Dopaminergic medication for motor symptoms in Parkinson’s disease (PD) recently has been linked with impulse control disorders, including pathological gambling (PG), which affects up to 8% of patients. PG often is considered a behavioral addiction associated with disinhibition, risky decision-making, and altered striatal dopaminergic neurotransmission. Using [11C]raclopride with positron emission tomography, we assessed dopaminergic neurotransmission during Iowa Gambling Task performance. Here we present data from a single patient with PD and concomitant PG. We noted a marked decrease in [11C]raclopride binding in the left ventral striatum upon gambling, indicating a gambling-induced dopamine release. The results imply that PG in PD is associated with a high dose of dopaminergic medication, pronounced motor symptomatology, young age at disease onset, high propensity for sensation seeking, and risky decision-making. Overall, the findings are consistent with the hypothesis of medication-related PG in PD and underscore the importance of taking clinical variables, such as age and personality, into account when patients with PD are medicated, to reduce the risk of PG.
Parkinson’s disease; pathological gambling; impulse control disorders; decision-making; dopamine
Pathological gambling is an impulse control disorder reported in association with dopamine agonists used to treat Parkinson’s disease. Although impulse control disorders are conceptualized as lying within the spectrum of addictions, little neurobiological evidence exists to support this belief. Functional imaging studies have consistently demonstrated abnormalities of dopaminergic function in patients with drug addictions, but to date no study has specifically evaluated dopaminergic function in Parkinson’s disease patients with impulse control disorders. We describe results of a [11C] raclopride positron emission tomography (PET) study comparing dopaminergic function during gambling in Parkinson’s disease patients, with and without pathological gambling, following dopamine agonists. Patients with pathological gambling demonstrated greater decreases in binding potential in the ventral striatum during gambling (13.9%) than control patients (8.1%), likely reflecting greater dopaminergic release. Ventral striatal bindings at baseline during control task were also lower in patients with pathological gambling. Although prior imaging studies suggest that abnormality in dopaminergic binding and dopamine release may be markers of vulnerability to addiction, this study presents the first evidence of these phenomena in pathological gambling. The emergence of pathological gambling in a number of Parkinson’s disease patients may provide a model into the pathophysiology of this disorder.
PMID: 19346328 CAMSID: cams2369
Parkinson’s disease; dopamine; impulse control disorders; pathological gambling; PET; functional imaging
Pathological gambling (PG) is a form of behavioural addiction that has been associated with elevated impulsivity and also cognitive distortions in the processing of chance, probability and skill. We sought to assess the relationship between the level of cognitive distortions and state and trait measures of impulsivity in treatment-seeking pathological gamblers.
Thirty pathological gamblers attending the National Problem Gambling Clinic, the first National Health Service clinic for gambling problems in the UK, were compared with 30 healthy controls in a case-control design. Cognitive distortions were assessed using the Gambling-Related Cognitions Scale (GRCS). Trait impulsivity was assessed using the UPPS-P, which includes scales of urgency, the tendency to be impulsive in positive or negative mood states. Delay discounting rates were taken as a state measure of impulsive choice.
Pathological gamblers had elevated impulsivity on several UPPS-P subscales but effect sizes were largest (Cohen's d>1.4) for positive and negative urgency. The pathological gamblers also displayed higher levels of gambling distortions, and elevated preference for immediate rewards, compared to controls. Within the pathological gamblers, there was a strong relationship between the preference for immediate rewards and the level of cognitive distortions (R2=0.41).
Impulsive choice in the gamblers was correlated with the level of gambling distortions, and we hypothesize that an impulsive decision-making style may increase the acceptance of erroneous beliefs during gambling play.
Behavioural addiction; decision making; delay discounting; problem gambling; risk taking
Previous research has shown that dopamine signaling in the limbic striatum is crucial for selecting adaptive, motivated behavior, and that disrupted dopamine transmission is associated with impulsive and maladaptive behavior. In humans, Positron Emission Tomography (PET) imaging studies have shown that cocaine dependence is associated with the dysregulation of striatal dopamine signaling, which is associated with cocaine seeking behavior. The goal of the present study was to investigate whether this association applies to the treatment setting. Our hypothesis was that dopamine signaling in the limbic striatum would be associated with response to a behavioral treatment that uses positive reinforcement to replace impulsive cocaine use with constructive personal goals. Prior to treatment, cocaine dependent subjects underwent two PET scans using [11C]raclopride, before and after the administration of a stimulant (methylphenidate), to measure striatal D2/3 receptor binding and pre-synaptic dopamine release. The results showed that both of these outcome measures were reduced in the volunteers who failed to respond to treatment compared to those who experienced a positive treatment response. These findings provide insight into the neurochemistry of treatment response and show that low dopamine transmission is associated with treatment failure. In addition, these data suggest that the combination of behavioral treatment with methods that increase striatal dopamine signaling might serve as a therapeutic strategy for cocaine dependence.
While methamphetamine addiction has been associated with both impulsivity and striatal dopamine D2/D3 receptor deficits, human studies have not directly linked the latter two entities. We therefore compared methamphetamine-dependent and healthy control subjects using the Barratt Impulsiveness Scale (version 11, BIS-11) and positron emission tomography with [18F]fallypride to measure striatal dopamine D2/D3 receptor availability. The methamphetamine-dependent subjects reported recent use of the drug 3.3 g per week, and a history of using methamphetamine, on average, for 12.5 years. They had higher scores than healthy control subjects on all BIS-11 impulsiveness subscales (p < 0.001). Volume-of-interest analysis found lower striatal D2/D3 receptor availability in methamphetamine-dependent than in healthy control subjects (p < 0.01) and a negative relationship between impulsiveness and striatal D2/D3 receptor availability in the caudate nucleus and nucleus accumbens that reached statistical significance in methamphetamine-dependent subjects. Combining data from both groups, voxelwise analysis indicated that impulsiveness was related to D2/D3 receptor availability in left caudate nucleus and right lateral putamen/claustrum (p < 0.05, determined by threshold-free cluster enhancement). In separate group analyses, correlations involving the head and body of the caudate and the putamen of methamphetamine-dependent subjects, and the lateral putamen/claustrum of control subjects were observed at a weaker threshold (p < 0.12 corrected). The findings suggest that low striatal D2/D3 receptor availability may mediate impulsive temperament and thereby influence addiction.
methamphetamine; impulsivity; addiction; dopamine; receptor; striatum
Positron Emission tomography (PET) imaging studies have shown that addiction to a number of substances of abuse is associated with a decrease in dopamine D2/3 receptor binding and decreased pre-synaptic dopamine release in the striatum. Some studies have also shown that these reductions are associated with the severity of addiction. For example, in cocaine dependence, low dopamine release is associated with the choice to self-administer cocaine. The goal of the present study was to investigate these parameters of striatal dopamine transmission in heroin dependence and their association with drug seeking behavior.
Heroin dependent and healthy control subjects were scanned with [11C]raclopride before and after stimulant administration (methylphenidate) to measure striatal D2/3 receptor binding and pre-synaptic dopamine release. Following the PET scans, the heroin dependent subjects performed heroin self-administration sessions.
Both striatal D2/3 receptor binding and dopamine release were reduced in the heroin dependent subjects compared to healthy controls. However, neither PET measure of dopamine transmission predicted the choice to self-administer heroin.
These findings show that heroin addiction, like addiction to other drugs of abuse, is associated with low D2/3 receptor binding and low pre-synaptic dopamine. However, neither of these outcome measures were associated with the choice to self-administer heroin.
PET imaging; dopamine; dopamine receptors; addiction; heroin dependence; drug self-administration
Stimulant addiction is often linked to excessive risk taking, sensation seeking, and impulsivity, but in ways that are poorly understood. We report here that a form of impulsivity in rats predicts high rates of intravenous cocaine self-administration and is associated with changes in dopamine (DA) function before drug exposure. Using positron emission tomography, we demonstrated that D2/3 receptor availability is significantly reduced in the nucleus accumbens of impulsive rats that were never exposed to cocaine and that such effects are independent of DA release. These data demonstrate that trait impulsivity predicts cocaine reinforcement and that D2 receptor dysfunction in abstinent cocaine addicts may, in part, be determined by premorbid influences.
Impulse control disorders such as pathological gambling (PG) are a serious and common adverse effect of dopamine (DA) replacement medication in Parkinson’s disease (PD). Patients with PG have increased impulsivity and abnormalities in striatal DA, in common with behavioural and substance addictions in the non-PD population. To date, no studies have investigated the role of extrastriatal dopaminergic abnormalities in PD patients with PG. We used the PET radiotracer, [11C] FLB-457, with high-affinity for extrastriatal DA D2/3 receptors. 14 PD patients on DA agonists were imaged while they performed a gambling task involving real monetary reward and a control task. Trait impulsivity was measured with the Barratt Impulsivity Scale (BIS). Seven of the patients had a history of PG that developed subsequent to DA agonist medication. Change in [11C] FLB-457 binding potential (BP) during gambling was reduced in PD with PG patients in the midbrain, where D2/D3 receptors are dominated by autoreceptors. The degree of change in [11C] FLB-457 binding in this region correlated with impulsivity. In the cortex, [11C] FLB-457 BP was significantly greater in the anterior cingulate cortex (ACC) in PD patients with PG during the control task, and binding in this region was also correlated with impulsivity. Our findings provide the first evidence that PD patients with PG have dysfunctional activation of DA autoreceptors in the midbrain and low DA tone in the ACC. Thus, altered striatal and cortical DA homeostasis may incur vulnerability for the development of PG in PD, linked with the impulsive personality trait.
PMID: 22766031 CAMSID: cams2373
Parkinson’s disease; Dopamine agonists; Pathological gambling; Impulsivity
Low levels of dopamine (DA) D2 receptor availability at a resting baseline have been previously reported in drug addicted individuals and have been associated with reduced ventral and dorsal prefrontal metabolism. The reduction in DA D2 receptor availability along with the reduced ventral frontal metabolism is thought to underlie compromised sensitivity to non-drug reward, a core characteristic of drug addiction. We therefore hypothesized that variability in DA D2 receptor availability at baseline will covary with dynamic responses to monetary reward in addicted individuals. Striatal DA D2 receptor availability was measured with [11C]raclopride and positron emission tomography and response to monetary reward was measured (an average of 3 years later) with functional magnetic resonance imaging in seven cocaine addicted individuals. Results show that low DA D2 receptor availability in the dorsal striatum was associated with decreased thalamic response to monetary reward; while low availability in ventral striatum was associated with increased medial prefrontal (Brodmann Area 6/8/32) response to monetary reward. These preliminary results, that need to be replicated in larger sample sizes and validated with healthy controls, suggest that resting striatal DA D2 receptor availability predicts variability in functional responses to a non-drug reinforcer (money) in prefrontal cortex, implicated in behavioral monitoring, and in thalamus, implicated in conditioned responses and expectation, in cocaine addicted individuals.
fMRI; PET; striatal dopamine D2 receptor availability; thalamus; prefrontal cortex; cocaine addiction; monetary reward
Excessive alcohol use, a major cause of morbidity and mortality, is less well understood than other addictive disorders. Dopamine release in ventral striatum is a common element of drug reward, but alcohol has an unusually complex pharmacology, and humans vary greatly in their alcohol responses. This variation is related to genetic susceptibility for alcoholism, which contributes more than half of alcoholism risk. Here, we report that a functional OPRM1 A118G polymorphism is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and [11C]-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. To directly establish the causal role of OPRM1 A118G variation, we generated two humanized mouse lines, carrying the respective human sequence variant. Brain microdialysis showed a four-fold greater peak dopamine response to an alcohol challenge in h/mOPRM1-118GG than in h/mOPRM1-118AA mice. OPRM1 A118G variation is a genetic determinant of dopamine responses to alcohol, a mechanism by which it likely modulates alcohol reward.
alcohol; dopamine; opioids; reward; polymorphism; positron emission tomography
Objectives: Pathological gambling (PG) is a highly prevalent and disabling impulse control disorder. A range of psychopharmacological options are available for the treatment of PG, including selective serotonin reuptake inhibitors, opioid receptor antagonists, anti-addiction drugs, and mood stabilizers. In our preliminary study, we examined the efficacy of two anti-addiction drugs, baclofen and acamprosate, in the treatment of PG. Materials and Methods: Seventeen male gamblers were randomly divided into two groups. Each group received one of the two drugs without being blind to treatment. All patients underwent a comprehensive psychiatric diagnostic evaluation and completed a series of semi-structured interviews. During the 6-months of study, monthly evaluations were carried out to assess improvement and relapses. Relapse was defined as recurrent gambling behavior. Results: None of the 17 patients reached the 6-months abstinence. One patient receiving baclofen sustained abstinence for 4 months. Fourteen patients succeeded in sustaining abstinence for 1–3 months. Two patients stopped attending monthly evaluations. Conclusion: Baclofen and acamprosate did not prove efficient in treating pathological gamblers.
pathological gambling; behavioral addiction; baclofen; acamprosate; GABA
Impulse control disorders (ICDs), including disordered gambling, can occur in a significant number of patients with Parkinson’s disease (PD) receiving dopaminergic therapy. The neurobiology underlying susceptibility to such problems is unclear, but risk likely results from an interaction between dopaminergic medication and a pre-existing trait vulnerability. Impulse control and addictive disorders form part of a broader psychopathological spectrum of disorders, which share a common underlying genetic vulnerability, referred to as externalizing. The broad externalizing risk factor is a continuously varying trait reflecting vulnerability to various impulse control problems, manifested at the overt level by disinhibitory symptoms and at the personality level by antecedent traits such as impulsivity and novelty/sensation seeking. Trait “disinhibition” is thus a core endophenotype of ICDs, and a key target for neurobiological investigation. The ventral striatal dopamine system has been hypothesized to underlie individual variation in behavioral disinhibition. Here, we examined whether individual differences in ventral striatal dopamine synthesis capacity predicted individual variation in disinhibitory temperament traits in individuals with PD. Eighteen early-stage male PD patients underwent 6-[18F]Fluoro-l-DOPA (FDOPA) positron emission tomography scanning to measure striatal dopamine synthesis capacity, and completed a measure of disinhibited personality. Consistent with our predictions, we found that levels of ventral, but not dorsal, striatal dopamine synthesis capacity predicted disinhibited personality, particularly a propensity for financial extravagance. Our results are consistent with recent preclinical models of vulnerability to behavioral disinhibition and addiction proneness, and provide novel insights into the neurobiology of potential vulnerability to impulse control problems in PD and other disorders.
dopa decarboxylase; dopamine; disordered gambling; externalizing; impulse control disorders; impulsivity; reward; ventral striatum
Previous PET imaging studies in non-human primates have shown that striatal dopamine type 2/3 (D2/3) receptors correlate with social hierarchy in monkeys, and that dominant animals exhibit higher levels of D2/3 receptor binding. The goal of the present study was to examine this phenomena in human subjects using Positron Emission Tomography (PET) and the radiotracer [11C]raclopride.
Fourteen healthy volunteers were scanned with [11C]raclopride to measure D2/3 receptor binding potential. Social status was assessed using the Barratt Simplified Measure of Social Status. In addition, participants were asked to assess their level of social support using the Multidimensional Scale of Perceived Social Support (MSPSS).
A correlation was seen between social status and dopamine D2/3 receptors, where volunteers with the higher status had higher values for [11C]raclopride BP. A similar correlation was seen with the perceived social support, where higher [11C]raclopride BP correlated with higher scores on the MSPSS.
The results of this study support the hypothesis that social status and social support is correlated with D2/3 receptor binding.
dopamine 2/3 receptor; [11C]raclopride; PET imaging; social status
Positron emission tomography (PET) imaging of small striatal brain structures such as the ventral striatum (VST) has been hampered by low spatial resolution causing partial-volume effects. The high-resolution research tomograph (HRRT) is a brain-dedicated PET scanner that has considerably better spatial resolution than its predecessors. However, its superior spatial resolution is associated with a lower signal-to-noise ratio. We evaluated the test–retest reliability of the striatal and thalamic dopamine D2 receptor binding using the HRRT scanner. Seven healthy male volunteers underwent two [11C]raclopride PET scans with a 2.5-hour interval. Dopamine D2 receptor availability was quantified as binding potential (BPND) using the simplified reference tissue model. To evaluate the reproducibility of repeated BPND estimations, absolute variability (VAR) and intraclass correlation coefficients (ICCs) were calculated. VAR values indicated fairly good reproducibility and were 3.6% to 4.5% for the caudate nucleus and putamen and 4.5% to 6.4% for the lateral and medial part of the thalamus. In the VST, the VAR value was 5.8% when the definition was made in the coronal plane. However, the ICC values were only moderate, in the range of 0.34 to 0.66, for all regions except the putamen (0.87). Experimental signal processing methods improved neither ICC nor VAR values significantly.
dopamine receptors; PET; raclopride; reproducibility; test–retest; ventral striatum
Normal aging is associated with a decrease in dopaminergic function and a reduced ability to form new motor memories with training. This study examined the link between both phenomena. We hypothesized that levodopa would (a) ameliorate aging-dependent deficits in motor memory formation, and (b) increase dopamine availability at the dopamine type 2-like (D2) receptor during training in task-relevant brain structures. The effects of training plus levodopa (100mg, plus 25 mg carbidopa) on motor memory formation and striatal dopamine availability were measured with [11C] raclopride (RAC) positron emission tomography (PET). We found that levodopa did not alter RAC-binding potential at rest but it enhanced training effects on motor memory formation as well as dopamine release in the dorsal caudate nucleus. Motor memory formation during training correlated with the increase of dopamine release in the caudate nucleus. These results demonstrate that levodopa may ameliorate dopamine deficiencies in the elderly by replenishing dopaminergic presynaptic stores, actively engaged in phasic dopamine release during motor training.
aging; motor; memory formation; positron emission tomography; neuropharmacology; neurotransmitter; neurorehabilitation
[11C]Raclopride ([11C]RAC) is a selective dopamine D2/D3 antagonist that is commonly used in positron emission tomography (PET) studies to assess both basal levels of receptor availability and changes in availability caused by alterations in striatal dopamine concentration. When designing [11C]RAC studies, it is important to understand what variables may affect the results. Here, we examined differences in baseline striatal [11C]RAC binding potential (BPND) under two different “rest” conditions. Thirteen subjects received [11C]RAC scans. Eight subjects were aware prior to initiation of scanning that they would receive a “baseline” scan, and that no additional procedures would take place during the scan (“certain rest” group, CER). Five subjects were informed that they might or might not receive an IV alcohol infusion during the scan (“uncertain rest” group, UNC). This group was informed five min after scan start that they would not receive alcohol. Voxel-wise analyses of binding potential (BPND) images generated for both “rest” conditions indicated that receptor availability was higher in UNC than in CER. This result was confirmed by a region-of-interest analysis, which indicated that the average BPND in right and left putamen was statistically higher in UNC. There were no differences in groups with respect to age or raclopride mass dose that could account for the difference in D2/D3 receptor availability. Our findings suggest that even slight differences in cognitive states between groups can have an effect on BPND, presumably mediated by changes in endogenous dopamine concentration.
positron emission tomography; raclopride; binding potential; dopamine; baseline; reward
Cocaine addiction is accompanied by a decrease in striatal dopamine signaling, measured as a decrease in dopamine D2 receptor binding as well as blunted dopamine release in the striatum. These alterations in dopamine transmission have clinical relevance, and have been shown to correlate with cocaine-seeking behavior and response to treatment for cocaine dependence. However, the mechanisms contributing to the hypodopaminergic state in cocaine addiction remain unknown. Here we review the positron emission tomography (PET) imaging studies showing alterations in D2 receptor binding potential and dopamine transmission in cocaine abusers and their significance in cocaine-seeking behavior. Based on animal and human studies, we propose that the kappa receptor/dynorphin system, because of its impact on dopamine transmission and upregulation following cocaine exposure, could contribute to the hypodopaminergic state reported in cocaine addiction, and could thus be a relevant target for treatment development.
imaging; kappa opioid receptor; dopamine; cocaine dependence; striatum; dopamine receptor
Bulimia nervosa (BN) has been characterized as similar to an addiction, though the empirical support for this characterization is limited. This study utilized PET imaging to determine whether abnormalities in brain dopamine (DA) similar to those described in substance use disorders occur in BN.
PET imaging with [11C]raclopride, pre/post methylphenidate administration, to assess dopamine type 2 (D2) receptor binding (BPND) and striatal DA release (ΔBPND).
There was a trend towards lower D2 receptor BPND in two striatal subregions in the patient group compared to the control group. DA release in the putamen in the patient group was significantly reduced and, overall, there was a trend towards a difference in striatal DA release. Striatal DA release was significantly associated with the frequency of binge eating.
These data suggest that BN is characterized by abnormalities in brain DA that resemble, in some ways, those described in addictive disorders.
Bulimia nervosa; eating disorders; PET imaging; dopamine; addictions; reward
Low striatal dopamine 2/3 receptor (D2/3) availability and low ventrostriatal (VST) dopamine (DA) release have been observed in alcoholism, cocaine and heroin dependence. Less is known about the dopaminergic system in cannabis dependence. We assessed D2/3 availability and DA release in abstinent cannabis users compared to controls and explored relationships to parameters of cannabis use history, using [11C]raclopride Positron Emission Tomography (PET) and an amphetamine challenge paradigm.
16 recently abstinent, medically and psychiatrically healthy cannabis-using participants (CD, 27.3 ± 6.1 years, 1 female, 15 males) and 16 matched controls (HC, 28.1 ± 6.7 years, 2 females, 14 males) completed two PET scans, before and after injection of i.v. d-amphetamine (0.3 mg/kg). Percent change in [11C]raclopride binding after amphetamine (ΔBPND) in subregions of the striatum was compared between groups. Correlations with clinical parameters were examined.
Cannabis dependent participants had an average consumption of 517± 465 estimated puffs per month, indicating overall mild to moderate cannabis dependence. Neither baseline BPND nor ΔBPND differed from controls in any ROI, including VST. In CD, earlier age of onset of use correlated with lower [ΔBPND] in the associative striatum (AST) when controlling for current age.
Unlike other addictions, cannabis dependence of mild to moderate severity is not associated with striatal DA alterations. However, earlier use, or longer duration of use, is related to lower DA release in the AST. These observations suggest a more harmful effect of use during adolescence; more research is needed to distinguish effects of chronicity versus onset.
cannabis; dopamine; PET imaging; addiction; amphetamine challenge; adolescent onset
Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis.
Microdialysis studies report that systemic alcohol increases extracellular dopamine in the rat striatum. The present study examined whether changes in striatal dopamine could be detected in rats using small animal positron emission tomography (PET). PET images were acquired in 44 alcohol-naïve male Wistar and alcohol-preferring (P) rats. Subjects received up to three [11C]raclopride scans (rest, alcohol, and saline). Animals were anesthetized with isoflurane and secured on a stereotactic-like holder during all scans. Blood samples were collected from the tail or lateral saphenous vein of 12 animals 10 minutes after tracer injection for determination of blood alcohol concentration (BAC). Time activity curves were extracted from the striatum and the cerebellum and binding potential (BPND) was calculated as a measure of D2 receptor availability. Wistars given 1.0g/kg alcohol (20%v/v) I.V. or 3.0g/kg alcohol (20%v/v) I.P showed significant alcohol-induced decreases in BPND. In P rats (given 1.5, 2.25, or 3.0 g/kg alcohol), no individual group showed a statistical effect of alcohol on BPND, but taken together, all P rats receiving I.P. alcohol had significantly lower BPND than rest or saline scans. Large decreases in BPND were primarily observed in rats with BAC above 200 mg%. Also, a significant difference was found between baseline BPND of Wistars who had undergone jugular catheterization surgery for I.V. alcohol administration and those who had not. These preliminary results suggest that alcohol-induced DA release in the rat striatum is detectable using small animal PET given sufficiently large cohorts and adequate blood alcohol levels.
binding potential; P rats; Wistars; striatum; BAC; stress; surgery
Impulsive behavior is thought to reflect a trait-like characteristic that can have broad consequences for an individual’s success and well-being, but its neurobiological basis remains elusive. Although striatal dopamine D2-like receptors have been linked with impulsive behavior and behavioral inhibition in rodents, a role for D2-like receptor function in frontostriatal circuits mediating inhibitory control in humans has not been shown. We investigated this role in a study of healthy research participants who underwent positron emission tomography with the D2/D3 dopamine-receptor ligand [18F]fallypride, and blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) while they performed the Stop-signal Task, a test of response inhibition. Striatal dopamine D2/D3-receptor availability was negatively correlated with speed of response inhibition (stop-signal reaction time), and positively correlated with inhibition-related fMRI activation in frontostriatal neural circuitry. Correlations involving D2/D3 receptor availability were strongest in the dorsal regions (caudate and putamen) of the striatum, consistent with findings of animal studies relating dopamine receptors and response inhibition. The results suggest that striatal D2-like receptor function in humans plays a major role in the neural circuitry that mediates behavioral control, an ability that is essential for adaptive responding and is compromised in a variety of common neuropsychiatric disorders.
Response Inhibition; fMRI; Stop-signal Task; Dopamine; PET
ADHD is typically characterized as a disorder of inattention and hyperactivity/impulsivity but there is increasing evidence of deficits in motivation. Using PET we showed decreased function in the brain dopamine reward pathway in adults with ADHD, which we hypothesized could underlie the motivation deficits in this disorder. To evaluate this hypothesis we performed secondary analyses to assess the correlation between the PET measures of dopamine D2/D3 receptor and dopamine transporter availability (obtained with [11C]raclopride and [11C]cocaine, respectively) in the dopamine reward pathway (midbrain and nucleus accumbens), and a surrogate measures of trait motivation (assessed using the Achievement scale on the Multidimensional Personality Questionnaire or MPQ) in 45 ADHD participants and 41 controls. The Achievement scale was lower in ADHD participants than in controls (11±5 vs 14±3, p<0.001) and was significantly correlated with D2/D3 receptors (accumbens: r=0.39, p<0.008; midbrain: r=0.41, p<0.005) and transporters (accumbens: r=0.35, p < 0.02) in ADHD participants, but not in controls. ADHD participants also had lower values in the Constraint factor and higher values in the Negative Emotionality factor of the MPQ but did not differ in the Positive Emotionality factor - and none of these were correlated with the dopamine measures. In ADHD participants scores in the Achievement scale were also negatively correlated with symptoms of inattention (CAARS A, E and SWAN-I). These findings provide evidence that disruption of the dopamine reward pathway is associated with motivation deficits in ADHD adults, which may contribute to attention deficits and supports the use of therapeutic interventions to enhance motivation in ADHD.
psychiatric disorder; brain imaging; PET; attention; catecholamines; personality
Problem gambling has been proposed to represent a ‘behavioural addiction’ that may provide key insights into vulnerability mechanisms underlying addiction in brains that are not affected by the damaging effects of drugs. Our aim was to investigate the neurocognitive profile of problem gambling in comparison with alcohol dependence. We reasoned that shared deficits across the two conditions may reflect underlying vulnerability mechanisms, whereas impairments specific to alcohol dependence may reflect cumulative effects of alcohol consumption.
Out-patient addiction treatment centres and university behavioural testing facilities.
A naturalistic sample of 21 male problem and pathological gamblers, 21 male alcohol-dependent out-patients and 21 healthy male control participants.
Neurocognitive battery assessing decision-making, impulsivity and working memory.
The problem gamblers and alcohol-dependent groups displayed impairments in risky decision-making and cognitive impulsivity relative to controls. Working memory deficits and slowed deliberation times were specific to the alcohol-dependent group.
Gambling and alcohol-dependent groups shared deficits in tasks linked to ventral prefrontal cortical dysfunction. Tasks loading on dorsolateral prefrontal cortex were selectively impaired in the alcohol-dependent group, presumably as a consequence of long-term alcohol use.
Addiction; alcohol; decision-making; impulsivity; pathological gambling; prefrontal cortex; risk-taking; vulnerability
The development of an impulse control disorder (ICD) is now recognized as a potential nonmotor adverse effect of dopamine replacement therapy in Parkinson’s disease (PD). Here, recent epidemiological, neurophysiological and genetic advances are summarized to outline potential mechanisms involved. It is safe to say that dopaminergic drugs, particularly dopamine agonists, are able to induce ICDs only in a minority of patients, while the majority are somehow protected from this adverse effect. While it seems clear that men with early-onset PD are more vulnerable, other predisposing factors, such as various current or pre-PD personality traits, are a matter of debate. In terms of neurophysiological advances, one may find striking analogies to the addiction literature suggesting a causal chain beginning with certain predisposing conditions of striatal dopamine synapses, an “unnatural” increase of dopamine stimulation and a characteristic pattern of resulting functional changes in remote networks of appetitive drive and impulse control. Future prospects include potential add-on medications and the possible identification of genetic predispositions at a genome-wide scale. Functional imaging of pharmacogenetic interactions (imaging pharmacogenomics) may be an important tool on that road.
Imaging; Gambling; Addiction; Impulsive; Compulsive; Dopamine agonist