PET Measures of Endogenous Opioid Neurotransmission Predict Impulsiveness Traits in Humans

doi:10.1001/archgenpsychiatry.2009.134

Arch Gen Psychiatry. Author manuscript; available in PMC 2011 May 2.

Published in final edited form as:

Arch Gen Psychiatry. 2009 October; 66(10): 1124–1134.

doi: 10.1001/archgenpsychiatry.2009.134

PMCID: PMC3085183

NIHMSID: NIHMS288445

PET Measures of Endogenous Opioid Neurotransmission Predict Impulsiveness Traits in Humans

Tiffany M. Love, BS, Christian S. Stohler, DMD, and Jon-Kar Zubieta, MD, PhD

Departments of Psychiatry and Radiology and the Molecular and Behavioral Neuroscience Institute (Dr. Zubieta, Ms. Love), University of Michigan, Ann Arbor. From the School of Dentistry (Dr. Stohler), University of Maryland, Baltimore

Corresponding author and reprints: Jon-Kar Zubieta, MD, PhD, Molecular and Behavioral Neuroscience Institute, 205 Zina Pitcher Pl, Ann Arbor, MI 48109-0720 (Email: zubieta/at/umich.edu).

The publisher's final edited version of this article is available at Arch Gen Psychiatry

See other articles in PMC that cite the published article.

Abstract

Objective

The endogenous opioid system and μ-opioid receptors are known to interface environmental events, both positive (e.g., relevant emotional stimuli) and negative (e.g., stressors) with pertinent behavioral responses, regulating motivated behavior. Here we examined the degree to which trait impulsiveness, the tendency to act on cravings and urges rather than delaying gratification, is predicted by either baseline μ-opioid receptor availability or the response of this system to a standardized, experientially-matched stressor.

Method

Nineteen (19) young healthy male volunteers completed a personality questionnaire (NEO PI-R) and positron emission tomography scans with the μ-opioid receptor selective radiotracer [¹¹C]carfentanil. Measures of receptor concentrations were obtained at rest and during the receipt of an experimentally maintained pain stressor of matched intensity between subjects. Baseline receptor levels and stress-induced activation of μ-opioid neurotransmission were compared between subjects scoring above and below the population median of the NEO impulsiveness subscale and the orthogonal dimension, deliberation, expected to interact with it.

Results

High impulsiveness and low deliberation scores were associated with significantly higher regional μ-opioid receptor concentrations and greater stress-induced endogenous opioid system activation. Effects were obtained in regions involved in motivated behavior and the effects of drugs of abuse: prefrontal and orbitofrontal cortex, anterior cingulate, thalamus, nucleus accumbens and basolateral amygdala. Mu-opioid receptor availability, and the magnitude of stress-induced endogenous opioid activation in these regions accounted for 21 to 49% of the variance in these personality traits.

Conclusions

Our data demonstrate that individual differences in the function of the endogenous μ-opioid system predicts personality traits that confer vulnerability or resiliency for risky behaviors, such as the predisposition to develop substance use disorders. These personality traits are also implicated in psychopathological states (e.g., personality disorders), where variations in the function of this neurotransmitter system may play a role as well.

Introduction

There is substantial interest in the mechanistic understanding of traits that may predispose individuals to the development of specific behaviors or psychopathologies.

Trait impulsivity has received substantial attention because of its association with risky behaviors (e.g., experimentation with drugs, sex, problem gambling reckless driving), personality disorders, or even the mortality associated with the mood disorders. Impulsivity, though frequently referred to as a single trait, is better conceptualized as heterogeneous characteristic consisting of multiple dimensions that include sensation seeking, lack of planning, lack of persistence and urgency^{1, 2}. The non-planning dimension in particular appears to be more strongly associated with negative risk taking (i.e. binge eating, problem gambling,²). The same holds true for the urgency dimension which predicts problem behaviors (problem gambling and drinking) whereas factors such as sensation seeking are perhaps more related to risk taking in general^{2, 3}.

Impulsivity as it refers to pathological behavior has been well studied in current and former substance users. In humans, opiate addicts are more impulsive than non-addicts as measured by an increase in the discounting of delayed rewards (i.e. the devaluation of rewards as a function of time)⁴ and by a reduction in reflection (i.e. the tendency to use information when making a decision)⁵. In animals, it has been shown that in rodents a preference for immediate reward over larger, delayed reward predicted the development of nicotine self-administration and maintenance of use⁶, suggesting that this is a trait that predisposes to drug dependence. This form of impulsive choice in rats has also been demonstrated to predict cocaine self-administration⁷. Other clinical populations are also characterized by or associated with impulsive behavior such as Attention-Deficit Hyperactivity Disorder (ADHD)⁸, Borderline Personality Disorder⁹, eating disorders¹⁰ and pathological gambling¹¹. Whether impulsivity represents exclusively a predisposing factor or is at least partially the result of prior exposure to drugs or ongoing disease is a matter of current debate.

Impulsive characteristics probably do not affect behavior in isolation but are also likely to interact with other factors such as stress. Stressors have a negative impact on drug initiation, maintenance, craving and relapse¹². High impulsive gamblers also show neuroendocrine stress axis and cardiovascular responses to gambling situations relative to their low impulsive counterparts¹³. In addition, stressors, particularly when combined with substance abuse, are thought to be modulated by individual impulsivity traits to increase the risk of completed suicides¹⁴, particularly in younger individuals¹⁵.

While it is increasingly clear that impulsivity and stress responses confer vulnerability to substance abuse and other risky behaviors, the neurobiological processes underlying these effects are still poorly understood, particularly in humans. DA neurotransmission appears to be one of the mechanisms involved. Utilizing an animal model of impulsivity that examines anticipatory responses to a food reward as proxy, Dalley and colleagues observed that rats demonstrating greater impulsivity prior to drug exposure exhibited lower dopamine DA D2/3 receptor concentrations in the nucleus accumbens, increased escalation and maintenance of drug self-administration relative to their lower impulsivity counterparts¹⁶. Though DA function in the ventral basal ganglia is thought to have an important role^17–19 it is unlikely to take place in isolation. The nucleus accumbens lies at the interface of sensorimotor and limbic systems, and through its connections with the ventral pallidum and the amygdala, forms part of a circuit involved in the integration of cognitive, affective and motor responses^{20, 21}. This pathway and interconnected regions (e.g., insular and prefrontal cortex, medial thalamus) are heavily modulated by the endogenous opioid system and μ-opioid receptors. For example, this neurotransmitter system is recruited when drug-induced DA release takes place in the context of environmental novelty and stressors^22–26. Further, the motivated pursuit and positive behavioral responses to rewards^{27, 28} are enhanced by the selective administration of μ-opioid receptor agonists in the nucleus accumbens and ventral pallidum, nuclei that are central to the regulation of motivated behavior.

The present report examined two orthogonal behavioral traits, impulsiveness (IMP) and deliberation (DLB), as defined by the NEO Personality Inventory Revised (NEO PI-R)²⁹ as a function of in vivo measures of μ-opioid receptor neurotransmission in humans. As defined by the NEO PI-R, the IMP dimension refers to the tendency to act without careful consideration for consequences of delayed gratification, and maps on to urgency, which appears related to problem behaviors such as drug use². DLB, which corresponds to the lack of planning dimension, is thought to act as a moderating, opposing trait³⁰.

We utilized positron emission tomography (PET) and the μ-opioid selective radiotracer [¹¹C]carfentanil at rest and during the experience of a physical and emotional stressor, moderate levels of sustained pain. Under these experimental conditions, reductions in the availability of μ-opioid receptors during the stress challenge reflect the activation of endogenous opioid neurotransmission and μ-opioid receptors³¹. It was hypothesized that individual levels of IMP and DBL would be positively and negatively associated, respectively, with the functional response of the μ-opioid system during the stressor. Furthermore, that these effects would take place in motivational circuits modulated by this neurotransmitter system, namely the rostral anterior cingulate and adjacent medial prefrontal cortex, nucleus accumbens/ventral pallidum, amygdala and medial thalamus.

Materials and Methods

Subjects

Nineteen (19) healthy right-handed, non-smoking men (age range 20–30 years; mean ± SD, 23 ± 3 years) were recruited via advertisement. In addition to completing physical and neurological examinations, subjects were screened using the Structured Clinical Interview for DSM-IV (non-patient version, SCID-NP). Subjects had no current or past history of medical, neurological, or psychiatric illnesses, including substance abuse or dependence and alcohol intake less than 5 drinks/week. Participants reported no current or recent (within 6 months) history of exposure to centrally active prescription or illicit drugs and were asked to restrain from any alcohol intake for 48 hours prior to scanning. Urine drug screens were performed immediately prior to imaging. Subjects reported no family history of psychiatric disease in first-degree relatives. The sample was restricted to males due to the known sex differences in the regional concentration of μ-opioid receptors³², and in the activity of this neurotransmitter system in response to stress³³, an effect that is influenced by circulating gonadal steroids³⁴. Furthermore, a link between impulsivity and substance use disorders has been shown most conclusively in males (see Discussion).

Protocols were approved by the Investigational Review Boards of the Universities of Michigan and Maryland and the Radioactive Drug Research Committee at the University of Michigan. Written informed consent was obtained in all subjects.

Personality Inventories

Subjects were administered the NEO Personality Inventory Revised (NEO PI-R)²⁹. The facets “Impulsiveness” (IMP), defined as “a lack of control over cravings or desires”, and “Deliberation” (DLB), or the “tendency to think carefully before acting”, were utilized as the primary scales of interest. These facets have been previously demonstrated to reflect the dimensions of impulsivity that have been associated with negative risk taking^{2, 3}. Individuals endorsing greater behavioral under-control or lack of reflection would display higher IMP and lower DLB scores. The median scores in population samples of comparable age were utilized to separate the study sample into high and low scoring groups (population data, IMP, mean ± SD, 15 ± 4; DLB, mean ± SD, 18 ± 4²⁹. Study sample data, IMP, mean ± SD, 15 ± 3; DLB, mean ± SD, 18 ± 3 (Median = 15, High, n = 9 subjects, Low, n = 10; DLB: median = 18, High, n = 9, Low, n = 10).

Stress Challenge

We employed a physical and emotional stressor, moderate levels of sustained pain of experientially adjusted intensity, to activate endogenous opioid-μ-opioid mediated neurotransmission, as previously described^{31, 35}. In short, a steady state of moderate muscle pain was maintained 45–65 min after the radiotracer administration by a computer-controlled delivery system through the infusion of medication-grade hypertonic saline (5%) into the left masseter muscle. In this model of sustained deep somatic pain, the intensity of the painful stimulus is standardized across subjects, as described in detail previously^{36, 37}. Pain intensity was rated every 15 sec from 0 (no pain) to 100 (most intense pain imaginable). During the baseline control condition, no infusions took place and the subject was instructed to lie quietly in the scanner. The pain intensity ratings obtained every 15 sec were recorded in the computer controller and averaged for statistical analyses.

Integrative measures of the pain experience (sensory and pain affect components) were obtained using the McGill pain questionnaire (MPQ), administered upon completion of the challenge³⁸. The Positive and Negative Affectivity Scale (PANAS)³⁹, assessing the internal affective state of the volunteers, was obtained before and after the challenge. The infusion volume required for pain maintenance was also recorded and provided a measure of sustained pain sensitivity for the individual subject.

Scanning Protocols

Two PET scans per subject were acquired with a Siemens HR⁺ scanner (Knoxville, KN) in 3-D mode (reconstructed FWHM resolution (5.5 mm in-plane and 5.0 mm axially), one at baseline and another using the stress challenge. Radiotracer synthesis and image acquisition, co-registration and reconstruction protocols were identical to those used in previous publications^{31, 33, 35}.

The total activity of [¹¹C]carfentanil administered to each subject in each scan was 14.5 ± 2.7 mCi (535.0 ± 100.9 MBq), with an average mass injected of 0.02 ± 0.01 μg/kg, ensuring that the compound was administered in tracer quantities, i.e., sub-pharmacological doses. Fifty (50) percent of the [¹¹C]carfentanil dose was administered as a bolus with the remainder delivered as a continuous infusion by a computer-controlled automated pump to more rapidly achieve steady-state tracer levels.

Dynamic image data for each of the receptor scans were transformed, on a voxel-by-voxel basis, into two sets of parametric maps, coregistered to each other: (a) a tracer transport measure (K₁ ratio), proportional to regional cerebral blood flow, and (b) a receptor-related measure, distribution volume ratio at equilibrium (DVReq). To avoid the need for arterial blood sampling, these parametric images were calculated using a modified Logan graphical analysis⁴⁰, using the occipital cortex (an area devoid of μ-opioid receptors) as the reference region. The Logan plot became linear by 5–7 minutes after the start of radiotracer administration, with a slope proportional to the (B_max/K_d)+1 for this receptor site. B_max/K_d is the “receptor related” measure (μ-opioid receptor availability or μ-opioid receptor “binding potential”, BP_ND) (B_max = receptor concentration; K_d = receptor affinity for the radiotracer).

MRI scans were acquired on a 1.5 Tesla scanner (Signa, General Electric, Milwaukee, WI) for anatomical localization and coregistration to standardized stereotactic coordinates. Acquisition sequences were axial spoiled gradient-recalled (SPGR) MR [echo time (TE)= 5.5; repetition time (TR)= 14; inversion time (TI)= 300; flip angle= 20°; number of excitations (NEX)= 1; 124 contiguous images; 1.5 mm-thick; 24 cm field-of-view; image matrix= 256 × 256 pixels, pixel size= 0.94 mm). T1-weighted MR and PET images of each subject were then co-registered to each other using a mutual information algorithm as previously described^{31, 35}.

Image Analyses

Differences between groups (high IMP / low IMP; low DLB / high DLB, two tail, unpaired t tests) were mapped into stereotactic space using z maps of statistical significance with a modified version of SPM99 (Welcome Department of Cognitive Neurology, University College, London) and Matlab software (MathWorks, Natick, MA), using a general linear model. No global normalization was applied to the data, and therefore the calculations presented are based on absolute B_max/K_d estimates. Only regions with specific μ-opioid receptor binding were included in the analyses (voxels with BP_ND values > 0.2 as calculated with SPM). A priori hypothesized regions were deemed significant at p < 0.0001 uncorrected for multiple comparisons. For other regions, significant differences were detected using a statistical threshold that controls for a Type-I error rate at p = 0.05 for multiple comparisons⁴¹. Numerical values for each region were obtained by averaging the values of voxels contained in each significant cluster, up to a p = 0.001. These data were extracted for quantification of regional changes in BP, graphing, determination of correlation coefficients (Pearson correlations at p < 0.05), rule out the presence of outliers, and further statistical analyses with SPSS for Macintosh 11.0.3 (SPSS Inc., Chicago, IL).

Results

Psychophysical Measures

The use of the adaptive, experientially-adjusted stimulus delivery system employed, produced comparable perceptions of the pain stressor among participants by individually titrating the rate of infusion of the algesic substance. No significant group differences were obtained in psychophysical measures of pain or affective state during the stress challenge (high vs. low IMP, high vs. low DLB) (Table 1). As would be expected, IMP and DLB scores were negatively correlated (r = −0.55, p = 0.015).

Table 1

Psychophysical Measures

Baseline μ-Opioid Receptor BP

Impulsiveness

Significant differences in baseline μ-opioid receptor BP_ND were observed between high and low IMP groups. Specifically, greater regional μ-opioid receptor BP_ND was observed in the high, compared to low IMP subjects, in the right anterior cingulate and adjacent medial frontal cortex, right ventral basal ganglia (nucleus accumbens, extending into ventral pallidum), and the basolateral area of the right amygdala (Table 2, Figure 1). No effects were obtained in the opposite direction.

Table 2

Differences in Baseline Regional μ-Opioid Receptor BP

Figure 1

Association between Impulsiveness and Deliberation scores and baseline μ-opioid receptor availability.

Significant positive correlations were obtained between μ-opioid receptor BP_ND and IMP scores within all these clusters (right dorsal anterior cingulate, r = 0.59, p < 0.01; right ventral basal ganglia, r = 0.50, p = 0.03; right amygdala, r = 0.49, p = 0.03).

Deliberation

Subjects with high DLB scores showed significantly lower baseline regional μ-opioid receptor BP_ND compared to the low DLB group in the right dorsolateral prefrontal cortex, right dorsal anterior cingulate and medial frontal gyrus, left ventral basal ganglia, right thalamus extending inferiorly into hypothalamus and in the right basolateral amygdala (Table 2, Figure 1). No effects were observed in the opposite direction.

Significant negative correlations between μ-opioid receptor BP_ND and DLB scores were noted within the right prefrontal cortex (r = − 0.65, p = 0.003), right anterior cingulate (two peaks, x,,y,,z, coordinates in mm, 16, 10, 39, r = − 0.56, p = 0.01; x, y, z, 8, 14, 26, r = − 0.46, p < 0.05), and right amygdala (r = − 0.54, p = 0.02).

Stress – Induced Activation of μ-Opioid Neurotransmission

Impulsiveness

Subjects with higher IMP scores demonstrated significantly greater stress-induced activation of μ-opioid mediated neurotransmission, compared to subjects in the low IMP group, in the left orbitofrontal cortex, right dorsal anterior cingulate, ventral basal ganglia, bilaterally, extending into the hypothalamus, left anterior thalamus and basolateral amygdala bilaterally. (Table 3, Figure 2). There were no regions where the high IMP group showed significantly lower stress-induced changes in μ-opioid receptor BP_ND relative to the low IMP group.

Table 3

Differences in Stress-Induced Changes in Regional μ-Opioid Receptor BP

Figure 2

Association between Impulsiveness and Deliberation scores and stress-induced activation of μ-opioid receptor mediated neurotransmission.

Significant positive correlations between μ-opioid system activation (baseline BP_ND – pain BP_ND) and IMP scores were noted in the left orbitofrontal cortex (r = 0.63, p < 0.005), right ventral basal ganglia (r = 0.49, p = 0.03), left anterior thalamus (r = 0.61, p = 0.006), and right amygdala (r = 0.50, p < 0.03).

Deliberation

Significant differences in stress-induced activation of endogenous opioid neurotransmission were also detected between the high DLB and low DLB groups. Opposite to the high IMP group and in a direction similar to that observed for baseline binding measures, the high DLB group showed lower stress-induced activation of the endogenous opioid system compared to the low DLB group in a number of brain regions. These included the left dorsolateral prefrontal cortex, right anterior cingulate/medial frontal cortex, orbitofrontal cortex bilaterally, ventral basal ganglia, bilaterally, with extension into the anterior hypothalamus, and basolateral amygdala bilaterally. No effects were obtained in the opposite direction (Table 3, Figure 2).

Significant negative correlations between μ-opioid system activation and DLB scores were observed within the left dorsolateral prefrontal cortex (r = − 0.69, p = 0.001), right anterior cingulate (r = − 0.61, p = 0.005), right and left ventral basal ganglia (r = − 0.54, p < 0.02 and r = − 0.60, p < 0.01, respectively), and right amygdala (r = − 0.70, p = 0.001). The left amygdala cluster followed a similar pattern at trend levels of correlation (r = − 0.41, p = 0.08).

Interactions Among Measures: Conjunction Analyses

The above data suggested the presence of some, but not complete regional overlap for the effects of the related traits IMP and DLB, with neurochemical findings in opposite directions, as would be expected for opposing traits. In an additional analysis, we sought to determine how the individual combination of these two behavioral traits segregated at the levels of anatomical and neurochemical substrates (μ-opioid receptor availability and neurotransmitter responses to stress). Individuals were divided into “behavioral risk” groups based on their IMP and DLB classifications, resulting in three groups with relatively high (High IMP/Low DLB, n=7), low (Low IMP/High DLB, n=7) or intermediate (High IMP/High DLB, Low IMP/Low DLB, n=5) behavioral trait vulnerability. Intermediate groups were not separated because of the small sample sizes in those cells. Then, for both the baseline and activation conditions, we identified brain areas of coincidence, where BP_ND and stress-induced release were greater in both the high IMP and low DLB groups. For this purpose, the ImCalc function within SPM was utilized to generate a “mask” that contained only those voxels that were significantly different above a p =0.007 (T=1.99) in both of the contrasts (Contrast1 = High vs Low IMP, Contrast 2 = Low vs High IMP; Formula: [(Contrast 1 T score > 1.99)*(Contrast 2 T score > 1.99)]. The resulting area of coincidence contained voxels that were independently significant in each and both of the contrasts, whose joint probability is given by multiplying the probabilities for each contrast: 0.007 × 0.007 = p ≤ 0.000049 (e.g. ⁴²). Measurement values for the regions identified were then extracted for quantification of regional changes in BP_ND, graphing, and statistical analyses.

Baseline

Three regions showed significant overlap among the two traits: right anterior cingulate, right ventral pallidum, and right amygdala. The baseline BP_ND for each of the regions analyzed increased in a stepwise progression from the group with the lowest vulnerability traits (Low IMP/High DLB) to the highest (High IMP/Low DLB) (Figure 3, Table 4). This effect was tested statistically with ANOVA, which showed significant effects of “risk” classification for each of the regions ([right anterior cingulate (F(2,16) = 8.009, p = 0.004), right nucleus accumbens/ventral pallidum (F(2,16) = 8.157, p=0.004), right amygdala (F(2,16) = 5.280, p = 0.017)]). Post-hoc tests (Tukey HSD) are shown in Table 4. Of note, both intermediate groups High IMP/High DLB and Low IMP/Low DLB showed similar results for these regions (data not shown).

Figure 3

Conjunction analysis of impulsiveness and deliberation effects on μ-opioid receptor BP and stress-induced endogenous opioid system activity.

Table 4

Conjunction Analyses

Stress –Induced Activation of μ-Opioid Neurotransmission

Five regions showed significant activation overlap among traits: right anterior cingulate, right and left nucleus accumbens/ventral pallidum, and right and left amygdala. Again, we observed a stepwise progression in stress-induced endogenous opioid system activation, with the smallest change in the group with the fewest vulnerable behavioral traits (Low IMP/High DLB) and the greatest from the group with the most (High IMP/Low DLB) (Figure 3, Table 4). A significant main effect of group on stress-induced activation of μ-opioid neurotransmission was present for each of the regions ([right anterior cingulate (F(2,16) = 10.53, p=0.001), right ventral pallidum (F(2,16) = 40.91, p<0.0001), left ventral pallidum (F(2,16) = 5.10, p=0.019), right amygdala (F(2,16) = 23.54, p <0.001), left amygdala (F(2,16) = 5.05, p=0.020)]). Post-hoc tests results are shown in Table 4. As with the baseline data, intermediate groups showed similar results for the overlapping regions (data not shown).

Discussion

The present study demonstrates that impulsiveness and deliberation are highly predicted by measures of endogenous opioid function in limbic regions. The personality facets studied here refer to the tendency to act rashly and without forethought, and have been associated with various psychopathologies and risky phenotypes (e.g., drug consumption, pathological gambling, personality disorders)^{2, 3, 9, 11}. Our major findings are: First, we find that individuals displaying these risky phenotypes (e.g. high IMP or low DBL) have higher μ-opioid receptor BP_ND at rest within regions implicated in decision making, reward seeking and emotional responsivity. This higher BP_ND reflects a greater availability of μ-opioid receptors in a high affinity state (e.g., binding to an agonist radiotracer at low, tracer concentrations)⁴³. Second, following a pain stress challenge we find larger reductions in BP_ND from baseline in individuals displaying high IMP/low DLB in overlapping regions. These reductions reflect processes related to the release of endogenous opioid interacting with μ-opioid receptors, so these receptors are no longer available for binding to the radioligand^{43, 44}. Third, we demonstrate a cumulative effect of personality traits on in vivo measures of μ-opioid neurotransmission. We found that individuals exhibiting extreme traits (high IMP/low DLB and low IMP/high DLB) display the greatest and smallest, respectively, baseline μ-opioid receptor availability and endogenous opioid system responses to the pain stressor employed.

Personality traits, like impulsiveness, likely manifest as a result of a variety of factors, both biological and genetic. Converging lines of evidence point to the opioid system as one candidate system involved in the expression of the non-planning dimension of impulsiveness. Previous research on a measure related to the non-planning dimension of impulsiveness, delayed discounting, which refers to the devaluation of rewards as a function of time, has indicated prominent roles for several neurotransmitters: serotonin⁴⁵, dopamine⁴⁵ and based upon the present results, opioids. Manipulation of the opioid system affects preferences for immediate rewards; for instance, and in animal models, Kieres and colleagues demonstrated that morphine could increase the rate of delayed discounting among rats, an effect blocked by naloxone⁴⁶. Few human studies have directly addressed this issue, however, multiple studies have shown that several psychiatric groups show steeper discounting of delayed rewards such as pathological gamblers⁴⁷ and drug addicts (e.g. to opiates⁴). In addition, opiate addicts show a greater preference to immediate monetary rewards relative to non-addicts⁴, a preference that is potentiated following mild opiate deprivation⁴⁸.

In the present work we show that individuals displaying risky personality traits (high IMP, low DLB) showed significantly greater regional μ-opioid receptor availability at baseline and stress-induced regional μ-opioid system activation when compared to individuals endorsing low IMP, high DLB. These effects were observed in multiple brain regions including the orbitofrontal, medial prefrontal and cingulate cortex, nucleus accumbens/ventral pallidum and amygdala. Individually, these regions are known to be involved in impulsive choice, reward seeking, and cognitive-emotional integration and are heavily modulated by μ-opioid receptors^49–51. Many of these regions, particularly the prefrontal cortex and nucleus accumbens have been implicated in disorders characterized by or associated with impulsive behavior such as ADHD⁵², substance abuse disorders⁵³, and pathological gambling⁵⁴. Manipulation of nucleus accumbens activity can directly influence impulsive behavior, i.e, stimulation of the nucleus accumbens core has been shown to decrease impulsive choice⁵⁵, whereas lesions increase impulsive choice⁵⁶. Similar roles have been ascribed to the prefrontal cortex, orbitofrontal and amygdala, thought to contribute to decision making by the cognitive and emotional evaluation of future consequences^{57, 58}. Collectively, these regions are thought to be involved in the pursuit and receipt of natural rewards, decision-making and, more generally, motivated behavior^{25, 59–65}. Neurobiologically, this regulation of motivated behavior is thought to take place as a result of their extensive reciprocal connections, well-described between the nucleus accumbens, ventral pallidum, mediodorsal nucleus of the thalamus, prefrontal cortex and amygdala^{66, 67}.

We also observed greater stress-induced activation of this neurotransmitter system in subjects scoring above the population average of NEO IMP scores, compared with subjects scoring below, in regions at least partially overlapping with those where baseline differences were observed. Opposite effects (lower stress-induced opioid system activity in high scoring subjects) were observed for the orthogonal domain, DLB. These data then supports the contention that there are interactions between neurobiological processes related to stress responsiveness and impulsivity. Physiological stress responses seem greater in more impulsive individuals even among risky populations (e.g., pathological gamblers¹³) and therefore point to factors that may contribute to interindividual variations in risky behavior in various pathological states. Outbred rats exposed to the mild stress of a novel environment may show high (HR) or low (LR) rates of exploratory locomotion, and HR rats learned to self-administer psychostimulants faster than LRs^68–71. It has been proposed that activation of DA neurotransmission and stress responses during risky behavior are the critical variable underlying the reinforcement of this behavior in the more impulsive individuals⁷², an effect that may be mediated by the increase in corticosterone induced by the stressor^73–76. Relevant to the results presented here, HR rats, more prone to acquire drug-self administration also show increased nucleus accumbens proenkephalin gene expression⁷⁷.

A conjunction analysis more formally determined the overlap in the processes and brain regions where IMP and DLB effects were obtained. It demonstrated a cumulative effect of personality risk factors on measures of μ-opioid neurotransmission. Extreme traits (high IMP/low DLB, low IMP/high DLB) demonstrated greatest and smallest, respectively, endogenous opioid system responses to a standardized stressor and μ-opioid receptor availability at baseline. “Intermediate”, compounded traits (high IMP/high DLB, low IMP/low DLB) showed intermediate effects for both measures. This is consistent with the observation that the accumulation of risky traits is associated with a greater probability of problem behaviors and substance use problems⁷⁸. The coalescence of IMP and DLB effects were observed in the dorsal anterior cingulate, nucleus accumbens/ventral pallidum and amygdala, centrally implicated in decision-making and motivated behavior, as noted above^{20, 21, 79}.

Regional μ-opioid receptor availability and μ-opioid system activation during the stressor accounted for 24 to 40% of the variance in IMP scores, and 17 to 49% of the variance in DBL scores. In contrast, no significant relationships have been reported between NEO impulsiveness and dopamine D2/3 receptor binding in the basal ganglia as measured with [¹¹C]raclopride⁸⁰ or with dopamine turnover as measured with [¹⁸F]fluorodopa⁸¹. Amphetamine-induced dopamine release in the ventral basal ganglia accounted for 9–20% of the variance in NEO impulsiveness scores in a healthy sample similar to the one studied in the present report⁸⁰.

Because the study sample was restricted to males to reduce experimental complexity, additional questions remain that will need to be addressed in subsequent work. Effects of gender, gonadal steroids and age by gender interactions have been described for μ-opioid receptors and stress-induced μ-opioid system activation^32–34. These effects may or may not be related to IMP and DBL traits and will require specific studies addressing their effects. From a different perspective, impulsive behavior has been suggested to be a result of prefrontal cortex dysfunction. For instance, Bechara and others have described problems with decision-making, specifically insensitivity to future consequences, following damage to the ventromedial prefrontal cortex^{57, 58}. The relationship between ventral prefrontal cortex function and endogenous opioid system activity measures are presently unexplored.

It is also unlikely that complex personality domains are solely related to a single neurotransmitter system. Indeed, DA D2/3 receptor concentration within the ventral basal ganglia has been demonstrated to predict impulsive anticipatory responses to food reward in an animal model of impulsivity¹⁶. The involvement of DA mechanisms, however, is not exclusionary of effects by other systems, such as the endogenous opioid. Dopamine-opioid interactions have been described in the striatopallidal pathway and interconnected regions, where acute and chronic DA receptor stimulation induce opposite effects on the functional capacity of the μ-opioid system in animal models^82–87 and in humans^{35, 88}. These and other, not yet described neurotransmitter systems may underlie the psychophysical differences, such as heart rate and pupilary responses, classically noted between otherwise healthy shy and uninhibited children⁸⁹.

The present study provides the first evidence in humans that IMP and DBL, behavioral facets relevant to motivated behavior, the pursuit of reward and risk taking, including the development of substance use disorders, are related to the individual function of the endogenous opioid system. Baseline measures of μ-opioid receptor availability and the capacity to activate this neurotransmitter system in limbic and paralimbic regions in response to stress accounted for up to half of the variance in trait IMP and DBL scores in a healthy sample.

Acknowledgments

Grant Support: Supported by the National Institute of Drug Abuse grant R01 DA 016423

Footnotes

Disclosures: No known potential conflicts.

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