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Cocaine addiction remains without an effective pharmacotherapy and is characterized by an inability of addicts to inhibit relapse to drug use. Vulnerability to relapse arises from an enduring impairment in cognitive control of motivated behavior, manifested in part by dysregulated synaptic potentiation and extracellular glutamate homeostasis in the(More)
Cortico-striatal glutamate transmission has been implicated in both the initiation and expression of addiction related behaviors, such as locomotor sensitization and drug-seeking. While glutamate transmission onto dopamine cells in the ventral tegmental area undergoes transient plasticity important for establishing addiction-related behaviors, glutamatergic(More)
Dendritic spines are postsynaptic specializations thought to regulate the strength of synaptic transmission and play a critical role in neuronal plasticity. While changes in dendritic spine density can be pharmacologically- or environmentally-induced, the widespread utility of this important measure of synaptic plasticity in vivo has been hampered by the(More)
Coordinated proteolysis of synaptic proteins is required for synaptic plasticity, but a mechanism for recruiting the ubiquitin-proteasome system (UPS) into dendritic spines is not known. NAC1 is a cocaine-regulated transcriptional protein that was found to complex with proteins in the UPS, including cullins and Mov34. NAC1 and the proteasome were(More)
Persistent relapse to addictive drugs constitutes the most challenging problem in addiction therapy, and is linked to impaired prefrontal cortex regulation of motivated behaviors involving the nucleus accumbens. Using a rat model of heroin addiction, we show that relapse requires long-term potentiation (LTP)-like increases in synaptic strength in the(More)
In animal models of addiction, reducing glutamate stimulation of the metabotropic glutamate receptor 5 (mGluR5) inhibits drug-seeking. The present study used the reinstatement model of cocaine-seeking to show that blockade of mGluR5 directly in the core subcompartment of the nucleus accumbens (NAcore) prevented both conditioned cue- and cocaine-reinstated(More)
Addiction changes prefrontal cortex regulation of the nucleus accumbens, including reduced ability to induce long-term potentiation (LTP) and long-term depression (LTD). This important potential mechanism of impaired prefrontal regulation of behaviour has been shown only for cocaine. Here we show that animals trained to self-administer heroin demonstrate(More)
Cocaine addiction is characterized by long-lasting vulnerability to relapse arising because neutral environmental stimuli become associated with drug use and then act as cues that induce relapse. It is not known how cues elicit cocaine seeking, and why cocaine seeking is more difficult to regulate than seeking a natural reward. We found that(More)
Locomotor sensitization is a common and robust behavioral alteration in rodents whereby following exposure to abused drugs such as cocaine, the animal becomes significantly more hyperactive in response to an acute drug challenge. Here, we further analyzed the role of cocaine-induced silent synapses in the nucleus accumbens (NAc) shell and their contribution(More)
RATIONALE The dopamine transporter (DAT) and the vesicular monoamine transporter 2 (VMAT2) play pivotal roles in the action of methamphetamine (MAP), including acute locomotor effects and behavioral sensitization. However, the relative impact of heterozygous DAT and VMAT2 knockouts (KOs) on the behavioral effects of MAP remains unknown. OBJECTIVES To(More)