Abstract
Recreational drug use leads to compulsive substance abuse in some individuals. Studies on animal models of drug addiction indicate that persistent long-term potentiation (LTP) of excitatory synaptic transmission onto ventral tegmental area (VTA) dopamine (DA) neurons is a critical component of sustained drug seeking. However, little is known about the mechanism regulating such long-lasting changes in synaptic strength. Previously, we identified that translational control by eIF2α phosphorylation (p-eIF2α) regulates cocaine-induced LTP in the VTA (Huang et al., 2016). Here we report that in mice with reduced p-eIF2α-mediated translation, cocaine induces persistent LTP in VTA DA neurons. Moreover, selectively inhibiting eIF2α-mediated translational control with a small molecule ISRIB, or knocking down oligophrenin-1-an mRNA whose translation is controlled by p-eIF2α-in the VTA also prolongs cocaine-induced LTP. This persistent LTP is mediated by the insertion of GluR2-lacking AMPARs. Collectively, our findings suggest that eIF2α-mediated translational control regulates the progression from transient to persistent cocaine-induced LTP.
Highlights
Drug addiction is a complex behavioral disorder that starts with recreational use and, in some people, progresses to compulsive drug-seeking (Hyman, 2005)
Given that metabotropic glutamate receptors (mGluRs)-LTD blocks the persistence of cocaine-induced long-term potentiation (LTP) (Mameli et al, 2009), and our previous finding that p-eIF2 alpha subunit (eIF2a)–mediated translational control regulates both forms of long-lasting plasticity (Huang et al, 2016), we examined whether the same translational control program regulates the shift from a relatively transient cocaine-induced LTP to a more persistent one in ventral tegmental area (VTA) DA neurons
Two studies revealed that mGluR-LTD in VTA DA neurons blocks cocaine-evoked LTP in these same cells by replacing GluR2lacking calcium permeable amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) with GluR2-containing receptors (Bellone and Luscher, 2006; Mameli et al, 2007)
Summary
Drug addiction is a complex behavioral disorder that starts with recreational use and, in some people, progresses to compulsive drug-seeking (Hyman, 2005). The precise molecular and cellular mechanism underlying this transition remains unclear. In addicts, repeated drug use leads to longlasting changes in neuronal structure and function in key reward areas (Koob and Volkow, 2010), which have emerged as cellular correlates of drug addiction (Chen et al, 2008; Luscher and Malenka, 2011). Of particular interest are excitatory synaptic afferents to dopaminergic neurons in the ventral tegmental area (VTA). These activity-dependent changes in synaptic strength in the VTA
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