Molecular mechanisms of psychostimulant-induced structural plasticity

Abstract

Drug addiction is characterized by persistent behavioral and cellular plasticity throughout the brain's reward regions. Among the many neuroadaptations that occur following repeated drug administration are alterations in cell morphology including changes in dendritic spines. While this phenomenon has been well documented, the underlying molecular mechanisms are poorly understood. Here, within the context of drug abuse, we review and integrate several of the established pathways known to regulate synaptic remodeling, and discuss the contributions of neurotrophic and dopamine signaling in mediating this structural plasticity. Finally, we discuss how such upstream mechanisms could regulate actin dynamics, the common endpoint involved in structural remodeling in neurons.

Fig. 1

Neuronal subtypes in the neural circuitry underlying addiction. Projections of VTA dopamine neurons (shown in solid red lines) innervate directly NAc and mPFC neurons, as well as amygdala and hippocampal neurons (the latter projections are not shown in the figure). The solid purple line represents GABAergic afferents (some direct, some indirect) from the NAc to the VTA, which provide feedback to VTA dopamine neurons. The dotted purple lines represent glutamatergic afferents to the NAc from mPFC, amygdala, and hippocampus. Each structure contains specialized neuronal cell types thought to play an integral role in the complex behavioral phenotypes associated with drug reward and addiction. These cell types, color-coded in the key, include amygdala (green) and NAc (purple) spiny neurons, PFC (black) and hippocampal CA3 (blue) pyramidal neurons, and VTA dopamine neurons ^{adapted from} [84].

Fig. 2

Molecular pathways implicated in the structural changes that occur as a result of exposure to drugs of abuse. Transcription factors, such as NFκB, ΔFosB, CREB, and MEF2 play a role in regulating changes in dendritic spines, and can be activated by a variety of signaling pathways. Neurotrophins can signal via receptor tyrosine kinases to activate the PI3K-Akt and Ras-ERK pathways, which ultimately regulate transcriptional activity, and possibly control actin cytoskeletal dynamics through regulation of the Rho family of small GTPases. Dopaminergic stimulation of D1 and D2 receptors can in turn act on some of these same pathways by activation of PKA and PKC. Structural plasticity induced by psychostimulants can therefore result from manipulation of several signaling pathways that impinge on actin assembly processes as well as gene expression.

Fig. 3

Actin arrangement in the cytoskeleton. Top panel: Many proteins help regulate the polymerization and arrangement of actin filaments within the cytoskeletal network. Actin sequestering proteins provide a ready pool of actin monomers (globular actin, or g-actin) for the polymerization into filamentous actin (f-actin), while severing proteins cut the filaments and aid in depolmerization. A variety of capping, branching and bundling proteins provide the organization of these filaments in the cytoskeletal network. Bottom panel: Within each filament, there is a steady state of continuous polymerization and depolymerization such that ATP bound g-actin is favored for addition to the filament at one end, and dissociation of the hydrolyzed ADP bound g-actin at the other. This directionality of addition and subtraction of g-actin monomers to a filament results in a treadmilling effect, where an individual monomer be added at one end, and travel towards the opposite end before dissociating from the filament.