neuronal axons, varicosities, and dendrites (Nirenberg et al, 1996). In addition to helping maintain DA homeostasis, the DAT is a molecular target of psychostimulants such as cocaine and amphetamine (AMPH) (Giros et al, 1996;Chen et al, 2006).Significant progress during the last decade has demonstrated that DATs are rapidly regulated via trafficking-dependent and -independent mechanisms (Blakely and Bauman, 2000;Zahniser and Sorkin, 2009). In addition to DAT regulation by psychostimulants, several protein kinases influence DAT activity.…”

“…Significant progress during the last decade has demonstrated that DATs are rapidly regulated via trafficking-dependent and -independent mechanisms (Blakely and Bauman, 2000;Zahniser and Sorkin, 2009). In addition to DAT regulation by psychostimulants, several protein kinases influence DAT activity.…”