Positron emission tomography (PET) findings suggesting lower D2-type dopamine receptors and dopamine concentration in brains of stimulant users have prompted speculation that increasing dopamine signaling might help in drug-treatment. However, this strategy needs to consider the possibility, based on animal and postmortem human data, that dopaminergic activity at the related D3 receptor might, in contrast, be elevated, and thereby contribute to drug-taking behavior. We tested the hypothesis that D3 receptor binding is above-normal in methamphetamine (MA) polydrug users, using PET and the D3-preferring ligand [11C]-(+)-PHNO. Sixteen control subjects and 16 polydrug users reporting MA as their primary drug of abuse underwent PET scanning following [11C]-(+)-PHNO. Compared to control subjects, drug users had higher [11C]-(+)-PHNO binding in the D3-rich midbrain substantia nigra (SN, +46%, p<0.02) and in the globus pallidus (+9%, p=0.06) and ventral pallidum (+11%, p=0.1), whereas binding was slightly lower in the D2-rich dorsal striatum (~−4%, NS; −12% in heavy users, p=0.01) and related to drug-use severity. [11C]-(+)-PHNO binding ratio in D3-rich SN vs. D2-rich dorsal striatum was 55% higher in MA users (p=0.004), with heavy but not moderate users having ratios significantly different from controls. [11C]-(+)-PHNO binding in SN was related to self-reported “drug-wanting.” We conclude that the dopamine D3 receptor, unlike the D2 receptor, might be upregulated in brains of MA polydrug users although lower dopamine levels in MA users could have contributed to the finding. Pharmacological studies are needed to establish whether normalization of D3 receptor function could reduce vulnerability to relapse in stimulant abuse.

Drug addiction has been associated with deficits in mesostriatal dopamine (DA) function, but whether this state extends to behavioral addictions such as pathological gambling (PG) is unclear. Here we used positron emission tomography and the D3 receptor-preferring radioligand [(11)C]-(+)-PHNO during a dual-scan protocol to investigate DA release in response to oral amphetamine in pathological gamblers (n=12) and healthy controls (n=11). In contrast with human neuroimaging findings in drug addiction, we report the first evidence that PG is associated with greater DA release in dorsal striatum (54-63% greater [(11)C]-(+)-PHNO displacement) than controls. Importantly, dopaminergic response to amphetamine in gamblers was positively predicted by D3 receptor levels (measured in substantia nigra), and related to gambling severity, allowing for construction of a mechanistic model that could help explain DA contributions to PG. Our results are consistent with a hyperdopaminergic state in PG, and support the hypothesis that dopaminergic sensitization involving D3-related mechanisms might contribute to the pathophysiology of behavioral addictions.

The dopamine system is a primary treatment target for cocaine dependence (CD), but research on dopaminergic abnormalities (eg, D 2 receptor system deficiencies) has so far failed to translate into effective treatment strategies. The D 3 receptor system has recently attracted considerable clinical interest, and D 3 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 D 3 receptor system in CD, using the positron emission tomography (PET) radiotracer [ 11 C]-( þ )-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]-( þ )-PHNO to assess D 3 receptor binding (BP ND ; calculated regionally using the simplified reference tissue model), and for comparison, a second scan with [ 11 C]raclopride to assess D 2/3 binding. CD subjects also completed a behavioral battery to characterize the addiction behavioral phenotype. CD subjects showed higher [ 11 C]-( þ )-PHNO BP ND than HC in the substantia nigra, which correlated with behavioral impulsiveness and risky decision making. In contrast, [11 C]raclopride BP ND was lower across the striatum in CD, consistent with previous literature in X2 week abstinence. The data suggest that in contrast to a D 2 deficiency, CD individuals may have heightened D 3 receptor levels, which could contribute to addiction-relevant traits. D 3 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.

Compelling evidence shows that there is decreased neural specialization in the ventral visual cortex in older adults under passive viewing conditions. We assessed whether such specialization would be maintained on a working memory task and whether decreased specialization co-occurred with increased prefrontal activations. Participants encoded three faces or houses and maintained the set across an 8-s interval. Results provided evidence for less specialization of faces and houses in older adults than in younger adults, while the middle and inferior frontal cortex showed increased activation in elders compared with the young.

Unlike with substance use disorder, there appear to be no marked differences in D2 /D3 levels between healthy subjects and pathological gamblers, suggesting that low receptor availability may not be a necessary feature of addiction. However, relationships between [11C]-(+)-PHNO binding and gambling severity/impulsiveness suggests involvement of the D3 receptor in impulsive/compulsive behaviours.

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 of 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 bilateral ventral inferior frontal gyrus. During affect labeling, participants recruited 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.

Gambling is pertinent to neuroscience research for at least two reasons. First, gambling is a naturalistic and pervasive example of risky decision making, and thus gambling games can provide a paradigm for the investigation of human choice behavior and "irrationality." Second, excessive gambling involvement (i.e., pathological gambling) is currently conceptualized as a behavioral addiction, and research on this condition may provide insights into addictive mechanisms in the absence of exogenous drug effects. This article is a summary of topics covered in a Society for Neuroscience minisymposium, focusing on recent advances in understanding the neural basis of gambling behavior, including translational findings in rodents and nonhuman primates, which have begun to delineate neural circuitry and neurochemistry involved.

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.