Intravenous ethanol increases dopamine release in the ventral striatum in humans: PET study using bolus-plus-infusion administration of [(11)C]raclopride

Abstract

Ethanol increases the interstitial dopamine (DA) concentration in the nucleus accumbens (NAcc) of experimental animals, but positron emission tomography (PET) studies using the single-bolus protocol of the [(11)C]-raclopride competition paradigm have yielded conflicting results in humans. To resolve disparate previous findings, we utilized the bolus-plus-infusion (B/I) method, allowing both baseline and intervention quantification of [(11)C]raclopride binding during a single 105-minute PET scan, to investigate possible ethanol-induced DA release in nine healthy male subjects. A 25-minute intravenous ethanol (7.6%) infusion, resulting in a 1.3 g/L mean blood ethanol concentration, was administered using masked timing during the PET scan. Automated region-of-interest analysis testing the difference between baseline (40-50 minutes) and intervention (60-85 minutes) revealed an average 12.6% decrease in [(11)C]raclopride binding in the ventral striatum (VST, P=0.003) including the NAcc. In addition, a shorter time interval from the start of ethanol infusion to the first subjective effect was associated with a greater binding potential decrease bilaterally in the VST (r=0.92, P=0.004), and the feeling of pleasure was associated with a decrease in binding potential values in both the caudate nucleus (r=-0.87, P=0.003) and putamen (r=-0.74; P=0.02). These results confirm that ethanol induces rapid DA release in the limbic striatum, which can be reliably estimated using the B/I method in one imaging session.

Figure 1

Observed [¹¹C]raclopride time–activity curves for all regions. x-axis represents time (minutes) after the start of the scan and y-axis represents radioactivity concentration (Bq/mL).

Figure 2

Temporal profiles of the average regional BP_ND during positron emission tomography scan. X-axis represents time (minutes) after injection of [¹¹C]raclopride and y-axis shows BP_ND values. Baseline and ethanol intervention values were calculated using data from 40 to 50 minutes and 60 to 85 minutes, respectively (lines below time axis). The binding achieved equilibrium during the baseline phase. Intravenous ethanol was administered during 50–75 minutes (arrow above time axis). The largest decrease in binding in the limbic striatum takes place during 75–85 minutes, and thereafter started to recover close to baseline level.

Figure 3

Visualization of the results of voxel-based receptor mapping analysis. Statistical parametric map of T value of the analysis testing the decrease in [¹¹C]raclopride BP_ND during ethanol intervention in comparison to the baseline. The effect in the VST is localized in the NAcc bilaterally. The map is visualized on the magnetic resonance image template image, representing common stereotactic Montreal Neurologic Institute space and presented in accordance with the radiological convention (right is left). The color bar represents the T value according to the numerical scale.

Figure 4

Scatter plots describing the associations between ethanol-induced subjective responses and [¹¹C]raclopride BP_ND values. Upper panels: correlations between reported feeling of relaxation (left panel) and pleasure (right panel) versus change in [¹¹C]raclopride BP_ND in the putamen (left panel) and caudate nucleus (right panel). Correlation analysis testing revealed a significant correlation between the feeling of relaxation and change in [¹¹C]raclopride BP_ND in the putamen (left panel, r=−0.82, P=0.007) and between the feeling of pleasure and change in [¹¹C]raclopride BP_ND in the caudate nucleus (right panel, r=−0.87, P=0.003). Lower panels: correlations between latency of the first reported ethanol-related sensation and change in [¹¹C]raclopride BP_ND in the ventral striatum (VST; left panel, r=0.92, P=0.004) and between reported maximal intoxication level during the positron emission tomography scan and in [¹¹C]raclopride baseline BP_ND in the left VST (right panel, r=0.76, P=0.02). Changes in BP_ND were calculated as (BP_ND intervention−BP_ND baseline), and thus negative values indicate intervention-induced decrease in BP_ND, suggesting increased dopamine concentration.