Bertha K. Madras

Dopamine transporter density in patients with attention deficit hyperactivity disorder

Dopamine transporter density was measured in vivo in six adult patients with attention deficit hyperactivity disorder. We have shown a 70% increase in age-corrected dopamine transporter density in patients with attention hyperactivity disorder compared with healthy controls.

Office of National Drug Control Policy: a scientist in drug policy in Washington, DC.

This essay describes how a basic scientist was thrust into the epicenter, the political cauldron of our national drug control policy, and how the experience altered her professional trajectory and perspective.

Screening, brief interventions, referral to treatment (SBIRT) for illicit drug and alcohol use at multiple healthcare sites: comparison at intake and 6 months later

OBJECTIVES Alcohol screening and brief interventions in medical settings can significantly reduce alcohol use. Corresponding data for illicit drug use is sparse. A Federally funded screening, brief interventions, referral to treatment (SBIRT) service program, the largest of its kind to date, was initiated by the Substance Abuse and Mental Health Services Administration (SAMHSA) in a wide variety of medical settings. We compared illicit drug use at intake and 6 months after drug screening and interventions were administered. DESIGN SBIRT services were implemented in a range of medical settings across six states. A diverse patient population (Alaska Natives, American Indians, African-Americans, Caucasians, Hispanics), was screened and offered score-based progressive levels of intervention (brief intervention, brief treatment, referral to specialty treatment). In this secondary analysis of the SBIRT service program, drug use data was compared at intake and at a 6-month follow-up, in a sample of a randomly selected population (10%) that screened positive at baseline. RESULTS Of 459,599 patients screened, 22.7% screened positive for a spectrum of use (risky/problematic, abuse/addiction). The majority were recommended for a brief intervention (15.9%), with a smaller percentage recommended for brief treatment (3.2%) or referral to specialty treatment (3.7%). Among those reporting baseline illicit drug use, rates of drug use at 6-month follow-up (4 of 6 sites), were 67.7% lower (p<0.001) and heavy alcohol use was 38.6% lower (p<0.001), with comparable findings across sites, gender, race/ethnic, age subgroups. Among persons recommended for brief treatment or referral to specialty treatment, self-reported improvements in general health (p<0.001), mental health (p<0.001), employment (p<0.001), housing status (p<0.001), and criminal behavior (p<0.001) were found. CONCLUSIONS SBIRT was feasible to implement and the self-reported patient status at 6 months indicated significant improvements over baseline, for illicit drug use and heavy alcohol use, with functional domains improved, across a range of health care settings and a range of patients.

The Dopamine Transporter and Attention-Deficit/Hyperactivity Disorder.

The high incidence of attention-deficit/hyperactivity disorder (ADHD) and escalating use of ADHD medications present a compelling case for clarifying the pathophysiology of, and developing laboratory or radiologic tests for, ADHD. Currently, the majority of specific genes implicated in ADHD encode components of catecholamine signaling systems. Of these, the dopamine transporter (DAT) is a principal target of the most widely used antihyperactivity medications (amphetamine and methylphenidate); the DAT gene is associated with ADHD, and some studies have detected abnormal levels of the DAT in brain striatum of ADHD subjects. Medications for ADHD interfere with dopamine transport by brain-region- and drug-specific mechanisms, indirectly activating dopamine- and possibly norepinephrine-receptor subtypes that are implicated in enhancing attention and experiential salience. The most commonly used DAT-selective ADHD medications raise extracellular dopamine levels in DAT-rich brain regions. In brain regions expressing both the DAT and the norepinephrine transporter (NET), the relative contributions of dopamine and norepinephrine to ADHD pathophysiology and therapeutic response are obfuscated by the capacity of the NET to clear dopamine as well as norepinephrine. Thus, ADHD medications targeting DAT or NET might disperse dopamine widely and consign dopamine storage and release to regulation by noradrenergic, as well as dopaminergic neurons.

Modafinil Occupies Dopamine and Norepinephrine Transporters in Vivo and Modulates the Transporters and Trace Amine Activity in Vitro

2-[(Diphenylmethyl) sulfinyl]acetamide (modafinil), prescribed principally to treat narcolepsy, is undergoing assessment for other neuropsychiatric disorders and medical conditions. The neurochemical substrates of modafinil are unresolved. We postulated that modafinil enhances wakefulness by modulating dopamine (DAT), norepinephrine (NET), or serotonin (SERT) transporter activities. In vivo, we determined DAT and NET occupancy by modafinil by positron emission tomography imaging; in vitro, we determined modafinil activity at the DAT, NET, SERT, and rhesus monkey trace amine receptor 1 (TA1). In rhesus monkey, modafinil occupancy of striatal DAT was detected by [11C]2β-carbomethoxy-3β-4-(fluorophenyl)tropane and of thalamic NET by [11C](S,S)-2-(α-(2-methoxyphenoxy)-benzyl)morpholine. In vitro, modafinil effects in DAT-human embryonic kidney (HEK), NET-HEK, and SERT-HEK cells were investigated alone or combined with the TA1 receptor. Modafinil (i.v.) occupied striatal DAT sites (5 mg/kg: 35 ± 12%, n = 4; 8 mg/kg: 54 ± 3%, n = 3). In thalamus, modafinil occupied NET sites (5 mg/kg: 16 ± 7.8%, n = 6; 8 mg/kg: 44 ± 12%; n = 2). In vitro, modafinil inhibited [3H]dopamine (IC50 = 6.4 μM), [3H]norepinephrine (IC50 = 35.6 μM), and [3H]serotonin (IC50 > 500 μM) transport via the human DAT, NET, and SERT. Modafinil did not activate the TA1 receptor in TA1-HEK cells, but it augmented a monoamine transporter-dependent enhancement of phenethylamine activation of TA1 in TA1-DAT and TA1-NET cells, but not in TA1-SERT cells. The present data provide compelling evidence that modafinil occupies the DAT and NET in living brain of rhesus monkeys and raise the possibility that modafinil affects wakefulness by interacting with catecholamine transporters in brain.

Anti-hyperactivity medication: methylphenidate and amphetamine

How do ‘stimulants’ reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinsons disease? These apparent paradoxes are the focus of this brief review on the mechanism of action of stimulant medications used in the treatment of children, and of an increasing number of adults who meet diagnostic criteria for attention deficit hyperactivity disorder.

Asparagine Synthetase Activity of Mouse Leukemias

Various transplanted leukemias and normal tissues of the mouse were tested for asparagine synthetase activity. Leukemias susceptible to suppression by asparaginase have little or no synthetase activity. In contrast, leukemias insensitive to asparaginase exhibit substantial and often very high asparagine synthetase activity. Asparaginase-resistant variants of sensitive leukemias also have considerable synthetase activity. Thus the requirement by certain malignant cells of exogenous asparagine, which entails sensitivity to asparaginase, may be ascribed to lack of asparagine synthetase. Development of asparaginase-resistant variants from asparaginase-sensitive lines is consistently associated with acquisition of asparagine synthetase activity.

In vivo neuroreceptor imaging in attention-deficit/ hyperactivity disorder : A focus on the dopamine transporter

There is converging evidence of the role of catecholamine dysregulation in the underlying pathophysiology of attention-deficit/hyperactivity disorder (ADHD). The dopamine transporter (DAT) is known to be a key regulator of dopamine, and recent genetic, treatment, and imaging studies have highlighted the role of DAT in ADHD. There is an emerging literature on in vivo neuroreceptor imaging of DAT in ADHD and control subjects reported by a number of groups internationally. A comprehensive review of existing imaging studies of DAT binding in ADHD shows that six of eight independent studies by six different groups have reported increased DAT binding in (mostly) treatment-naïve children and adults with ADHD. Although there is fair agreement regarding the presence and direction of abnormal DAT binding, there remains disagreement as to the magnitude of the finding and the importance of many potentially confounding variables, including clinical characteristics and imaging methodology. Three studies by three different groups have reported decreased DAT binding after methylphenidate treatment. Interpretation of the latter finding awaits clarification of the issue of timing of drug administration and imaging to disentangle receptor occupancy from downregulation.

Relevance of free tryptophan in serum to tissue tryptophan concentrations

Abstract The consumption of a carbohydrate diet by fasted rats is followed by major decreases in serum nonesterified fatty acids (NEFA) and nonalbumin-bound tryptophan (unbound tryptophan), but by increases in serum total tryptophan and brain tryptophan; the tryptophan concentrations of liver and small intestine are unchanged, while that of skeletal muscle falls slightly. The addition of 15% or 30% fat to a protein-carbohydrate diet results in dose-related increases in serum NEFA and serum unbound tryptophan, but no significant changes in serum total tryptophan or brain tryptophan. The observation that diet-induced changes in serum unbound tryptophan does not correlate with brain tryptophan concentrations is independent of the method used to separate free from albumin-bound serum tryptophan. These studies confirm that, in the rat, a major physiologic regulator of the extent to which serum tryptophan binds to albumin is the concentration of NEFA in serum. These studies also provide additional evidence that the concentration of tryptophan in the brain is not necessarily determined by the size of the unbound pool of tryptophan in blood as measured in serum.

Rapid detection of Parkinson's disease by SPECT with altropane: A selective ligand for dopamine transporters

Increasing evidence indicates that dopamine (DA) transporter density declines in Parkinsons disease (PD). 2β‐Carbomethoxy‐3β‐(4‐fluorophenyl)‐n‐(1‐iodoprop‐1‐en‐3‐yl) nortropane (IACFT, Altropane™) is a cocaine analog with high affinity and selectivity for dopamine transporter (DAT) sites in the striatum. In this study, single photon emission computed tomography (SPECT) with [123I]altropane was used to measure DAT density in seven healthy volunteers (five males, age 37–75, and two females, ages 26 and 39) and eight male patients with Parkinsons disease (age 14–79, Hoehn and Yahr stage: 1.5–3 (n = 5) and 4–5 (n = 3)). Dynamic SPECT images and arterial blood samples were acquired over 1.5–2 hr and plasma radioactivity was analyzed chromatographically to obtain metabolite corrected arterial input functions. Binding potential (BP, B′max/KD) for striatal (Str) DAT sites was calculated by two methods using occipital cortex (Occ) as a reference. In the first method, tissue time–activity curves (TAC) and metabolite corrected arterial input functions were analyzed by a linear graphical method developed for reversible receptor ligands. In the second method, the expression (StrTAC − OccTAC) was fitted to a gamma variate function and the maximum divided by OccTAC at the same time was used to estimate BP. In five of the PD patients, the SPECT data were compared with the results of PET with [18F] 6‐fluoro DOPA (FD‐PET). Plasma analysis indicated that [123I]altropane is rapidly converted to polar metabolites. SPECT images in healthy volunteers showed that [123I]altropane accumulated rapidly and selectively in the striatum and yielded excellent quality images within 1 h after injection. Both methods of analysis revealed a 7.6%/decade reduction in BP and average striatal values (corrected to age 25) were 1.83 ± 0.22 and 2.09 ± 0.20 by methods 1 and 2. In all the PD patients, striatal accumulation was markedly reduced and the pattern of loss was similar to that reported for DA; most profound in the posterior putamen with relative sparing of the caudate nuclei. A comparable pattern was observed with FD‐PET. For total striatum, age‐corrected BP was significantly (P < 0.001) reduced; 0.83 ± 0.06 (method 1), 0.84 ± 0.07 (method 2). BPs measured by the two methods were remarkably similar and highly correlated r2 = 0.88, (P < 0.001). These results indicate that [123I]altropane is an excellent SPECT ligand for imaging the DAT/DA neurons in human brain. The high selectivity and rapid striatal accumulation of the ligand allows for accurate quantitation of DAT sites in less than 2 hr. The results further demonstrate that [123I]altropane is an effective marker for PD. Synapse 29:128–141, 1998.