The exclusion criteria were: central nervous system, cardiovascular, pulmonary, hepatic, or systemic disease; HIV seropositive status; pregnancy; lack of English fluency; MRI ineligibility ; current use of psychotropic medications; current Axis I disorder including substance abuse or dependence for any substance other than nicotine . A diagnosis of MA dependence and a positive urine test for MA at intake were required for MA-group participants, who completed the study as inpatients at the UCLA General Clinical Research Center, and were prohibited from using any drugs for 4–7 days before testing. MA users completed the behavioral and imaging measures 2 days apart on average .All participants were required to provide a urine sample on each test day that was negative for amphetamine, cocaine, MA, benzodiazepines, opioids, and cannabis. Compensation was provided in the form of cash, gift certificates, and vouchers.Delay discounting was assessed with the Monetary-Choice Questionnaire , which presents participants with 27 hypothetical choices between a smaller, immediate monetary amount and a larger, delayed alternative. Most of the participants completed the task using a paper-and-pencil format, but some completed the task on a computer ; the questions were presented in the same sequence, regardless of task format. A logistic regression was performed on the data from each participant, separately, using his/her responses to all 27 choices as the dependent variable, and the natural log of the equivalence k value associated with each test question as the independent variable. This k-equivalence value was the number that would equalize the immediate option with the delayed alternative,flood tray assuming the hyperbolic discounting function: V = A/, where V represents the perceived value of amount A made available D days in the future .

The parameter estimates from the logistic regression were used to calculate the k-equivalence value at which the function intersected 0.5 . This derived k value characterized the individual’s discount rate . Because the MCQ only probes discounting between a minimum k-equivalence of 0.0002 and a maximum of 0.25, these values were designated as the minimum and maximum k values, respectively, that could be assigned.Dopamine D2 /D3 receptor availability was assessed using a Siemens EXACT HR+ positron emission tomography scanner in 3D mode with [18F]fally pride as the radioligand . Following a 7min transmission scan acquired using a rotating 68Ge/68Ga rod source to measure and correct for attenuation, PET dynamic data acquisition was initiated with a bolus injection of [18F]fally pride . Emission data were acquired in two 80min blocks, separated by a 10–20min break. Raw PET data were corrected for decay, attenuation, and scatter, and then reconstructed using ordered-subsets expectation-maximization , using ECAT v7.2 software . Reconstructed data were combined into 16 images , and the images were motion-corrected using FSL McFLIRT , and co-registered to the individual’s structural MRI scan image using a six-parameter, rigidbody transformation computed with the ART software package . Structural images were magnetization prepared, rapid-acquisition, gradient-echo scans acquired during a separate session using a Siemens Sonata 1.5T MRI scanner. All images were registered to MNI152 space using FSL FLIRT . Volumes of interest were derived from the Harvard-Oxford atlases transformed into individual native space, or defined using FSL FIRST . VOIs of the functional striatal subdivisions were created as described previously . Time-activity data within VOIs were imported into the PMOD 3.2 kinetic modeling analysis program , and time-activity curves were fit using the simplified reference tissue model 2 . The cerebellum was used as the reference region . The rate constant for transfer of the tracer from the reference region to plasma was computed as the volume-weighted average of estimates from receptor-rich regions , calculated using the simplified reference tissue model , as suggested by Ichise et al. .

Time-activity curves were re-fit using SRTM2 , with the computed k2 ′ value applied to all brain regions. Regional binding potential referred to non-displaceable binding, calculated as BPND = − 1), where R1 = K1 /K1 ′ is the ratio of tracer-delivery parameters for the tissue of interest and reference tissue, and k2a is the effective rate parameter for transfer of tracer from the tissue of interest to the plasma . Volume-weighted bilateral averages of all VOIs were used for analyses.Continuous variables were assessed for homogeneity of variance across groups using Levene’s tests. Demographic variables were examined for group differences using two-tailed independent samples t-tests, Mann-Whitney U-tests, or Fisher’s exact tests, as appropriate. Group differences in discount rate and BPND were tested using separate independent samples t-tests, and potential confounding variables were assessed as covariates. As expected, the distribution of discount rates was positively skewed. Because a natural log transform yielded a more normal distribution, ln was used for analyses. The threshold for statistical significance was set at α = 0.05 for all analyses. Onetailed p-values are reported for analyses where a specific directional effect was predicted . Exploratory analyses were also carried out to investigate whether discount rate is negatively correlated with BPND in extrastriatal regions. These analyses were restricted to regions that exhibit appreciable [18F]fallypride BPND .In line with previous reports, MA users displayed lower striatal D2 /D3 receptor availability and higher discount rates than controls, on average. As hypothesized, discount rate was significantly negatively correlated with striatal D2 /D3 receptor availability in the combined sample and among MA users alone. Although the slopes of the striatal correlations were not significantly different between controls and MA users, the relationship did not reach statistical significance among controls alone. Exploratory analyses revealed negative relationships between discount rate and D2 /D3 receptor availability in every extrastriatal region examined among MA users, but none retained significance following correction for multiple comparisons. While substantial evidence implicates dopamine as a key determinant of intertemporal choice , this study is the first to link temporal discounting directly with a measure of dopamine signaling capacity.

The findings indicate that deficient D2 /D3 receptor availability may contribute to steep temporal discounting among individuals with substance use disorders, attention-deficit hyperactivity disorder, or obesity , and carriers of the A1 allele of the ANKK1 Taq1A polymorphism . This reasoning is supported by reports that rats treated chronically with MA or cocaine display evidence of greater discounting of delayed rewards than saline-treated rats , as both of both of these stimulants induce persistent reductions in striatal D2 /D3 receptor availability in rats and monkeys following chronic exposure. The results are also compatible with the literature concerning the neuroanatomical substrates of intertemporal choice. There was evidence of correlations involving several brain regions that have been implicated by functional neuroimaging and lesion studies as playing a role in selecting between immediate and delayed rewards: e.g. the midbrain, dorsal striatum, globus pallidus, thalamus, amygdala, hippocampus, ACC, and insula . The prefrontal cortex is critically important for the ability to resist temptation for instant gratification in order to achieve long-term goals , and striatal D2 /D3 receptor availability modulates PFC activity when goal-directed choices are made . Moreover, D2 /D3 receptor availability in the putamen has been shown to be negatively correlated with glucose metabolism in the orbitofrontal cortex, which is implicated in delaying gratification , especially among MA users . Choosing a smaller, more immediately available reward over a larger, more delayed alternative can be considered as an impulsive choice. However, while striatal D2 /D3 receptor availability has been shown to be negatively correlated with trait impulsivity among MA users , there was no evidence that BIS-11 total scores were correlated with discount rates in this sample of participants . Still, as expected, total BIS-11 scores were robustly higher among MA users than controls on average in this sample,grow table and were negatively correlated with striatal D2 /D3 receptor availability when controlling for age in the combined sample . This result implies that even though both trait impulsivity and temporal discounting are related to striatal D2 /D3 receptor availability, they represent at least partially separable constructs. One limitation of this study is that [18F]fallypride has comparably high affinity for both D2 and D3 dopamine receptors , particularly as levels of D3 receptors may be higher than once estimated in multiple brain regions, including the striatum . Nevertheless, several lines of research suggest that individuals with substance use disorders, including MA users , have higher densities of D3 receptor levels in striatal and extrastriatal brain regions than those who do not frequently abuse drugs . Thus, it seems probable that the lower [18F]fallypride BPND among MA users primarily reflects lower D2 receptor availability in this group compared to controls. An additional limitation includes the possibility of competition with endogenous dopamine influencing [18F]fallypride BPND . That IQ was not assessed is also a limitation, because IQ has been found to be significantly correlated with delay discounting , and a group difference in the former could therefore overshadow the true group difference in the latter.

There are also some caveats that should be considered when interpreting the results of this study. First, the MCQ has limited ability to provide precise estimates of discount rates for individuals who discount very steeply. That is, the choice items only probe preference up to a maximum k-equivalence value of 0.25, and this value was assigned as a conservative estimate of discount rate to individuals whose calculated k value was predicted to exceed this value . Second, BPND values were highly correlated across all VOIs examined in both groups of participants, which limits the ability to draw conclusions regarding the relative importance of D2 /D3 receptor availability in specific brain regions to discount rate. Finally, as there is some evidence that abstinence from drugs can increase temporal discounting among addicted individuals , it is possible that abstinence from MA may have amplified the difference in discount rate between MA users and controls. The results of this study may help to explain why low striatal D2 /D3 receptor availability is associated with poor treatment response among individuals with MA dependence and cocaine dependence . This view seems reasonable given that steep temporal discounting has also been linked with poor treatment response among coca inedependent individuals , and predicts relapse among smokers . The present results lend empirical support to a theoretical model in which Trifilieff and Martinez propose that, “low D2 receptor levels and dopamine transmission in the ventral striatum lead to impulsive behavior, including the choice for smaller, immediate rewards over larger, but delayed or more effortful, rewards, which may represent an underlying behavioral pattern in addiction.” Consistent with this model, we found evidence of a negative correlation between discount rate and D2 / D3 receptor availability in the limbic striatal subdivision . The correlation in the limbic striatum did not reach statistical significance, possibly due to the high D3 /D2 receptor ratio in this region and partial volume effects. An important question for future research is to determine whether interventions that increase D2 /D3 receptor availability can reduce temporal discounting, at least among those with low D2 /D3 receptor availability. Pharmacological interventions could prove useful to this end. For example, varenicline increases striatal D2 /D3 receptor availability in rats , and in a study of human smokers, males treated with varenicline showed lower temporal discounting than placebo-treated controls . This finding is compelling considering that dorsal striatal D2 /D3 receptor availability is lower in male smokers compared to nonsmoker controls . There also is evidence that rimonabant increases striatal D2 /D3 receptor availability , and can decrease discounting of delayed rewards in rats . Nonpharmacological approaches may be useful as well, as there is preliminary evidence that intensive exercise can increase striatal D2 /D3 receptor availability in MA-dependent individuals and patients with early-stage Parkinson’s disease . Similarly, in a mouse model of Parkinson’s disease, higher striatal D2 /D3 receptor availability and D2 receptor expression was noted among those exposed to high-intensity exercise relative to non-exercising controls . Establishing a causal link between D2 /D3 receptor availability and temporal discounting is likely to have significant clinical implications. This is because there is evidence that interventions that reduce temporal discounting are useful for treating disorders that are associated with both steep discounting and low striatal D2 /D3 receptor availability. For instance, contingency management decreases discounting among cocaine-dependent individuals and smokers , and methylphenidate decreases discounting in children with attention-deficit hyperactivity disorder .