Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB.

BACKGROUND: One of the major mechanisms for terminating the actions of the endocannabinoid anandamide is hydrolysis by fatty acid amide hydrolase (FAAH), and inhibitors of the enzyme were suggested as potential treatment for human cannabis dependence. However, the status of brain FAAH in cannabis use disorder is unknown. METHODS: Brain FAAH binding was measured with positron emission tomography and [11C]CURB in 22 healthy control subjects and ten chronic cannabis users during early abstinence. The FAAH genetic polymorphism (rs324420) and blood, urine, and hair levels of cannabinoids and metabolites were determined. RESULTS: In cannabis users, FAAH binding was significantly lower by 14%-20% across the brain regions examined than in matched control subjects (overall Cohen's d = 0.96). Lower binding was negatively correlated with cannabinoid concentrations in blood and urine and was associated with higher trait impulsiveness. CONCLUSIONS: Lower FAAH binding levels in the brain may be a consequence of chronic and recent cannabis exposure and could contribute to cannabis withdrawal. This effect should be considered in the development of novel treatment strategies for cannabis use disorder that target FAAH and endocannabinoids. Further studies are needed to examine possible changes in FAAH binding during prolonged cannabis abstinence and whether lower FAAH binding predates drug use.

Emotion dysregulation and amygdala dopamine D2-type receptor availability in methamphetamine users.

BACKGROUND: Individuals who use methamphetamine chronically exhibit emotional and dopaminergic neurochemical deficits. Although the amygdala has an important role in emotion processing and receives dopaminergic innervation, little is known about how dopamine transmission in this region contributes to emotion regulation. This investigation aimed to evaluate emotion regulation in subjects who met DSM-IV criteria for methamphetamine dependence, and to test for a relationship between self-reports of difficulty in emotion regulation and D2-type dopamine receptor availability in the amygdala. METHOD: Ninety-four methamphetamine-using and 102 healthy-control subjects completed the Difficulties in Emotion Regulation Scale (DERS); 33 of those who used methamphetamine completed the Addiction Severity Index (ASI). A subset of 27 methamphetamine-group and 20 control-group subjects completed positron emission tomography with [(18)F]fallypride to assay amygdala D2-type dopamine receptor availability, measured as binding potential (BPND). RESULTS: The methamphetamine group scored higher than the control group on the DERS total score (p<0.001), with DERS total score positively correlated with the Drug Composite Score on the ASI (p=0.02) in the methamphetamine group. The DERS total score was positively correlated with amygdala BPND in both groups and the combined group of participants (combined: r=0.331, p=0.02), and the groups did not differ in this relationship. CONCLUSION: These findings highlight problems with emotion regulation linked to methamphetamine use, possibly contributing to personal and interpersonal behavioral problems. They also suggest that D2-type dopamine receptors in the amygdala contribute to emotion regulation in both healthy and methamphetamine-using subjects.

D3 dopamine receptor-preferring [11C]PHNO PET imaging in Parkinson patients with dyskinesia.

OBJECTIVE: To investigate whether levodopa-induced dyskinesias (LID) are associated with D3 overexpression in levodopa-treated humans with Parkinson disease (PD). METHODS: In this case-control study, we used PET with the D3-preferring radioligand [(11)C]-(+)-PHNO to estimate D2/3 receptor binding in patients with levodopa-treated PD with LID (n = 12) and without LID (n = 12), and healthy control subjects matched for age, sex, education, and mental status (n = 18). RESULTS: Compared to nondyskinetic patients, those with LID showed heightened [(11)C]-(+)-PHNO binding in the D3-rich globus pallidus. Both PD groups also showed higher binding than controls in the sensorimotor division of the striatum. In contrast, D2/3 binding in the ventral striatum was lower in patients with LID than without, possibly reflecting higher dopamine levels. CONCLUSIONS: Dopaminergic abnormalities contributing to LID may include elevated D2/3 binding in globus pallidus, perhaps reflecting D3 receptor upregulation. The findings support therapeutic strategies that target and diminish activity at D3 to prevent LID.

Relationship of Alexithymia Ratings to Dopamine D2-type Receptors in Anterior Cingulate and Insula of Healthy Control Subjects but Not Methamphetamine-Dependent Individuals.

BACKGROUND: Individuals with substance-use disorders exhibit emotional problems, including deficits in emotion recognition and processing, and this class of disorders also has been linked to deficits in dopaminergic markers in the brain. Because associations between these phenomena have not been explored, we compared a group of recently abstinent methamphetamine-dependent individuals (n=23) with a healthy-control group (n=17) on dopamine D2-type receptor availability, measured using positron emission tomography with [(18)F]fallypride. METHODS: The anterior cingulate and anterior insular cortices were selected as the brain regions of interest, because they receive dopaminergic innervation and are thought to be involved in emotion awareness and processing. The Toronto Alexithymia Scale, which includes items that assess difficulty in identifying and describing feelings as well as externally oriented thinking, was administered, and the scores were tested for association with D2-type receptor availability. RESULTS: Relative to controls, methamphetamine-dependent individuals showed higher alexithymia scores, reporting difficulty in identifying feelings. The groups did not differ in D2-type receptor availability in the anterior cingulate or anterior insular cortices, but a significant interaction between group and D2-type receptor availability in both regions, on self-report score, reflected significant positive correlations in the control group (higher receptor availability linked to higher alexithymia) but nonsignificant, negative correlations (lower receptor availability linked to higher alexithymia) in methamphetamine-dependent subjects. CONCLUSIONS: The results suggest that neurotransmission through D2-type receptors in the anterior cingulate and anterior insular cortices influences capacity of emotion processing in healthy people but that this association is absent in individuals with methamphetamine dependence.

Personality disorder symptomatology is associated with anomalies in striatal and prefrontal morphology.

Personality disorder symptomatology (PD-Sx) can result in personal distress and impaired interpersonal functioning, even in the absence of a clinical diagnosis, and is frequently comorbid with psychiatric disorders such as substance use, mood, and anxiety disorders; however, they often remain untreated, and are not taken into account in clinical studies. To investigate brain morphological correlates of PD-Sx, we measured subcortical volume and shape, and cortical thickness/surface area, based on structural magnetic resonance images. We investigated 37 subjects who reported PD-Sx exceeding DSM-IV Axis-II screening thresholds, and 35 age, sex, and smoking status-matched control subjects. Subjects reporting PD-Sx were then grouped into symptom-based clusters: N = 20 into Cluster B (reporting Antisocial, Borderline, Histrionic, or Narcissistic PD-Sx) and N = 28 into Cluster C (reporting Obsessive-Compulsive, Avoidant, or Dependent PD-Sx); N = 11 subjects reported PD-Sx from both clusters, and none reported Cluster A (Paranoid, Schizoid, or Schizotypal) PD-Sx. Compared to control, Cluster C PD-Sx was associated with greater striatal surface area localized to the caudate tail, smaller ventral striatum volumes, and greater cortical thickness in right prefrontal cortex. Both Cluster B and C PD-Sx groups also showed trends toward greater posterior caudate volumes and orbitofrontal surface area anomalies, but these findings did not survive correction for multiple comparisons. The results point to morphological abnormalities that could contribute to Cluster C PD-Sx. In addition, the observations parallel those in substance use disorders, pointing to the importance of considering PD-Sx when interpreting findings in often-comorbid psychiatric disorders.

[¹¹C]-(+)-PHNO PET imaging of dopamine D(2/3) receptors in Parkinson's disease with impulse control disorders.

Dopamine agonist medications with high affinity for the D3 dopamine receptor are commonly used to treat Parkinson's disease, and have been associated with pathological behaviors categorized under the umbrella of impulse control disorders (ICD). The aim of this study was to investigate whether ICD in Parkinson's patients are associated with greater D3 dopamine receptor availability. We used positron emission tomography (PET) radioligand imaging with the D3 dopamine receptor preferring agonist [¹¹C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) in Parkinson's patients with (n = 11) and without (n = 21) ICD, and age-, sex-, and education-matched healthy control subjects (n = 18). Contrary to hypotheses, [¹¹C]-(+)-PHNO binding in D3 -rich brain areas was not elevated in Parkinson's patients with ICD compared with those without; instead, [¹¹C]-(+)-PHNO binding in ventral striatum was 20% lower (P = 0.011), correlating with two measures of ICD severity (r = -0.8 and -0.9), which may reflect higher dopamine tone in ventral striatum. In dorsal striatum, where [¹¹C]-(+)-PHNO binding is associated with D2 receptor levels, [¹¹C]-(+)-PHNO binding was elevated across patients compared with controls. We conclude that although D3 dopamine receptors have been linked to the occurrence of ICD in Parkinson's patients. Our findings do not support the hypothesis that D3 receptor levels are elevated in Parkinson's patients with ICD. We also did not find ICD-related abnormalities in D2 receptor levels. Our findings argue against the possibility that differences in D2/3 receptor levels can account for the development of ICD in PD; however, we cannot rule out that differences in dopamine levels (particularly in ventral striatum) may be involved.

Measuring cigarette smoking-induced cortical dopamine release: A [¹¹C]FLB-457 PET study.

Striatal dopamine (DA) is thought to have a fundamental role in the reinforcing effects of tobacco smoking and nicotine. Microdialysis studies indicate that nicotine also increases DA in extrastriatal brain areas, but much less is known about its role in addiction. High-affinity D2/3 receptor radiotracers permit the measurement of cortical DA in humans using positron emission tomography (PET). [(11)C]FLB-457 PET scans were conducted in 10 nicotine-dependent daily smokers after overnight abstinence and reinstatement of smoking. Voxel-wise [(11)C]-FLB-457-binding potential (BPND) in the frontal lobe, insula, and limbic regions was estimated in the two conditions. Paired t-tests showed BPND values were reduced following smoking (an indirect index of DA release). The overall peak t was located in the cingulate gyrus, which was part of a larger medial cluster (BPND change -12.1±9.4%) and this survived false discovery rate correction for multiple comparisons. Clusters were also identified in the left anterior cingulate cortex/medial frontal gyrus, bilateral prefrontal cortex (PFC), bilateral amygdala, and the left insula. This is the first demonstration of tobacco smoking-induced cortical DA release in humans; it may be the result of both pharmacological (nicotine) and non-pharmacological factors (tobacco cues). Abstinence increased craving but had minimal cognitive effects, thus limiting correlation analyses. However, given that the cingulate cortex, PFC, insula, and amygdala are thought to have important roles in tobacco craving, cognition, and relapse, these associations warrant investigation in a larger sample. [(11)C]FLB-457 PET imaging may represent a useful tool to investigate individual differences in tobacco addiction severity and treatment response.

Heightened D3 dopamine receptor levels in cocaine dependence and contributions to the addiction behavioral phenotype: a positron emission tomography study with [11C]-+-PHNO.

The dopamine system is a primary treatment target for cocaine dependence (CD), but research on dopaminergic abnormalities (eg, D2 receptor system deficiencies) has so far failed to translate into effective treatment strategies. The D3 receptor system has recently attracted considerable clinical interest, and D3 antagonism is now under investigation as a novel avenue for addiction treatment. The objective here was to evaluate the status and behavioral relevance of the D3 receptor system in CD, using the positron emission tomography (PET) radiotracer [(11)C]-(+)-PHNO. Fifteen CD subjects (many actively using, but all abstinent 7-240 days on scan day) and fifteen matched healthy control (HC) subjects completed two PET scans: one with [(11)C]-(+)-PHNO to assess D3 receptor binding (BPND; calculated regionally using the simplified reference tissue model), and for comparison, a second scan with [(11)C]raclopride to assess D2/3 binding. CD subjects also completed a behavioral battery to characterize the addiction behavioral phenotype. CD subjects showed higher [(11)C]-(+)-PHNO BPND than HC in the substantia nigra, which correlated with behavioral impulsiveness and risky decision making. In contrast, [(11)C]raclopride BPND was lower across the striatum in CD, consistent with previous literature in 2 week abstinence. The data suggest that in contrast to a D2 deficiency, CD individuals may have heightened D3 receptor levels, which could contribute to addiction-relevant traits. D3 upregulation is emerging as a biomarker in preclinical models of addiction, and human PET studies of this receptor system can help guide novel pharmacological strategies for treatment.

Overlapping neural substrates between intentional and incidental down-regulation of negative emotions.

Emotion regulation can be achieved in various ways, but few studies have evaluated the extent to which the neurocognitive substrates of these distinct operations overlap. In the study reported here, functional magnetic resonance imaging (fMRI) was used to measure activity in the amygdala and prefrontal cortex of 10 participants who completed two independent tasks of emotion regulation-reappraisal, measuring intentional emotion regulation, and affect labeling, measuring incidental emotion regulation-with the objective of identifying potential overlap in the neural substrates underlying each task. Analyses focused on a priori regions of interest in the amygdala and inferior frontal gyrus (IFG). For both tasks, fMRI showed decreased amygdala activation during emotion regulation compared with emotion conditions. During reappraisal, this decrease in amygdala activation was accompanied by a proportional decrease in emotional intensity ratings; during affect labeling, the decrease in amygdala activation correlated with self-reported aggression. Importantly, across participants, the magnitude of decrease in amygdala activation during reappraisal correlated with the magnitude of decrease during affect labeling, even though the tasks were administered on separate days, and values indexing amygdala activation during each task were extracted independently of one another. In addition, IFG-amygdala connectivity, assessed via psychophysiological interaction analysis, overlapped between tasks in two regions within the right IFG. The results suggest that the two tasks recruit overlapping regions of prefrontal cortex, resulting in similar reductions in amygdala activation, regardless of the strategy employed. Intentional and incidental forms of emotion regulation, despite their phenomenological differences, may therefore converge on a common neurocognitive pathway.

Neural correlates of affect processing and aggression in methamphetamine dependence.

CONTEXT: Methamphetamine abuse is associated with high rates of aggression but few studies have addressed the contributing neurobiological factors. OBJECTIVE: To quantify aggression, investigate function in the amygdala and prefrontal cortex, and assess relationships between brain function and behavior in methamphetamine-dependent individuals. DESIGN: In a case-control study, aggression and brain activation were compared between methamphetamine-dependent and control participants. SETTING: Participants were recruited from the general community to an academic research center. PARTICIPANTS: Thirty-nine methamphetamine-dependent volunteers (16 women) who were abstinent for 7 to 10 days and 37 drug-free control volunteers (18 women) participated in the study; subsets completed self-report and behavioral measures. Functional magnetic resonance imaging (fMRI) was performed on 25 methamphetamine-dependent and 23 control participants. MAIN OUTCOME MEASURES: We measured self-reported and perpetrated aggression and self-reported alexithymia. Brain activation was assessed using fMRI during visual processing of facial affect (affect matching) and symbolic processing (affect labeling), the latter representing an incidental form of emotion regulation. RESULTS: Methamphetamine-dependent participants self-reported more aggression and alexithymia than control participants and escalated perpetrated aggression more following provocation. Alexithymia scores correlated with measures of aggression. During affect matching, fMRI showed no differences between groups in amygdala activation but found lower activation in methamphetamine-dependent than control participants in the bilateral ventral inferior frontal gyrus. During affect labeling, participants recruited the dorsal inferior frontal gyrus and exhibited decreased amygdala activity, consistent with successful emotion regulation; there was no group difference in this effect. The magnitude of decrease in amygdala activity during affect labeling correlated inversely with self-reported aggression in control participants and perpetrated aggression in all participants. Ventral inferior frontal gyrus activation correlated inversely with alexithymia in control participants. CONCLUSIONS: Contrary to the hypotheses, methamphetamine-dependent individuals may successfully regulate emotions through incidental means (affect labeling). Instead, low ventral inferior frontal gyrus activity may contribute to heightened aggression by limiting emotional insight.

Differences in cortical activity between methamphetamine-dependent and healthy individuals performing a facial affect matching task.

As individuals who abuse methamphetamine (MA) often exhibit socially maladaptive behaviors such as violence and aggression, it is possible that they respond abnormally to social cues. To investigate this issue, we exposed 12 MA-dependent participants (abstinent 5-16 days) and 12 healthy comparison participants to fearful and angry faces while they performed an affect matching task during functional magnetic resonance imaging (fMRI). Although the groups did not differ in task performance, the healthy participants showed more task-related activity than the MA-dependent participants in a set of cortical regions consisting of the ventrolateral prefrontal cortex (VLPFC), temporoparietal junction (TPJ), anterior and posterior temporal cortex, and fusiform gyrus in the right hemisphere, and the cuneus in the left hemisphere. In contrast, the MA-dependent participants showed more task-related activity than the healthy participants in the dorsal anterior cingulate cortex (dACC). As expected, the task elicited activation of the amygdala in both groups; however, contrary to expectation, we found no difference between groups in this activation. Dorsal ACC hyperactivity, along with high self-ratings of hostility and interpersonal sensitivity in the MA-dependent group, suggest a hyper-sensitivity to socially threatening cues in the MA-dependent participants, while lower VLPFC activation could point to a deficit in integrating socio-emotional information and/or regulating this limbic hyperactivity. Additional activation differences in neural circuitry related to social cognition (TPJ, anterior, and posterior temporal cortex) suggest further socio-emotional deficits. Together, the results point to cortical abnormalities that could underlie the socially inappropriate behaviors often shown by individuals who abuse MA.