Neurotrophic factors and structural plasticity in addiction

Abstract

Drugs of abuse produce widespread effects on the structure and function of neurons throughout the brain's reward circuitry, and these changes are believed to underlie the long-lasting behavioral phenotypes that characterize addiction. Although the intracellular mechanisms regulating the structural plasticity of neurons are not fully understood, accumulating evidence suggests an essential role for neurotrophic factor signaling in the neuronal remodeling which occurs after chronic drug administration. Brain-derived neurotrophic factor (BDNF), a growth factor enriched in brain and highly regulated by several drugs of abuse, regulates the phosphatidylinositol 3'-kinase (PI3K), mitogen-activated protein kinase (MAPK), phospholipase Cgamma (PLCgamma), and nuclear factor kappa B (NFkappaB) signaling pathways, which influence a range of cellular functions including neuronal survival, growth, differentiation, and structure. This review discusses recent advances in our understanding of how BDNF and its signaling pathways regulate structural and behavioral plasticity in the context of drug addiction.

Figure 1. Major cell types in the neural circuitry underlying addiction

Projections of VTA dopamine neurons (shown in solid red lines) impinge directly on NAc and mPFC neurons, as well as on 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 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 (red). Each of these cell types has been shown to be structurally altered by drugs of abuse (Table 1).

Figure 2. Intracellular signaling pathways downstream of neurotrophins

Neurotrophins (NT), which include BDNF, NGF, NT-3, and NT4/5, signal through Trk receptors (TrkB is the preferred receptor for BDNF) to activate 3 major pathways, IRS–PI3K–Akt, Ras–MEK–ERK, and PLCγ. The neurotrophins also signal through the p75 receptor (p75NTR) to activate several intracellular cascades, including TNF (tumor necrosis factor) receptor-associated factor 4/6 (TRAF4/6) or receptor interacting protein 2 (RIP2) and NFκB. Activation of these pathways affects a wide range of cellular functions, including differentiation, survival, apoptosis, growth, and cytoskeleton reorganization. There is considerable crosstalk among these pathways, not shown in the figure. For example, upon activation of the TrK receptor by these neurotrophins, transcription factors downstream of Ras–MEK–ERK, PLCγ, and IRS–PI3K-Akt activity can bind DNA and regulate a number of gene targets involved in cytoskeletal reoganization.

Figure 3. Adaptations in BDNF signaling cascades associated with opiate and stimulant-induced structural plasticity in the VTA-NAc circuit

A VTA dopamine neuron is shown innervating a NAc medium spiny neuron. Opiates and cocaine produce generally opposite effects on the morphology of these two neuronal cell types. Chronic opiate administration decreases the surface area of VTA dopamine neurons, which is associated with decreased levels of neurofilament proteins and decreased axoplasmic transport to the NAc, however, their effects on dendritic spines and synaptic connectivity in the VTA are not known. The decrease in VTA neuron cell size is mediated by decreased activity of the IRS–PI3K–Akt pathway; chronic morphine also increases activity of the PLCγ pathway and causes variable effects on ERK in this brain region. In the NAc, opiates decrease neuronal branching and synapse number, effects that correspond with decreases in IRS–PI3K–Akt and ERK activity, although the molecular basis of the structural changes remain unknown. In stark contrast to opiates, stimulants increase dendritic branching and spine number in VTA dopamine neurons and NAc medium spiny neurons. This structural plasticity is associated with activation of ERK in both regions and with activation of PLCγ and NKκB in the NAc, with variable effects reported for IRS–PI3K–Akt. However, the molecular adaptations responsible for this dendritic growth in both regions are poorly understood.