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. 2013 Mar 6;33(10):4527-35.
doi: 10.1523/JNEUROSCI.5261-12.2013.

Predominance of D2 receptors in mediating dopamine's effects in brain metabolism: effects of alcoholism

Nora D Volkow  1 , Dardo Tomasi, Gene-Jack Wang, Frank Telang, Joanna S Fowler, Jean Logan, L Jayne Maynard, Christopher T Wong
Affiliations

Predominance of D2 receptors in mediating dopamine's effects in brain metabolism: effects of alcoholism

Nora D Volkow et al. J Neurosci. .

Abstract

Dopamine signals through D1-like and D2-like receptors, which can stimulate or inhibit, respectively, neuronal activity. Here we assessed the balance between D1 or D2 receptor signaling in the human brain and how it is affected in alcoholism. Using PET, we measured the relationship between changes in dopamine and brain glucose metabolism induced by methylphenidate in controls and alcoholics. We show that methylphenidate induced significant DA increases in striatum, amygdala, and medial orbitofrontal cortex, whereas it decreased metabolism in these brain regions. Methylphenidate-induced dopamine increases were greater in controls than in alcoholics, whereas methylphenidate-induced metabolic decreases were greater in alcoholics. For both groups, methylphenidate-induced dopamine increases were associated with decreases in regional brain metabolism, and the correlations were strongest in subthalamic nuclei, anterior cingulate, and medial orbitofrontal cortex. These correlations were more extensive and robust and the slopes steeper in alcoholics than in controls despite their attenuated dopamine responses to methylphenidate, which suggests an impaired modulation of dopamine signals in the brain of alcoholic subjects. These findings are consistent with a predominant inhibitory effect of dopamine in the human brain that is likely mediated by the prominence of dopamine D2/D3 receptors.

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Figures

Figure 1.
Figure 1.
Diagram of the experimental design. Subjects were tested on two separate days. On each day, they were scanned first with [11C]raclopride, and this was followed by an FDG scan. On one of the days, the subjects received intravenous placebo (saline solution); and on the other day, they received intravenous MP, which was given 5 min before [11C]raclopride injection.
Figure 2.
Figure 2.
Behavioral (A) and cardiovascular (B) effects of MP in controls (black symbols) and alcoholics (gray symbols). A, Self-reports of drug effects, high, and stimulated were significantly larger in controls than in alcoholics (p < 0.05). Cardiovascular effects did not differ between groups.
Figure 3.
Figure 3.
SPM results for the comparison of MP versus placebo on the BPND images from [11C]raclopride in the controls and in the alcoholic subjects (pu < 0.005). The regions shown are those where MP decreased BPND, which correspond to the regions where MP increased DA. The contrast controls > alcoholics indicates that MP induced greater decreases in BPND (reflecting greater DA increases) in the controls than in the alcoholics. There were no regions where alcoholics showed greater BPND decreases than the controls. The color scale indicates the t values for the comparisons.
Figure 4.
Figure 4.
SPM results for the comparison of MP versus placebo on the relative metabolic images in the controls and in the alcoholic subjects (pu < 0.005). The contrast shows the regions where MP increased metabolism (yellow/red) and where it decreased metabolism (blue). The contrast alcoholic > controls indicates the regions where MP induced greater decreases in metabolism (blue) and greater increases in metabolism (red) in alcoholics than in the controls. The color scale indicates the t values for the comparisons.
Figure 5.
Figure 5.
SPM results for the voxelwise analysis where the correlations (positive) between MP-induced changes in BPND (reflecting DA increases) and regional brain metabolism (reflecting changes in brain activity) were significant for the controls and the alcoholic (pu > 0.001). Decreases in BPND reflect DA increases, such that positive correlations indicate that DA increases are associated with decreases in metabolism. There are more extensive cortical correlations in the alcoholics than in the controls. The color scale indicates the t values for the comparisons.
Figure 6.
Figure 6.
Regression plots for the controls and the alcoholics for the correlation between MP-induced changes in BPND and changes in relative metabolism. The negative values for ΔBPND reflect lower BPND measures with MP (i.e., DA increases with MP), and negative ΔFDG reflect lower values with MP (decreased metabolism with MP). Open symbols and dashed lines represent controls; and closed symbols and continuous lines represent alcoholics. STN, Subthalamic nucleus; L, left; R, right; Sup, superior; Inf, inferior.
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