Variability in paralimbic dopamine signaling correlates with subjective responses to D-amphetamine

Abstract

Subjective responses to psychostimulants vary, the basis of which is poorly understood, especially in relation to possible cortical contributions. Here, we tested for relationships between participants' positive subjective responses to oral d-amphetamine (dAMPH) versus placebo and variability in striatal and extrastriatal dopamine (DA) receptor availability and release, measured via positron emission tomography (PET) with the radiotracer 18 F-fallypride. Analyses focused on 35 healthy adult participants showing positive subjective effects to dAMPH measured via the Drug Effects Questionnaire (DEQ) Feel, Like, High, and Want More subscales (Responders), and were repeated after inclusion of 11 subjects who lacked subjective responses. Associations between peak DEQ subscale ratings and both baseline 18 F-fallypride binding potential (BPnd; an index of D2/D3 receptor availability) and the percentage change in BPnd post dAMPH (%ΔBPnd; a measure of DA release) were assessed. Baseline BPnd in ventromedial prefrontal cortex (vmPFC) predicted the peak level of High reported following dAMPH. Furthermore, %ΔBPnd in vmPFC positively correlated with DEQ Want More ratings. DEQ Want More was also positively correlated with %ΔBPnd in right ventral striatum and left insula. This work indicates that characteristics of DA functioning in vmPFC, a cortical area implicated in subjective valuation, are associated with both subjective high and incentive (wanting) responses. The observation that insula %ΔBPnd was associated with drug wanting converges with evidence suggesting its role in drug craving. These findings highlight the importance of variability in DA signaling in specific paralimbic cortical regions in dAMPH's subjective response, which may confer risk for abusing psychostimulants.

Lack of consistent sex differences in d-amphetamine-induced dopamine release measured with [18F]fallypride PET

“…Previously, we found relationships between %ΔBP ND and the subjective effect of Wanting More dAMPH in vmPFC, left insula, and right VS in Dataset 1 (Smith et al 2016a). In Dataset 1, females had lower Drug Effects Questionnaire (Morean et al 2013) ratings (max FEEL, LIKE, HIGH, and WANT MORE dAMPH-placebo from one of 5 timepoints from 60 minutes to 345 minutes post drug) than males (all Ts<−2.28, ps<0.03; see Supplementary Table 3).…”

“…In addition, it should be noted that although [ 11 C]raclopride and [ 18 F]fallypride are sensitive to dopamine release, the overall sensitivity is relatively modest, with [ 11 C]raclopride being somewhat more sensitive than [ 18 F]fallypride (Morris and Yoder 2007). However, the overall effect of dAMPH on [ 18 F]fallypride binding was statistically significant, especially in striatum (see Supplementary Figure 2) and has been shown to be sensitive enough to detect associations with other individual differences such as subjective responses to dAMPH (Smith et al 2016a), effort-based decision making (Treadway et al 2012), and the effects of dAMPH on task switching (Samanez-Larkin et al 2013).…”

“…All female participants were either postmenopausal (Dataset 2: n=10), on hormonal birth control (Dataset 1: n=11; Dataset 2: n=6 Young Adults, 4 on birth control pill, 2 on Mirena IUD; n=1 Middle-aged Adult using birth control as hormone replacement therapy) or naturally cycling (Dataset 1: n=7; Dataset 2: n=4 Young Adults), in which case they completed both PET scans within the first 10 days of their menstrual cycle. Dataset 1 consisted of previously published dopamine release data (Buckholtz et al 2010;Samanez-Larkin et al 2013;Smith et al 2016a) from 18 females (age=22.9±3.0) and 16 males (age=21.8±3.2). Dataset 1 scan order was fixed as 1) Placebo, 2) dAMPH, with participants blind to drug administration order.…”

“…In Dataset 1, females had lower Drug Effects Questionnaire (Morean et al 2013) ratings (max FEEL, LIKE, HIGH, and WANT MORE dAMPH-placebo from one of 5 timepoints from 60 minutes to 345 minutes post drug) than males (all Ts<−2.28, ps<0.03; see Supplementary Table 3). To rule out the possibility that subjective effect differences by sex in Dataset 1 obscured our ability to detect Sex × Drug effects on %ΔBP ND , we reran the flexible factorial analysis in SPM8 controlling for WANT MORE max rating, given it was associated with %ΔBP ND in this dataset previously (Smith et al 2016a). We still observed no significant clusters displaying a Sex × Drug effect on BP ND in this voxelwise analysis.…”

Partial-volume correction increases estimated dopamine D2-like receptor binding potential and reduces adult age differences

“…Acquisition times for the dynamic PET scans have been reported previously. 23 After decay correction and attenuation correction, PET scan frames were corrected for motion using SPM8 24 with the 20th dynamic image frame of the first series serving as the reference image. The realigned PET frames were then merged and re-associated with their acquisition timing info in PMOD’s PVIEW module to create a single 4D file for use in PMOD’s PNEURO tool for further analysis (see below).…”