These findings may suggest that in settings in which time and funding are too limited to perform partner services in all new HIV diagnoses, partner services should be focused on individuals diagnosed with AEH and performed within 30 days of diagnosis. Increased focus of partner services on individuals with AEH in these settings may potentially improve partner services delivery by clinicians and public health departments, identification of HIV-unawares and persons during AEH and identification of a high-risk HIV-uninfected cohort appropriate for prioritized prevention services and PrEP. Taken together, these could translate into a larger impact on HIVepidemic control than partner services has had to date. Modeling studies evaluating the downstream effects of targeted partner services, that is the effects of combined identification and treatment of high-transmission risk persons, PrEP in those found to be HIV-uninfected and also real-time identification of AEH outbreaks are needed. These studies would further elucidate the impact of partner services in persons with AEH on epidemic control.Drug addiction is characterized by persistent drug use despite adverse consequences, perhaps in part because the instant pleasure garnered by using drugs is perceived to outweigh the long-term benefits of sobriety. Consistent with this idea, laboratory studies routinely find that individuals with substance use disorders display greater preference for smaller, more immediately available rewards over larger, delayed alternatives than healthy controls . Moreover,drying rack cannabis research indicates that those who most strongly favor the immediate options on such laboratory-based choice tasks are also most likely to relapse during attempted abstinence .

Nonetheless, few studies have attempted to elucidate the neural mechanisms underlying addicts’ inordinate preference for immediate rewards. Dopamine is heavily implicated in intertemporal choice , and indirect evidence suggests that deficient dopamine D2 /D3 -type receptor-mediated dopaminergic neurotransmission in the striatum may be an important contributing factor to this immediacy bias. Like steep temporal discounting, low striatal D2 /D3 receptor availability is observed among individuals with substance use disorders , and has been linked with an increased likelihood of relapse . Chronic exposure to methamphetamine or cocaine induces persistent reductions in striatal D2 /D3 receptor availability in rats and monkeys , and rats treated chronically with either of these drugs exhibit greater temporal discounting than controls . Humans with attention-deficit hyperactivity disorder or obesity—two other disorders that are associated with low striatal D2 /D3 receptor availability — also display greater temporal discounting than healthy controls . Greater temporal discounting has also been observed among carriers of the A1 allele of the ANKK1 Taq1A polymorphism , a genetic variant associated with low striatal D2 receptor density/binding in humans relative to A2 homozygotes . Although an association between low striatal D2 /D3 receptor availability and steep temporal discounting has been implied, this link has not been directly evaluated. We therefore examined striatal D2 /D3 receptor availability in relation to temporal discounting in research participants who met DSM-IV criteria for MA dependence and a group of healthy controls. MA-dependent individuals were selected as a group for study because case-control studies find that they display deficits in striatal D2 /D3 receptor availability and exaggerated temporal discounting . We hypothesized that striatal D2 / D3 receptor availability would be negatively correlated with discount rates among MA users, and possibly also among controls. Because tobacco use has also been linked with low striatal D2 /D3 receptor availability and steep temporal discounting , the association was explored as well in the control-group smokers.

Because chronic MA abusers also display lower D2 /D3 receptor availability than non-users in extrastriatal brain areas , including several that have been implicated in intertemporal choice , exploratory analyses were performed to investigate whether extrastriatal D2 /D3 receptor availability might also be negatively correlated with discount rate.Procedures were approved by the University of California Los Angeles Office for Protection of Research Subjects. Participants were recruited using the Internet and local newspaper advertisements. All provided written informed consent and underwent eligibility screening using questionnaires, the Structured Clinical Interview for DSM-IV , and a physical examination. Twenty-seven individuals who met criteria for current MA dependence but were not seeking treatment for their addiction and 27 controls completed the study. D2 /D3 receptor availability data from approximately half of the MA users and controls have been reported previously , and smaller subsets were included in other studies from our laboratory regarding D2 /D3 receptor availability . 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 . Controls were studied on a nonresidential basis and completed the measures 22 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,commercial greenhouse supplies 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 radio ligand . 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.

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. One tailed 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]fally pride 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, 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]fally pride 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 .