In this study, methamphetamine subjects viewed themselves as more impulsive than did healthy control subjects; and they exhibited lower striatal D2/D3 receptor availability. VOI analysis indicated a significant negative relationship between striatal D2/D3 receptor availability and impulsiveness in methamphetamine-dependent subjects, while voxelwise analysis revealed striatal regions where D2/D3 receptor availability was significantly related to impulsiveness across both subject groups.
PET with [18
F]fallypride replicated findings of deficits in D2
receptor availability in the caudate nucleus and putamen, observed with [11
C]raclopride (Volkow et al., 2001
), and extended analysis to the nucleus accumbens, where there was no group difference. The nucleus accumbens is smaller and less well defined than the caudate nucleus and putamen, leading to greater variability in determining its D2
, therefore providing less power to detect a group difference in that structure.
The deficit in striatal D2
receptor availability in the methamphetamine group was related to cumulative methamphetamine exposure but not frequency of recent methamphetamine abuse. This observation contrasts with some findings that some indices of methamphetamine exposure were not related to various outcome measures, including cerebral blood flow (Chang et al., 2002
), striatal dopamine transporter availability (McCann et al., 2008
), or microglial activation in the brain (Sekine et al., 2008
), and with a few reports linking cognitive deficits to frequency of recent methamphetamine use (Simon et al., 2000
; Monterosso et al., 2005
). Finding of a cumulative effect, however, is consistent with prior findings of deficits in frontal white matter structure (Ernst et al., 2000
) and metabolic activity (Kim et al., 2009
), cerebral N-acetylaspartate (Nordahl et al., 2005
), striatal size (Chang et al., 2005
) and dopamine and serotonin transporter availability (Sekine et al., 2006
We also found a negative relationship between striatal D2/D3 receptor availability and impulsiveness. VOI analysis revealed such a relationship involving the caudate nucleus and nucleus accumbens in the methamphetamine group only. However, correlation coefficients also were negative for the putamen of the methamphetamine group and for striatal structures of the healthy control group, and our lack of a significant finding may reflect inadequate power. Along this line, effects at discrete sites can be diluted when sampling an entire striatal volume in VOI analysis; and voxelwise analysis revealed a negative association between D2/D3 receptor availability and impulsivity in the putamen of the methamphetamine subjects (p < 0.05, TFCE corrected) and in striatal regions in the control group albeit at a statistical threshold of p < 0.12 (TFCE corrected).
The negative correlation between impulsivity and striatal D2
receptor availability in humans, reported here, is in line with a relationship observed between impulsivity and D2
receptor availability of the ventral striatum in rats (Dalley et al., 2007
) althougth the present study reports changes in additional regions of the striatum. The discrepancy in subregions of the striatum linked to impulsive behavior in the two species likely reflects profound differences between the subjective self-report of impulsivity taken here and in operant measures of impulsivity in experimental animals as well as possible lack of homology in striatal substructures across species.
As the negative relationship between striatal D2
receptor availability and impulsivity extends to healthy control subjects, it appears to be fundamental (albeit exaggerated in subjects who self-administer methamphetamine). In addition, the association between duration of methamphetamine abuse and striatal D2
receptor availability suggests that methamphetamine exposure has a negative impact on the D2
receptor system, thereby promoting impulsivity. This view is consistent with findings that stimulant administration promotes impulsive behavior in animals (e.g., Jentsch and Taylor, 1999
). Nonetheless, we cannot exclude the possibility that lower D2
receptor availability (with attendant greater impulsivity) contributes to the self-administration of methamphetamine.
The mechanism by which striatal D2
receptors can influence impulsivity is not completely clear, but accumulating evidence points to a ‘fronto-striatal system’ in influencing various dimensions of impulsivity (Aron et al., 2007
; Dalley et al., 2008
). Prefrontal cortical inhibition of subcortical and posterior cortical structures is thought to play a key role in modulating behavior, and lesions of the prefrontal cortex have been linked with deficits in motor response inhibition (Aron et al., 2004
). In addition, striatal lesions in rats increase impulsivity, as measured on the delayed discounting task (Cardinal et al., 2001
; Pothuizen et al., 2005
) and the Stop Signal Task (Eagle and Robbins, 2003
). Similarly, patients with basal ganglia lesions also have impaired performance on the Stop Signal Task (Rieger et al., 2003
). Neuroimaging studies have provided evidence for striato-cortical link in a network that may be related to impulsivity. In this regard, striatal D2
receptor availability was positively related to glucose metabolism in cortical regions involved in inhibitory control (e.g., orbitofrontal cortex, cingulate gyrus, and dorsolateral prefrontal cortex). This positive correlation has been observed in individuals who engage in stimulant abuse (Volkow et al., 1993
; Volkow et al., 2001
) and in obese subjects (Volkow et al., 2008
Our results provide direct empirical evidence that striatal D2/D3 receptor availability is associated with impulsiveness in humans, suggesting an important link between a striatal dopaminergic system and cortical influence on a wide variety of disorders that involve uninhibited maladaptive behavior.