The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens

Abstract

Addictive drugs cause persistent restructuring of several neuronal cell types in the limbic regions of brain thought to be responsible for long-term behavioral plasticity driving addiction. Although these structural changes are well documented in nucleus accumbens medium spiny neurons, little is known regarding the underlying molecular mechanisms. Additionally, it remains unclear whether structural plasticity and its synaptic concomitants drive addictive behaviors or whether they reflect homeostatic compensations to the drug not related to addiction per se. Here, we discuss recent paradoxical data, which either support or oppose the hypothesis that drug-induced changes in dendritic spines drive addictive behavior. We define areas where future investigation can provide a more detailed picture of drug-induced synaptic reorganization, including ultrastructural, electrophysiological and behavioral studies.

Figure 1. Model of addiction-related synaptic and structural plasticity

Chronic exposure to cocaine results in a time–dependent and transient reorganization of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors at nucleus accumbens (NAc) medium spiny neuron (MSN) synapses, as well as structural changes in the spine head of NAc MSNs that correlate with distinct forms of synaptic plasticity. For example, chronic cocaine induces surface expression of NMDA receptors, silent synapse formation, and long-term depression (LTD) at early withdrawal time points. During more prolonged withdrawal, these synaptic changes reverse with the result being increased expression of surface AMPA receptors, a consolidation of the synapse into a mushroom-shaped spine, and long-term potentiation (LTP). These effects rapidly revert back again upon exposure to a challenge dose of cocaine leading to restructuring of the spine into thin spines and a depression of synaptic strength.

Figure 2. Signaling pathways involved in addiction-related cytoskeleton reorganization

Transcription factors, such as nuclear factor kappaB (NFκB), ΔFosB, cyclic AMP response element binding protein (CREB), and myocyte enhancing factor-2 (MEF2), play a role in regulating dendritic spines, and can be activated by a variety of signaling pathways. In addition to dopamine and opioid neurotransmitters, a key upstream signal may be brain-derived neurotrophic factor (BDNF) or other neurotrophins, which via receptor tyrosine kinases activate the Phosphoinositide 3-kinases (PI3K)-thymoma viral proto-oncogene (Akt), Ras-extracellular regulated kinase (ERK), and NFκB pathways, and ultimately regulate transcriptional activity and possibly control actin cytoskeletal dynamics through regulation of the Rho family of small GTPases (including Rac1 and p21-activated kinase (PAK1)). Activation of NFκB may occur additionally through a cytokine receptor mechanism to control spine plasticity, however, this remains speculative. Structural plasticity induced by psychostimulants can therefore result from manipulation of several signaling pathways that impinge upon actin assembly processes, with some of the changes mediated via altered gene expression. We hypothesize that the net effect of cocaine-induced activation of these fundamental signaling pathways are sensitized behavioral responses, although each pathway in isolation may produce distinct effects on addiction-like behavior and synaptic plasticity. PLCγ, phospholipase Cγ; IκK, inhibitory kappa kinase; IκB, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor; TrKB, tyrosine receptor kinase B; Drd, dopamine receptor; LIMK, lim domain kinase; WASP, Wiskott-Aldrich Syndrome proteins; Cdk5, cyclin-dependent kinase-5.

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