Glutamate is a key transmitter for neuronal plasticity and learning. My lab and others have shown that behavioral changes in animal models of addiction require glutamate-dependent forms of plasticity, and that learning and addiction involve common brain signaling pathways and cellular changes. Thus, addiction may be viewed as a form of maladaptive but extremely strong learning. An important question is how drugs like cocaine and amphetamine, which initially target dopamine (DA) systems in the brain, ultimately produce adaptations in glutamate neurotransmission. A better understanding of plasticity mechanisms engaged by drugs of abuse may lead to the development of pharmacological treatments for drug dependency and craving.
Glutamate receptor trafficking is critical for controlling the strength of glutamate synapses in well-studied forms of plasticity such as LTP. My lab focuses on the role of glutamate receptor trafficking in addiction-related plasticity. Some members of the lab use primary neuronal cultures to study mechanisms by which psychomotor stimulants influence glutamate receptor trafficking, while others use biochemical methods to investigate the functional significance of receptor trafficking for in vivo models of addiction. This work is funded by a Merit Award (R37), R01 and K05 Award from the National Institute on Drug Abuse.
Our in vivo studies currently focus on the role of GluR2-lacking, calcium-permeable AMPA receptors (CP-AMPARs) in the incubation model of cocaine addiction, in which cue-induced cocaine craving progressively intensifies ("incubates") during withdrawal from extended access cocaine self-administration (for review, see Wolf and Tseng, 2012). In drug-naïve rats or rats with limited cocaine exposure, CP-AMPARs are normally expressed at very low levels by NAc neurons (Boudreau et al., 2009; Reimers et al., 2010). However, CP-AMPARs are added to NAc synapses after withdrawal from extended access cocaine self-administration and mediate the expression of "incubated" cue-induced cocaine craving (Conrad et al., 2008). This work, published in Nature, was conducted in collaboration with the laboratories of Dr. Michela Marinelli and Dr. Kuei Tseng (both at Rosalind Franklin University of Medicine and Science) and Dr. Yavin Shaham (NIDA). Current goals include understanding mechanisms that enable CP-AMPARs to accumulate in NAc synapses during "incubation" (Ferrario et al., 2011b; Li et al., 2013; Loweth et al., 2013b) and strategies for normalizing synaptic transmission by stimulating mGluR1 and thereby removing CP-AMPARs from synapses (McCutcheon et al., 2011b; Loweth et al., 2013a). New areas of focus include: 1) the role of the ubiquitin-proteasome system (UPS) and local protein synthesis in cocaine-induced AMPAR adaptations in the NAc, and 2) the relationship between AMPAR plasticity and changes in the density, morphology and function of dendritic spines (Ferrario et al., 2012; Wang et al., 2013). Major techniques involve drug self-administration, protein crosslinking, biotinylation, immunoprecipitation, spine analysis using Lucifer yellow, patch-clamping (in collaboration with Dr. Kuei Tseng) and 2-photon calcium imaging (in collaboration with Dr. Grace Stutzmann).
Our in vitro studies focus on similar scientific questions, but take advantage of the ability to more directly examine mechanisms using cultured neurons. We prepare primary cultures and co-cultures of neurons from addiction-related brain regions such as the NAc, prefrontal cortex, hippocampus, and ventral tegmental area (for review, see Wolf, 2010b). Principal neurons in the first three regions receive convergent DA and glutamate inputs. We have shown that DA receptors regulate AMPA receptor trafficking to extrasynaptic sites on the cell surface and thereby modulate synaptic plasticity (Chao et al., 2002a,b; Mangiavacchi & Wolf, 2004a.b; Sun et al., 2005; Gao et al., 2006; Sun et al., 2008). More recently, we have demonstrated that synaptic scaling occurs in the NAc (Sun & Wolf, 2009). This and other types of homeostatic plasticity may be important during drug withdrawal. Current projects focus on the roles of BDNF and metabotropic glutamate receptors in regulating AMPA receptor trafficking in the NAc. Major techniques involved are cell culture, fluorescence microscopy and immunocytochemistry.