Original articleAmphetamine-induced dopamine release in human ventral striatum correlates with euphoria
Introduction
The existence of brain regions specialized for reward processing was initially suggested by studies showing that rats responded operantly to stimulation of specific sites to the exclusion of other activities (Olds and Milner 1954). Sites that proved particularly sensitive to electrical self-stimulation included the midbrain dopaminergic projections from the ventral tegmental area (VTA) into the nucleus accumbens shell region and the medial prefrontal cortex (PFC; reviewed in Spanagel and Weiss 1999). This mesolimbic DA system was subsequently shown to play important roles in the reinforcing properties of some drugs of abuse and of natural rewards such as food and gender in studies of experimental animals Carboni et al 1989, Everitt et al 1989, Fibiger 1991, Wise and Rompre 1989. Nevertheless, the relationship between endogenous DA release, stimulation by primary rewards, and reward-directed behavior is complex, and the specific role of dopamine release in the striatum in these behaviors has remained unclear Grace 1995, Spanagel and Weiss 1999.
Human studies may contribute to understanding the role of mesolimbic DA release because humans can describe subjective experiences under experimental conditions in which dopamine concentration ([DA]) is altered. Such studies are possible using recently developed positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging techniques that indirectly measure [DA] via the change in DA receptor radioligand binding to DA D2/D3 receptors Dewey et al 1991, Innis et al 1992. The striatal [11C]raclopride binding thus decreases during administration of drugs that stimulate DA release, such as dextroamphetamine (AMPH), or block DA reuptake such as methylphenidate and cocaine Breier et al 1997, Carson et al 1997, Dewey et al 1993, Hartvig et al 1997, Laruelle et al 1995, Schlaepfer et al 1997, Volkow et al 1994a, Volkow et al 1994b. In combined PET- or SPECT-microdialysis studies of nonhuman primates, the change in DA D2/D3 receptor radioligand specific binding was linearly related to the integral of the DA pulse induced by AMPH administration over the AMPH doses tested Endres et al 1997, Laruelle et al 1997. The most sensitive of these neuroimaging techniques uses PET to measure changes in the binding potential (BP; Mintun et al 1984) of the DA D2/D3-receptor antagonist, [11C]raclopride. [11C]Raclopride’s sensitivity to changes in endogenous [DA] may be partly conferred by its relatively fast dissociation rate (in vivo koff of 0.10 min−1 in humans; Farde et al 1989) and low affinity for DA D2 receptors (KD = 1.2 nmol/L; Kohler et al 1985, Seeman et al 1989). Nevertheless, the reduction in [11C]raclopride binding following administration of pharmacologic agents that increase extracellular [DA] does not appear solely explained by competition between radioligand and endogenous DA for DA D2/D3 receptors and may also involve agonist-mediated internalization of DA D2/D3 receptors (Laruelle 2000).
The portion of the mesolimbic dopaminergic system where DA release is most clearly measurable by extant neuroimaging methods is the ventral striatum because available radioligands that are sensitive to endogenous [DA] have very low specific-to-nonspecific binding ratios in extrastriatal tissues. Within the striatum, the anteroventral subregion may comprise the area where PET measures will prove most sensitive to changes in DA release induced by drugs of abuse because microdialysis studies of rats show greater increases in extracellular fluid [DA] in the accumbens than the dorsal caudate-putamen during AMPH, cocaine, phencyclidine, nicotine, narcotic analgesic, and ethanol challenge Brazell et al 1990, Carboni et al 1989, Di Chiara 1993, Di Chiara 1988a, Di Chiara 1988b, Imperato et al 1986, Imperato and Di Chiara 1986, Kuczenski and Segal 1992, Segal and Kuczenski 1992, Sharp et al 1987. In the case of AMPH, a preferential sensitivity of the accumbens to DA release was shown by Di Chiara and Imperato (1988a) and confirmed by some (Sharp et al 1987) but not other Kuczenski and Segal 1992, Pehek et al 1990, Robinson and Camp 1990 studies. The inconsistency of these results appeared to reflect differences in dialysis probe placement, such that the ability to detect regional differences in AMPH-induced DA release required that the dialysate from the dorsal caudate-putamen exclude extracellular fluid from the accumbens and that the dialysate from the accumbens include fluid from the accumbens shell Di Chiara 1991, Di Chiara 1993.
In primates, the cells with connectional and histochemical features of the accumbens blend with those of the anteroventral putamen and ventromedial caudate, such that the nucleus accumbens lacks distinct microscopic and macroscopic borders (Heimer and Alheid 1991). Nevertheless, by obtaining PET measures over the anteroventral striatal region that would encompass cells of the accumbens shell, DA release can be compared relative to the dorsal caudate (DCA) in a manner that approximates the microdialysis probe positions of Di Chiara and Imperato (1988a). Using this approach in a PET study of baboons, Drevets et al (1999) found that the reduction in [11C]raclopride BP in the AVS exceeded that in the DCA (p < .002). The proportional magnitude of this difference appeared similar to that of the difference in the AMPH-induced increase in extracellular fluid [DA] in the accumbens relative to the dorsal caudate-putamen in microdialysis studies of rats (Di Chiara et al 1993).
Our study applies the PET-[11C]raclopride method to human studies to test the hypothesis that the hedonic response to AMPH will correlate more strongly with DA release in the AVS than in the DCA. The AVS is innervated by the amygdala and the orbital and medial PFC areas implicated in reward-related and emotional processing, whereas the DCA primarily receives afferent connections from cortical areas involved in sensorimotor function Everitt et al 1989, Haber et al 1995, Kunishio and Haber 1994, Kunzle 1975, Nauta and Domesick 1984, Ongur and Price 2000, Parent 1990, Selemon and Goldman-Rakic 1985. Dissociating the effects of DA release in these striatal subregions may thus prove functionally relevant to studies of emotion.
Previous human imaging studies that correlated emotional responses with DA receptor radioligand displacement during AMPH, cocaine, or methylphenidate administration did not obtain measures specifically from the ventral striatum or compare the strength of such correlations across striatal subregions (Laruelle et al 1995, Schlaepfer et al 1997, Volkow et al 1994a, 1999). Perhaps as a result, the findings from these studies are in disagreement (see Discussion). Nevertheless, recent improvements in the spatial resolution and sensitivity of PET scanners and in the accuracy of PET-MRI coregistration methods now permit valid comparisons across distinct striatal subregions that may refine understanding about the relationship between regional DA release and emotion.
Section snippets
Subjects
Seven medically and psychiatrically healthy subjects were selected (mean age = 26 ± 3.6 years, range 20–30; 3 women). After full explanation of the procedures, all subjects provided written informed consent as approved by the University of Pittsburgh Institutional Review Board and the U.S. Food and Drug Administration. Exclusion criteria included pregnancy (documented by serum testing) or lactation; blood pressure > 140 mm Hg systolic or > 90 mm Hg diastolic; weight > 250 pounds; exposure to
Results
Immediately after [11C]raclopride infusion, radioactivity accumulated bilaterally in the striatum, reaching a peak in 10 to 20 min and clearing to between 60 and 80% of the peak at 60 min (Figure 3). Cerebellar radioactivity reached a peak within 5 min but cleared more rapidly.
The mean ROI volumes were (in mL ± one SD): DCA, 3.16 ± 0.528; AVS, 2.77 ± 0.722; MCA, 2.14 ± 0.294; DPU, 2.94 ± 0.399; VPU, 2.66 ± 0.279. All striatal ROI were positioned within 20 mm of the center of the axial
Discussion
These data confirm the hypothesis that the euphoric response to AMPH correlates positively with the magnitude of DA release in the AVS, as reflected by the inverse correlation with ΔBP. Conversely, the anxiety response to AMPH was inversely correlated with the magnitude of DA release in the AVS. Similar relationships may exist between these emotional responses and DA release and the VPU. In contrast, AMPH-induced emotional changes did not correlate with DA release in the DCA or the DPU. These
Acknowledgements
This study was supported by a grant from NARSAD (WCD), NIH Grants Nos. MH01713 (WCD) and MH30915 (DJK), and NIH/NCRR/GCRC Grant No. RR00056.
The authors thank David Townsend, Ph.D., for advice regarding image acquisition; Michael Zigmond, Ph.D., for discussions relevant to data interpretation; Phil Greer, M.S., for assistance with image alignments; and the UPMC PET Laboratory staff for technical assistance.
References (101)
- et al.
Acute administration of nicotine increases the in vivo extracellular levels of DA, 3,4-dihydroxyphenylacetic acid and ascorbic acid preferentially in the nucleus accumbens of the ratComparison with caudate-putamen
Neuropsychopharmacology
(1990) - et al.
Acute effects of cocaine on human brain activity and emotion
Neuron
(1997) - et al.
Amphetamine, cocaine, phencyclidine, and nomifensine increase extracellular DA concentrations preferentially in nucleus accumbens of freely moving rats
Neuroscience
(1989) - et al.
PET measures of amphetamine-induced dopamine release in ventral versus dorsal striatum
Neuropsychopharmacology
(1999) - et al.
Interactions between the amygdala and ventral striatum in stimulus-reward associationsStudies using a second-order schedule of sexual reinforcement
Neuroscience
(1989) - et al.
Detecting activations in PET and fMRILevels of inference and power
Neuroimage
(1996) Phasic versus tonic dopamine release and the modulation of dopamine system responsivityA hypothesis for the etiology of schizophrenia
Neuroscience
(1991)The tonic/phasic model of dopamine system regulation; its relevance for understanding how stimulant abuse can alter basal ganglia function
Drug Alcohol Depend
(1995)- et al.
Quantitative analysis of [carbonyl-11C]WAY-100635 PET studies
Nuclear Med Biol
(2000) - et al.
Parametric imaging of ligand-receptor binding in PET using a simplified reference region model
Neuroimage
(1997)