Dopamine receptor expression and distribution dynamically change in the rat nucleus accumbens after withdrawal from cocaine self-administration

Abstract

Dopamine receptors (DARs) in the nucleus accumbens (NAc) are critical for cocaine's actions but the nature of adaptations in DAR function after repeated cocaine exposure remains controversial. This may be due in part to the fact that different methods used in previous studies measured different DAR pools. In the present study, we used a protein crosslinking assay to make the first measurements of DAR surface expression in the NAc of cocaine-experienced rats. Intracellular and total receptor levels were also quantified. Rats self-administered saline or cocaine for ten days. The entire NAc, or core and shell subregions, were collected one or 45 days later, when rats are known to exhibit low and high levels of cue-induced drug seeking, respectively. We found increased cell surface D1 DARs in the NAc shell on the first day after discontinuing cocaine selfadministration (designated withdrawal day 1, or WD1) but this normalized by WD45. Decreased intracellular and surface D2 DAR levels were observed in the cocaine group. In shell, both measures decreased on WD1 and WD45. In core, decreased D2 DAR surface expression was only observed on WD45. Similarly, WD45 but not WD1 was associated with increased D3 DAR surface expression in the core. Taking into account many other studies, we suggest that decreased D2 DAR and increased D3 DAR surface expression on WD45 may contribute to enhanced cocaine-seeking after prolonged withdrawal, although this is likely to be a modulatory effect, in light of the mediating effect previously demonstrated for AMPA-type glutamate receptors. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 August 11. Alterations in dopamine (DA) receptor (DAR) signaling are widely believed to contribute to addiction (Volkow et al., 2009). Many studies have therefore examined the effects of cocaine self-administration and withdrawal on the expression of D1-like (D1 and D5) and D2-like (D2, D3, and D4) classes of DARs in the nucleus accumbens (NAc). Studies in humans and non-human primates have used positron emission topography (PET) to provide an indirect measure of available DAR cell surface receptors. In rat studies, binding assays or in vitro receptor autoradiography have been utilized; these techniques measure DARs in a number of compartments, including but not limited to the cell surface pool. Particularly in rodent studies, results appear to depend on the drug regimen and timing of the experiment (Anderson and Pierce, 2005). However, another important variable is the use...

Increased vulnerability to cocaine in mice lacking dopamine D3receptors

“…All of these findings support a conclusion that D 3 R deletion leads to enhanced susceptibility to cocaine use and abuse. This conclusion appears to conflict with previous reports that cocaine overdose or chronic cocaine administration up-regulates D 3 R expression in the NAc in cocaine addicts or experimental animals (52)(53)(54)(55)(56). However, we point out that our finding that D 3 R deletion causes an increase in cocaine-taking and cocaine-seeking was observed during the acquisition and maintenance of cocaine self-administration and early extinction, whereas D 3 R up-regulation in the aforementioned studies was observed after prolonged abstinence (30-45 d of withdrawal from the last cocaine administration), not during self-administration or within 7 d of withdrawal (53,55,56).…”

“…This conclusion appears to conflict with previous reports that cocaine overdose or chronic cocaine administration up-regulates D 3 R expression in the NAc in cocaine addicts or experimental animals (52)(53)(54)(55)(56). However, we point out that our finding that D 3 R deletion causes an increase in cocaine-taking and cocaine-seeking was observed during the acquisition and maintenance of cocaine self-administration and early extinction, whereas D 3 R up-regulation in the aforementioned studies was observed after prolonged abstinence (30-45 d of withdrawal from the last cocaine administration), not during self-administration or within 7 d of withdrawal (53,55,56). Moreover, findings of D 3 R up-regulation were based on the use of lowselective D 3 /D 2 receptor ligands, such as [ 3 H]-7-OH-DPAT and [ 125 I]-7-OH-PIPAT, and no control experiments were conducted to rigorously identify the receptor-binding specificity of such ligands (52,53,55).…”

microRNA-Seq reveals cocaine-regulated expression of striatal microRNAs

“…Recent studies have demonstrated the importance of miRNAs in the pathophysiology of several neuropsychiatric disorders and mental retardation syndromes (Conrad et al 2010;Sulzer 2011), including schizophrenia (Burmistrova et al 2007;Beveridge et al 2010;Moreau et al 2011;Santarelli et al 2011), bipolar disorder, Fragile X mental retardation (Edbauer et al 2010;Krol et al 2010;Wulff et al 2011), Rett syndrome (Wu et al 2010), Alzheimer's disease, Parkinson's disease (Junn et al 2009), and Huntington's disease (Martí et al 2010). A number of the cocaine-responsive miRNAs identified in this study are important in controlling dendritic morphology; these miRNAs, and many others, may contribute to long-lasting forms of drugmediated synaptic plasticity through control of regulatory Lugli et al 2008 (adult mouse cortex and hippocampus; measured by microarray) with RNA-Seq data (adult mouse striatum) from these experiments (Lugli et al 2008).…”

Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model

“…These molecules are differentially expressed in the bHR and bLR rat lines (19,29) and have been previously implicated in addiction-related behaviors (e.g., refs. [30][31][32]. We have shown that administration of FGF2 early in life increases the acquisition of cocaine self-administration in adulthood (33) and renders bLRs more bHR-like (34), supporting a role for FGF2 as a neuromolecular antecedent of drugtaking behavior (18,35).…”