Motivated attention to cocaine and emotional cues in abstinent and current cocaine users--an ERP study.

Event-related potentials (ERPs) are a direct measure of neural activity and are ideally suited to study the time-course of attentional engagement with emotional and drug-related stimuli in addiction. In particular, the late positive potential (LPP) appears to be enhanced following cocaine-related compared with neutral stimuli in human participants with cocaine use disorders (CUD). However, previous studies have not directly compared cocaine-related with emotional stimuli while examining potential differences between abstinent and current cocaine users. The present study examined ERPs in 55 CUD (27 abstinent and 28 current users) and 29 matched healthy controls while they passively viewed pleasant, unpleasant, neutral and cocaine-related pictures. To examine the time-course of attention to these stimuli, we analysed both an early and later window in the LPP as well as the early posterior negativity (EPN), established in assessing motivated attention. Cocaine pictures elicited increased electrocortical measures of motivated attention in ways similar to affectively pleasant and unpleasant pictures in all CUD, an effect that was no longer discernible during the late LPP window for the current users. This group also exhibited deficient processing of the other emotional stimuli (early LPP window - pleasant pictures; late LPP window - pleasant and unpleasant pictures). Results were unique to the LPP and not EPN. Taken together, results support a relatively early attention bias to cocaine stimuli in cocaine-addicted individuals, further suggesting that recent cocaine use decreases such attention bias during later stages of processing but at the expense of deficient processing of other emotional stimuli.

Gene x disease interaction on orbitofrontal gray matter in cocaine addiction.

CONTEXT: Long-term cocaine use has been associated with structural deficits in brain regions having dopamine-receptive neurons. However, the concomitant use of other drugs and common genetic variability in monoamine regulation present additional structural variability. OBJECTIVE: To examine variations in gray matter volume (GMV) as a function of lifetime drug use and the genotype of the monoamine oxidase A gene, MAOA, in men with cocaine use disorders (CUD) and healthy male controls. DESIGN: Cross-sectional comparison. SETTING: Clinical Research Center at Brookhaven National Laboratory. PATIENTS: Forty individuals with CUD and 42 controls who underwent magnetic resonance imaging to assess GMV and were genotyped for the MAOA polymorphism (categorized as high- and low-repeat alleles). MAIN OUTCOME MEASURES: The impact of cocaine addiction on GMV, tested by (1) comparing the CUD group with controls, (2) testing diagnosis × MAOA interactions, and (3) correlating GMV with lifetime cocaine, alcohol, and cigarette smoking, and testing their unique contribution to GMV beyond other factors. RESULTS: (1) Individuals with CUD had reductions in GMV in the orbitofrontal, dorsolateral prefrontal, and temporal cortex and the hippocampus compared with controls. (2) The orbitofrontal cortex reductions were uniquely driven by CUD with low- MAOA genotype and by lifetime cocaine use. (3) The GMV in the dorsolateral prefrontal cortex and hippocampus was driven by lifetime alcohol use beyond the genotype and other pertinent variables. CONCLUSIONS: Long-term cocaine users with the low-repeat MAOA allele have enhanced sensitivity to gray matter loss, specifically in the orbitofrontal cortex, indicating that this genotype may exacerbate the deleterious effects of cocaine in the brain. In addition, long-term alcohol use is a major contributor to gray matter loss in the dorsolateral prefrontal cortex and hippocampus, and is likely to further impair executive function and learning in cocaine addiction.

Dopaminergic response to drug words in cocaine addiction.

When exposed to drug conditioned cues (stimuli associated with the drug), addicted individuals experience an intense desire for the drug, which is associated with increased dopamine cell firing. We hypothesized that drug-related words can trigger activation in the mesencephalon, where dopaminergic cells are located. During functional magnetic resonance imaging (fMRI), 15 individuals with cocaine use disorders and 15 demographically matched healthy control subjects pressed buttons for color of drug-related versus neutral words. Results showed that the drug words, but not neutral words, activated the mesencephalon in the cocaine users only. Further, in the cocaine users only, these increased drug-related mesencephalic responses were associated with enhanced verbal fluency specifically for drug words. Our results for the first time demonstrate fMRI response to drug words in cocaine-addicted individuals in mesencephalic regions as possibly associated with dopaminergic mechanisms and with conditioning to language (in this case drug words). The correlation between the brief verbal fluency test, which can be easily administered (crucial for clinical studies), and fMRI cue reactivity could be used as a biomarker of neurobiological changes in addiction.

Subjective sensitivity to monetary gradients is associated with frontolimbic activation to reward in cocaine abusers.

Drug addiction is characterized by marked disruptions in the ability to process reward. Here we evaluated in cocaine addicted and healthy control participants the subjective sensitivity to reward gradients and its association with neural responses to sustained reward. A self-report questionnaire was used to assess the former. A functional magnetic resonance imaging task that utilized monetary reward as feedback in a blocked design was used to assess the latter. Results revealed that whereas control subjects valued high money more than low money, over half of the cocaine addicted subjects valued all monetary amounts equally. This compromised subjective sensitivity to gradients in reward value was significantly correlated with higher activations to money in the lateral orbitofrontal cortex/inferior frontal gyrus (BA 47) and amygdala, and lower activations in the middle frontal gyrus (BA 6), which together explained 85% of the variability on this rating scale in the cocaine abusers only. These results provide for the first time evidence of restricted subjective sensitivity to gradients of reward in cocaine addiction and of the involvement of frontolimbic brain regions (including the orbitofrontal cortex) in this deficit.

Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction.

The ability of drugs of abuse to increase dopamine in nucleus accumbens underlies their reinforcing effects. However, preclinical studies have shown that with repeated drug exposure neutral stimuli paired with the drug (conditioned stimuli) start to increase dopamine by themselves, which is an effect that could underlie drug-seeking behavior. Here we test whether dopamine increases occur to conditioned stimuli in human subjects addicted to cocaine and whether this is associated with drug craving. We tested eighteen cocaine-addicted subjects using positron emission tomography and [11C]raclopride (dopamine D2 receptor radioligand sensitive to competition with endogenous dopamine). We measured changes in dopamine by comparing the specific binding of [11C]raclopride when subjects watched a neutral video (nature scenes) versus when they watched a cocaine-cue video (scenes of subjects smoking cocaine). The specific binding of [11C]raclopride in dorsal (caudate and putamen) but not in ventral striatum (in which nucleus accumbens is located) was significantly reduced in the cocaine-cue condition and the magnitude of this reduction correlated with self-reports of craving. Moreover, subjects with the highest scores on measures of withdrawal symptoms and of addiction severity that have been shown to predict treatment outcomes, had the largest dopamine changes in dorsal striatum. This provides evidence that dopamine in the dorsal striatum (region implicated in habit learning and in action initiation) is involved with craving and is a fundamental component of addiction. Because craving is a key contributor to relapse, strategies aimed at inhibiting dopamine increases from conditioned responses are likely to be therapeutically beneficial in cocaine addiction.

The human immunodeficiency virus reduces network capacity: acoustic noise effect.

OBJECTIVE: Increased acoustic noise (AN) during working memory leads to increased brain activation in healthy individuals and may have greater impact in human immunodeficiency virus (HIV) patients. RESULTS: Compared with control subjects, HIV patients showed reduced AN activation and lower neuronal marker N-acetylaspartate in prefrontal and parietal cortices. Competing use of the working memory network between AN and cognitive load showed lower dynamic range of the hemodynamic responses in prefrontal and parietal cortices in HIV patients. INTERPRETATION: These findings suggest that reduced reserve capacity of the working memory network in HIV patients and additional stress (eg, AN) might exhaust the impaired network for more demanding tasks.

Comparison of monoamine oxidase a in peripheral organs in nonsmokers and smokers.

UNLABELLED: Smokers have reduced levels of brain monoamine oxidase A (MAO A) leading to speculation that MAO A inhibition by tobacco smoke may underlie some of the neurophysiologic effects of smoking. Because smoking exposes peripheral organs as well as the brain to MAO A-inhibitory compounds, we determined whether smokers would also have reduced MAO A in peripheral organs. METHODS: We measured MAO A in peripheral organs in a group of 9 smokers and compared it with a group of nonsmokers studied previously. MAO A was measured using PET and serial scans with the MAO A-specific radiotracers (11)C-clorgyline and deuterium-substituted (11)C-clorgyline ((11)C-clorgyline-D2) using the deuterium isotope effect to assess binding specificity. The time course of radiotracer in the arterial plasma was also measured and data from the tissue time-activity curves and the arterial input function were analyzed using a 3-compartment model to estimate k(3), which represents the rate-limiting step for the irreversible binding of labeled clorgyline to MAO A. RESULTS: Tracer uptake at plateau was reduced with deuterium substitution for the heart, lungs, and kidneys, indicating specificity for MAO. There was no difference in organ uptake at plateau between nonsmokers and smokers though, for the smokers, the efflux of tracer from peak uptake to plateau was slower for the lungs. The area under the time-activity curve for the arterial plasma was also significantly reduced for smokers versus nonsmokers and the reduction occurred in the first few minutes after radiotracer injection. Smokers had an approximately 50% reduction in k(3) when compared with nonsmokers; however, k(3) did not differ for nonsmokers and smokers for the heart and the kidneys. CONCLUSION: Because MAO A breaks down serotonin, norepinephrine, dopamine, and tyramine, and because the lung is a major metabolic organ in degrading some of these substances, reduced lung MAO A may contribute to some of the physiologic effects of smoking. This study also revealed that the concentration of the radiotracers in the arterial plasma is significantly lower for the smoker versus the nonsmoker and that this appears to be caused in part by retention of the radiotracer in lungs. If this is generally true for other substances that are administered intravenously, then this needs to be considered as a variable that may contribute to different short-term behavioral responses to intravenously administered drugs for nonsmokers versus smokers.

Decreased brain dopaminergic transporters in HIV-associated dementia patients.

HIV has a propensity to invade subcortical regions of the brain, which may lead to a subcortical dementia termed HIV-cognitive motor complex. Therefore, we aimed to assess whether dopamine (DA) D2 receptors and transporters (DAT) are affected in the basal ganglia of subjects with HIV, and how these changes relate to dementia status. Fifteen HIV subjects (age 44.5 +/- 11 years; CD4 185 +/- 130/mm3)) and 13 seronegative controls (42 +/- 12 years) were evaluated with PET to assess availability of DAT ([11C]cocaine) and DA D2 receptor ([11C]raclopride). HIV patients with associated dementia (HAD), but not those without dementia (ND) had significantly lower DAT availability in putamen (-19.3%, P = 0.009) and ventral striatum (-13.6%, P = 0.03) compared with seronegative controls. Higher plasma viral load in the HIV dementia patients correlated with lower DAT in the caudate (r = -0.7, P = 0.02) and putamen (r = -0.69, P = 0.03). DA D2 receptor availability, however, showed mild and non-significant decreases in HIV patients. These results provide the first evidence of DA terminal injury in HIV dementia patients, and suggest that decreased DAT may contribute to the pathogenesis of HIV dementia. The greater DAT decrease in the putamen than in the caudate parallels that observed in Parkinson's disease. The inverse relationship between viral burden and DAT availability further supports HIV-mediated neurotoxicity to dopaminergic terminals.

Low monoamine oxidase B in peripheral organs in smokers.

One of the major mechanisms for terminating the actions of catecholamines and vasoactive dietary amines is oxidation by monoamine oxidase (MAO). Smokers have been shown to have reduced levels of brain MAO, leading to speculation that MAO inhibition by tobacco smoke may underlie some of the behavioral and epidemiological features of smoking. Because smoking exposes peripheral organs as well as the brain to MAO-inhibitory compounds, we questioned whether smokers would also have reduced MAO levels in peripheral organs. Here we compared MAO B in peripheral organs in nonsmokers and smokers by using positron emission tomography and serial scans with the MAO B-specific radiotracers,l-[11C]deprenyl and deuterium-substituted l-[11C]deprenyl (l-[11C]deprenyl-D2). Binding specificity was assessed by using the deuterium isotope effect. We found that smokers have significantly reduced MAO B in peripheral organs, particularly in the heart, lungs, and kidneys, when compared with nonsmokers. Reductions ranged from 33% to 46%. Because MAO B breaks down catecholamines and other physiologically active amines, including those released by nicotine, its inhibition may alter sympathetic tone as well as central neurotransmitter activity, which could contribute to the medical consequences of smoking. In addition, although most of the emphases on the carcinogenic properties of smoke have been placed on the lungs and the upper airways, this finding highlights the fact that multiple organs in the body are also exposed to pharmacologically significant quantities of chemical compounds in tobacco smoke.

Monoamine oxidase A imaging in peripheral organs in healthy human subjects.

Monoamine oxidase (MAO) catalyzes the oxidative deamination of many biogenic and dietary amines. Though studies of MAO have focused mainly on its regulatory role in the brain, MAO in peripheral organs also represents a vast mechanism for detoxifying vasoactive compounds as well as for terminating the action of physiologically active amines, which can cross the blood brain barrier. Indeed, robust central and peripheral MAO activity is a major requirement in the safe use of many CNS drugs, particularly antidepressants, and thus an awareness of the MAO inhibitory potential of drugs is essential in therapeutics. In this study, we examined the feasibility of quantifying MAO A in peripheral organs in healthy human subjects using comparative positron emission tomography (PET) imaging with carbon-11 (t(1/2): 20.4 min) labeled clorgyline ([(11)C]clorgyline) a suicide inactivator of MAO A and its deuterium labeled counterpart ([(11)C]clorgyline-D2). Heart, lungs, kidneys, thyroid, and spleen showed a robust deuterium isotope effect characteristic of MAO and the magnitude of the effect was similar to that of trancylcypromine, an irreversible MAO inhibitor used in the treatment of depression. Liver time-activity curves were not affected by deuterium substitution precluding the estimation of liver MAO in vivo. In organs showing an isotope effect, MAO A is greatest in the lungs and kidneys followed by the thyroid and heart. This method, which has been previously applied in the human brain, opens the possibility to also directly assess the effects of different variables including smoking, dietary substances, drugs, disease, and genetics on peripheral MAO A in humans.