Brain reward regulated by AMPA receptor subunits in nucleus accumbens shell - PubMed (original) (raw)

Comparative Study

Brain reward regulated by AMPA receptor subunits in nucleus accumbens shell

Mark S Todtenkopf et al. J Neurosci. 2006.

Abstract

Drugs of abuse alter expression of AMPA-type glutamate receptor subunits (GluRs) in the nucleus accumbens (NAc), a key component of brain reward systems. The impact of this regulation on general motivational states is unclear. Here, we used herpes simplex virus vectors to examine how transient increases in the expression of GluR1 or GluR2 protein in the shell component of NAc affect the rewarding impact of electrical stimulation of the medial forebrain bundle, as reflected by intracranial self-stimulation (ICSS) thresholds in rats. We found that elevated GluR1 in NAc shell increases ICSS thresholds, an effect similar to that caused by treatments that cause anhedonia and dysphoria (prodepressive effects) in rats and humans (e.g., drug withdrawal, kappa-opioid agonists). In contrast, elevated GluR2 decreases ICSS thresholds, an effect similar to that caused by rewarding treatments (e.g., drugs of abuse). To confirm that viral vector-mediated elevations of GluR1 in the NAc shell produce molecular consequences that are different from those of elevated GluR2, we examined the expression of a set of drug-regulated genes 3 d after treatment using quantitative PCR. Elevated GluR1 was accompanied by sustained increases in the gene for GluR1, whereas elevated GluR2 was accompanied by decreases in prodynorphin. These data suggest that GluR1 and GluR2 in the NAc shell play opposing roles in the regulation of motivated behavior.

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Figures

Figure 1.

Effects of HSV vector-mediated alterations in gene expression in the NAc shell on ICSS. a, Expression of β-galactosidase, induced by bilateral microinjections of HSV-LacZ into the NAc (ac) shell, 3 d after gene transfer in a brain section costained for TH (magnification, 40×). b–d, Elevated GluR1 (b) expression in this region caused rightward shifts in rate-frequency functions, whereas elevated GluR2 (c) expression caused leftward shifts and β-galactosidase (d) had no effect. Data are from representative rats tested 3 d after gene transfer; for clarity, only the third of four daily rate-frequency determinations is shown. e, Effect of gene transfer on mean (±SEM) ICSS thresholds in 1 h test sessions across the 8 d test period. f, Elevated GluR2 decreased ICSS thresholds, whereas elevated GluR1 increased thresholds relative to rats treated with HSV-LacZ (F(14,182) = 2.15; p < 0.02), although none of the treatments affected response rates. Data are expressed as percentage of pre-gene transfer baselines. *p < 0.05, **p < 0.01 (Fisher's tests).

Figure 2.

Effects of HSV vector-mediated alterations in gene expression in the NAc shell, as measured by Q-PCR. Elevated GluR2 expression decreased prodynorphin (DYN) mRNA, whereas elevated GluR1 expression increased GluR1 mRNA. Data are mean (±SEM) levels of mRNA normalized to β-actin and general transcription factor 2β (GTF-2β) and expressed as percentage of HSV-LacZ control. *p < 0.05, **p < 0.01 (Fisher's tests). Inset, Areas of the NAc shell targeted for dissection (gray shading). MOR, μ-Opioid receptor gene; DOR, δ-opioid receptor gene.

Figure 3.

Histological reconstruction of ICSS electrode placements for each treatment group. Headings indicate the gene that was virally transferred; the circles localize the electrode tips. The distance posterior to bregma (in millimeters) is indicated.

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Brain reward regulated by AMPA receptor subunits in nucleus accumbens shell - PubMed (original) (raw)