Akt Is Essential for Insulin Modulation of Amphetamine-Induced Human Dopamine Transporter Cell-Surface Redistribution

Abstract

Uptake by the dopamine transporter (DAT) is the primary pathway for the clearance of extracellular dopamine (DA) and consequently for regulating the magnitude and duration of dopaminergic signaling. Amphetamine (AMPH) has been shown to decrease simultaneously DAT cell-surface expression and Dopaminergic neurotransmission is determined by extracellular DA levels, which in turn are regulated principally by DAT-mediated DA reuptake. Because DA uptake capacity depends on the turnover rate of an individual transporter and on the number of functional transporters expressed at the plasma membrane, regulation of DAT cell-surface expression is an important mechanism for fine-tuning DA neurotransmission (Beckman and Quick, 1998;Robinson, 2001;Kahlig and Galli, 2003).Several studies have identified signal transduction pathways that modulate DAT trafficking and activity. Activation of protein kinase C (PKC), either by phorbol esters (phorbol 12-myristate 13-acetate) or by G␣ q -coupled substance P receptor, decreases both DAT cell-surface expression and transport capacity (Zhang et al

Alterations in blood glucose levels under hyperinsulinemia affect accumbens dopamine

“…The possible direct effects [11][12][13] of insulin on the mesoaccumbens DA neurons are dependent on this principle. In particular, it has been reported that insulin increases DA uptake in striatal tissue from >24 h fasted rats [12] and following amphetamine incubation in rat striatal synaptosomes and HEK transfected with hDAT preincubated with insulin [11].…”

“…Central administration of insulin also has been shown to increase DA transporter (DAT) mRNA in the VTA/SNpc [10]. This increase in transporter likely influences DA signaling, since exogenously administered insulin has been shown in vitro to increase DA uptake in striatal tissue [11,12] and human DATtransfected cells [11,13]. On this basis, the present experiments focused on the role of acute elevation in plasma insulin on mesoaccumbens DA function.…”

Modulation of food reward by adiposity signals

“…We have demonstrated that ICV insulin increases DAT mRNA (42), and that in vitro insulin reverses the effect of acute, in vivo, food restriction to decrease DA re-uptake (i.e., insulin stimulates DAT function) (10). Subsequent studies in cellular systems have demonstrated that this action of insulin is caused by enhanced recruitment of DATs to the cell membrane and is dependent on insulin-stimulation of the PI3 kinase pathway (43). This collective set of evidence strongly suggests that the DAT is likely a physiological target of insulin action.…”

Behavioral effects of amphetamine in streptozotocin-treated rats

“…Dopamine uptake was decreased in synaptosomes from rats made hypoinsulinemic by food deprivation and was restored by administration of insulin . These effects appear to be the result of insulin acting on receptors (insulin, IGF-1) since inhibition of insulin signaling caused dopamine transporters to be translocated away from the plasma membrane, thereby reducing dopamine transport (Carvelli et al, 2002;Garcia et al, 2005). In addition to effects on dopamine uptake, insulin can also modulate other components of the dopamine system; for example, hypoinsulinemic rats show decreased synthesis (Saller, 1984) and turnover (Kwok and Juorio, 1986;Lim et al, 1994) of dopamine and they are hyporesponsive to the behavioral effects of direct-acting dopamine drugs (Sevak et al, 2007a).…”