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 Cγ (PLCγ), and nuclear factor kappa B (NFκB) 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.

Introduction

An essential feature of drug addiction is that an individual continues to use drug despite the threat of severely adverse physical or psychosocial consequences. Although it is not known with certainty what drives these behavioral patterns, it has been hypothesized that long-term changes that occur within the brain's reward circuitry are important (Fig. 1). In particular, adaptations in dopaminergic neurons of the ventral tegmental area (VTA) and in their target neurons in the nucleus accumbens (NAc) are thought to alter an individual's responses to drug and natural rewards, leading to drug tolerance, reward dysfunction, escalation of drug intake, and eventually compulsive use (Everitt et al., 2001, Kalivas and O'Brien, 2008, Koob and Le Moal, 2005, Nestler, 2001, Robinson and Kolb, 2004).

There has been a major effort in recent years to determine the cellular and molecular changes that occur during the transition from initial drug use to compulsive intake. Among many types of drug-induced adaptations, it has been proposed that changes in brain-derived neurotrophic factor (BDNF), or related neurotrophins, and their signaling pathways alter the function of neurons within the VTA–NAc circuit and other reward regions to modulate the motivation to take drugs (Bolanos and Nestler, 2004, Pierce and Bari, 2001). A corollary of this hypothesis is that such growth factor-induced cellular and molecular adaptations are reflected in morphological changes of reward-related neurons. For example, chronic stimulant administration increases branching of dendrites and the number of dendritic spines and dynamically increases levels of BDNF in several brain reward regions, whereas chronic opiate administration decreases dendritic branching and spines as well as BDNF levels in some of the same regions (for review see (Robinson and Kolb, 2004, Thomas et al., 2008). Moreover, chronic opiates decrease the size of VTA dopamine neurons, an effect reversed by BDNF (Russo et al., 2007, Sklair-Tavron et al., 1996). However, direct, causal evidence that these structural changes drive addiction remains lacking.

The proposal that BDNF may be related to structural plasticity of the VTA–NAc circuit in addiction models is consistent with a large literature which has implicated this growth factor in regulation of dendritic spines. For instance, studies using conditional deletions of BDNF or its TrkB receptor show that they are required for proliferation and maturation of dendritic spines in developing neurons as well as the maintenance and proliferation of spines on neurons throughout the adult brain (Chakravarthy et al., 2006, Danzer et al., 2008, Horch et al., 1999, Tanaka et al., 2008a, von Bohlen Und Halbach et al., 2008).

Although the exact molecular mechanisms by which BDNF mediates structural plasticity of the brain's reward circuitry remain unknown, recent studies suggest that specific pathways downstream of BDNF are modulated by drugs of abuse, and that these neurotrophic factor-dependent signaling changes correlate with morphological and behavioral endpoints in animal models of drug addiction. In this review, we discuss new advances in our understanding of how opiates and stimulants regulate neurotrophic factor signaling and the cellular and behavioral consequences of these effects. We also propose areas for future investigation to address the paradoxically opposite effects of stimulants and opiates on neuronal morphology and certain behavioral phenotypes consistent with addiction.