Showing papers by "Nora D. Volkow published in 2006"

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

Abstract: 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.

High Levels of Dopamine D2 Receptors in Unaffected Members of Alcoholic Families: Possible Protective Factors

Abstract: Context Predisposition to alcoholism is likely an interaction between genetic and environmental factors that confer vulnerability and protection. Alcoholic subjects have low levels of dopamine D 2 receptors in striatum, and increasing D 2 receptor levels in laboratory animals reduces alcohol consumption. Objectives To test whether high levels of D 2 receptors may be protective against alcoholism and whether this is mediated by their modulation of activity in orbitofrontal cortex and cingulate gyrus (regions involved in salience attribution, emotional reactivity, and inhibitory control). Design Research (nonalcoholic subjects with a family history of alcoholism) and comparison (nonalcoholic subjects with a negative family history) sample. Setting Outpatient setting. Participants Fifteen nonalcoholic subjects who had an alcoholic father and at least 2 other first- or second-degree relatives who were alcoholics (family-positive group) and 16 nonalcoholic controls with no family history of alcoholism (family-negative group). Main Outcome Measures Results of positron emission tomography with raclopride C 11 to assess D 2 receptors and with fludeoxyglucose F 18 to assess brain glucose metabolism (marker of brain function). Personality measures were obtained with the Multidimensional Personality Questionnaire. Results Availability of D 2 receptors was significantly higher in caudate and ventral striatum in family-positive than family-negative subjects. In family-positive but not family-negative subjects, striatal D 2 receptors were associated with metabolism in anterior cingulate (Brodmann area 24/25) and orbitofrontal (Brodmann area 11) and prefrontal (Brodmann area 9/10) cortices, and with personality scores of positive emotionality. Conclusions The higher-than-normal D 2 receptor availability in nonalcoholic members of alcoholic families supports the hypothesis that high levels of D 2 receptors may protect against alcoholism. The significant associations between D 2 receptors and metabolism in frontal regions involved with emotional reactivity and executive control suggest that high levels of D 2 receptors could protect against alcoholism by regulating circuits involved in inhibiting behavioral responses and in controlling emotions.

Gastric stimulation in obese subjects activates the hippocampus and other regions involved in brain reward circuitry.

Abstract: The neurobiological mechanisms underlying overeating in obesity are not understood. Here, we assessed the neurobiological responses to an Implantable Gastric Stimulator (IGS), which induces stomach expansion via electrical stimulation of the vagus nerve to identify the brain circuits responsible for its effects in decreasing food intake. Brain metabolism was measured with positron emission tomography and 2-deoxy-2[18F]fluoro-d-glucose in seven obese subjects who had the IGS implanted for 1–2 years. Brain metabolism was evaluated twice during activation (on) and during deactivation (off) of the IGS. The Three-Factor Eating Questionnaire was obtained to measure the behavioral components of eating (cognitive restraint, uncontrolled eating, and emotional eating). The largest difference was in the right hippocampus, where metabolism was 18% higher (P < 0.01) during the “on” than “off” condition, and these changes were associated with scores on “emotional eating,” which was lower during the on than off condition and with “uncontrolled eating,” which did not differ between conditions. Metabolism also was significantly higher in right anterior cerebellum, orbitofrontal cortex, and striatum during the on condition. These findings corroborate the role of the vagus nerve in regulating hippocampal activity and the importance of the hippocampus in modulating eating behaviors linked to emotional eating and lack of control. IGS-induced activation of regions previously shown to be involved in drug craving in addicted subjects (orbitofrontal cortex, hippocampus, cerebellum, and striatum) suggests that similar brain circuits underlie the enhanced motivational drive for food and drugs seen in obese and drug-addicted subjects, respectively.

Therapeutic doses of amphetamine or methylphenidate differentially increase synaptic and extracellular dopamine.

Abstract: Methylphenidate (MP) and amphetamine (AMP) are first-line treatments for attention-deficit hyperactivity disorder. Although both drugs have similar therapeutic potencies, the stimulatory effect of AMP on extracellular dopamine (ECF DA) is greater than that of MP. We compared extracellular effects directly against synaptic changes. ECF DA was assessed by microdialysis in freely moving rodents and synaptic dopamine (DA) was measured using PET and [11C]-raclopride displacement in rodents and baboons. Microdialysis data demonstrated that MP (5.0 mg/kg, i.p.) increased ECF DA 360% +/- 31% in striatum, which was significantly less than that by AMP (2.5 mg/kg, i.p.; 1398% +/- 272%). This fourfold difference was not reflected by changes in synaptic DA. In fact, rodent PET studies showed no difference in striatal [11C]-raclopride binding induced by AMP (2.5 mg/kg, i.p.; 25% +/- 4% reduction) compared with that by MP (5.0 mg/kg, i.p.; 21% +/- 4% reduction). Primate PET experiments also showed no differences between AMP (0.5 mg/kg, i.v.; 24% +/- 4% reduction) and MP (1.0 mg/kg, i.v.; 25% +/- 7% reduction) induced changes in [11C]-raclopride binding potential. The similar potencies of MP and AMP to alter synaptic DA, despite their different potencies in raising ECF DA, could reflect their different molecular mechanisms.

Cocaine Increases the Intracellular Calcium Concentration in Brain Independently of Its Cerebrovascular Effects

Abstract: Cocaine abuse increases the risk of life-threatening neurological complications such as strokes and seizures. Although the vasoconstricting properties of cocaine underlie its cerebrovascular effects, the mechanisms underlying its neurotoxicity remain incompletely understood. Here, we use optical techniques to measure cerebral blood volume, hemoglobin oxygenation (S(t)O(2)), and intracellular calcium ([Ca(2+)](i)) to test the hypothesis that cocaine increases [Ca(2+)](i) in the brain. The effects of cocaine were compared with those of methylphenidate, which has similar catecholaminergic effects as cocaine (except for serotonin increases) but no local anesthetic properties, and of lidocaine, which has similar local anesthetic effects as cocaine but is devoid of catecholaminergic actions. To control for the hemodynamic effects of cocaine, we assessed the effects of cocaine in animals in which normal blood pressure was maintained by infusion of phenylephrine, and we also measured the effects of transient hypotension (mimicking that induced by cocaine). We show that cocaine induced significant increases ( approximately 10-15%) in [Ca(2+)](i) that were independent of its hemodynamic effects and of the anesthetic used (isofluorance or alpha-chloralose). Lidocaine but not methylphenidate also induced significant [Ca(2+)](i) increases ( approximately 10-13%). This indicates that cocaine at a dose within the range used by drug users significantly increases the [Ca(2+)](i) in the brain and its local anesthetic, but neither its catecholaminergic nor its hemodynamic actions, underlies this effect. Cocaine-induced [Ca(2+)](i) increases are likely to accentuate the neurotoxic effects from cocaine-induced vasoconstriction and to facilitate the occurrence of seizures from the catecholaminergic effects of cocaine. These findings support the use of calcium channel blockers as a strategy to minimize the neurotoxic effects of cocaine.

Common Human 5′ Dopamine Transporter (SLC6A3) Haplotypes Yield Varying Expression Levels In Vivo

Abstract: 1. Individuals display significant differences in their levels of expression of the dopamine transporter (DAT; SLC6A3). These differences in DAT are strong candidates to contribute to individual differences in motor, mnemonic and reward functions. To identify “cis”-acting genetic mechanisms for these individual differences, we have sought variants in 5′ aspects of the human DAT gene and identified the haplotypes that these variants define. 2. We report (i) significant relationships between 5′ DAT haplotypes and human individual differences in ventral striatal DAT expression assessed in vivo using [11C] cocaine PET and (ii) apparent confirmation of these results in studies of DAT expression in postmortem striatum using [3H] carboxyflurotropane binding. 3. These observations support the idea that cis-acting variation in 5′ aspects of the human DAT/SLC6A3 locus contributes to individual differences in levels of DAT expression in vivo. 5′ DAT variation is thus a good candidate to contribute to individual differences in a number of human phenotypes.

"Imaging the Addicted Human Brain: from Molecules to Behavior"

Abstract: Addiction is a disorder that involves complex interactions between a wide array of biological and environmental variables. Studies employing neuroimaging technology paired with sophisticated behavioral measurement paradigms have led to extraordinary progress in elucidating many of the neurochemical and functional changes that occur in the brains of addicts. Although large and rapid increases in dopamine have been linked with the rewarding properties of drugs, the addicted state, in striking contrast, is marked by significant decreases in brain dopamine function. Such decreases are associated with dysfunction of prefrontal regions including orbitofrontal cortex and cingulate gyrus. In addiction, disturbances in salience attribution result in enhanced value given to drugs and drug-related stimuli at the expense of other reinforcers. Dysfunction in inhibitory control systems, by decreasing the addict's ability to refrain from seeking and consuming drugs, ultimately results in the compulsive drug intake that characterizes the disease. Discovery of such disruptions in the fine balance that normally exists between brain circuits underling reward, motivation, memory and cognitive control have important implications for designing multi-pronged therapies for treating addictive disorders.

Research funding: the view from NIH.

Abstract: For many scientists seeking funding from NIH, this seems like the best of times and the worst of times. The opportunities to make scientific discoveries have never been better. Following the completion of the Human Genome Project and the International HapMap Project, we have guides to the common variations in the human genome. These maps yield an unprecedented opportunity to identify the genomic vulnerability to complex diseases and phenotypes, including mental illness, addiction, and alcohol dependence. New neuroimaging tools allow us to detect the circuits involved in the pathophysiology of brain disorders, revealing, for the first time, details of normal and abnormal functioning and development of the human brain. We now have national networks for clinical trials, facilitating large-scale studies of important public health questions. As directors of three NIH Institutes, we believe passionately that there has not been a better time for progress in clinical neuroscience. But in this time of unprecedented opportunities, we are also keenly aware of the anxiety in our fields. From young investigators who are wondering if there is a future for a scientific career to seasoned scientists who are concerned about paylines, we are hearing that these are the worst of times. A sampling of recent questions would include the following: How can NIH have so little money to pay new grants when its budget was just doubled? How can you cut training when there are too few investigators in the field? What should I tell my graduate student who is thinking of leaving science? Are you funding any new grants? We understand that there is both confusion and anxiety about the state of NIH funding. This brief editorial is one attempt to dispel the confusion and allay the anxiety. Similar articles are available elsewhere and may answer questions that we do not address here (1, 2). What is the state of NIH funding? Funding for NIH derives entirely from Congress, based on an annual appropriation process that commits a budget to each Institute. As part of the Department of Human Health and Services (DHHS), NIH is part of the executive branch of government and, as such, we may testify to defend funding for our Institutes, but we are legally prohibited from lobbying Congress for appropriations. From 1998–2003, there was an overall doubling of the NIH appropriation. However, since 2003, there has been relatively little change. The NIH appropriation for 2006 (the fiscal year that ended September 30, 2006) for our three Institutes averaged close to 0.4% above the previous year. The NIH appropriation for the current year has not been determined, but is expected to drop below the 2006 level. If the budget is reduced, doesn't this mean we will fund fewer new grants? Not necessarily. Roughly 70% of our grant support in any given year is for “continuations,” the out-years of multi-year grants. The remaining 30% is a combination of new funds from our appropriation and uncommitted funds from the churn of multi-year grants that are completing their funding cycle. Thus, to project the funds available for new grants in 2007, one needs to look at the appropriation and at what was funded in 2002 and subsequent years. While some of these completed grants will return for competitive renewals, not all will compete successfully. Our most optimistic projections for 2007, assuming a nearly flat Congressional appropriation, suggest that we will be funding roughly the same number of grants as in 2006, due to the turnover from our current portfolio. Of course, any significant reduction in our budget will mean we have less money than we had in 2006 to fund new and continuing grants. However, 2006 was not a growth year. The NIH success rate (the chance that a grant will be funded either in its original or amended form) dropped from 31% in 1998 to 19% in 2006. How can the success rate be dropping when the budget was just doubled? The success rate is the ratio of the number of grants funded divided by the number of applications submitted. This ratio is related but not identical to the payline, which is the percentile for funding in any given round of competition (http://www.nih.gov/about/researchresultsforthepublic/successrates.pdf). Clearly, if the number of grants funded stays the same but the number of applications increases, the success rate will fall. At NIH, the number of grants funded has increased. Indeed, our three Institutes collectively supported 4,393 research project grants in 2005, a 44% increase over the number in 1998. Just focusing on new competing grants, the number has increased to 1,148 in 2005, a 25.5% increase over the number of new grants funded in 1998. During this same period, the average cost of each awarded grant at our three Institutes increased by 34% to an average cost of $368,100 in 2005. However, at the same time that we were funding more grants, there was roughly a 60% increase in the number of grant applications. The result is an imbalance of demand and supply, especially in the past 3 years when the increase in applications and applicants has accelerated. While every Institute and Center is facing slightly different constraints, the fundamental challenge is shared across NIH: just as the demand took off in 2003, the budget hit a plateau. We believe this imbalance between supply and demand is a major source of the current angst in the research community. Even though in the post-doubling era we have been funding more grants than at any time in our history, the drop in paylines leaves many scientists feeling like we are in a fiscal famine. The reality is that competition is greater, funding requires more submissions with delays in research and sometimes loss of personnel, and many of the grants funded are being cut which, in turn, leads to more submissions. Moreover, with continued annual biomedical inflation at 3.5% or greater, following 3 or more years of sub-inflationary budgets, our purchasing power is falling substantially. It is this perfect storm of increased demand with reduced supply that has turned this scientific “best of times” into the “worst of times” for individual investigators. NIH and each of the Institutes have addressed these tough times proactively. We have been especially concerned that the “worst of times” scenario could result in a loss of young investigators and a tendency to avoid high-risk research at the very time when new scientists and innovation can have the greatest impact. The NIH Roadmap and the Neuroscience Blueprint represent joint efforts to support enabling tools and resources for the community, allowing smaller labs and innovative ideas to be competitive. The Roadmap and Blueprint have introduced several new training opportunities to permit training in specific areas of need. In addition, NIH launched a new training mechanism, the Pathway to Independence Award (K99 R00), to facilitate more rapid transition from mentored training to independence. Each Institute has identified priorities for funding, ensuring that certain critical areas will be supported notwithstanding dropping paylines. For prospective and current grantees, there has never been a more important time to work with program officers who can advise about specific priorities and opportunities for funding. As NIH Institute directors, we feel the urgency of delivering breakthroughs for human health, and we are passionate about the unprecedented opportunities to make those breakthroughs with new tools for discovery. We have witnessed previous funding cycles of feast followed by famine. This one is somewhat more dramatic because it follows such a profound increase in the NIH budget and because the research capacity has grown so quickly. But this period of angst will end just as previous difficult periods have ended, biomedical science will continue, and the supply and demand for funding will realign. Our short-term strategies to deliver scientific breakthroughs during this fiscal famine include reducing the size of awards and sharpening our priorities. These short-term strategies may help us through 2007, but these strategies are clearly not sustainable. With each additional year that the nation's support of science falls behind inflation, we are losing ground in our support of discoveries that will reduce the burden of mental illness, addiction, and alcohol dependence.

Response to: “Rescuing the NIH before it is too late”

Abstract: We, the directors of the 27 NIH institutes and centers, wanted to respond to the points made by Andrew Marks in his recent editorial. While we appreciate that the scientific community has concerns, the current initiatives and directions of the NIH have been developed through planning processes that reflect openness and continued constituency input, all aimed at assessing scientific opportunities and addressing public health needs.