Naomi R. Pappas

Regional brain metabolic activation during craving elicited by recall of previous drug experiences

Cocaine cues elicit craving and physiological responses. The cerebral circuits involved in these are poorly understood. The purpose of this study was to assess the relation between regional brain activation and cocaine cue elicited responses. Thirteen right-handed cocaine abusers were scanned with positron emission tomography (PET) and [F-18] fluorodeoxyglucose (FDG) twice; during an interactive interview about neutral themes and during an interactive interview about cocaine themes designed to elicit cocaine craving. In parallel the behavioral (rated from 0: felt nothing to 10: felt extreme) and cardiovascular responses were recorded. During the cocaine theme interview subjects reported higher self reports for cocaine craving (+2.5+/-3.3, p < or = 0.02) and had higher heart rates (+4.7+/-7.2%, p < or = 0.001), systolic (+4+/-4%, p < or = 0.0001), and diastolic blood pressures (+2.6+/-3.8%, p < or = 0.003) than during the neutral interview. Absolute and relative metabolic values in the orbitofrontal (+16.4+/-17.1%, p < or = 0.005; +11.3+/-14.3%, p < or = 0.008) and left insular cortex (+21.6+/-19.6%, p < or = 0.002; +16.7+/-19.7%, p < or = 0.01) and relative values in cerebellum (+17.9+/-14.8%, p < or = 0.0008) were higher during the cocaine theme than during the neutral theme interview. Relative metabolic values in the right insular region (p < or = 0.0008) were significantly correlated with self reports of cocaine craving. Activation of the temporal insula, a brain region involved with autonomic control, and of the orbitofrontal cortex, a brain region involved with expectancy and reinforcing salience of stimuli, during the cocaine theme support their involvement with craving in cocaine addicted subjects.

Age-Related Increases in Brain Monoamine Oxidase B in Living Healthy Human Subjects

Several studies of human brain postmortem report that monoamine oxidase B (MAO B) increases with age and it has been proposed that this increase reflects age-associated increases in glial cells. We measured brain MAO B in a group of normal healthy human subjects (n = 21; age range 23-86; 9 females and 12 males; nonsmokers) using [11C]L-deprenyl-D2 and positron emission tomography. Brain glucose metabolism was also measured with 18FDG in 15 of the subjects. MAO B increased (p < 0.004) in all brain regions examined except the cingulate gyrus. In contrast, subjects showed the expected regional age-related decreases in blood flow and metabolism. In the 15 subjects in whom both MAO B and LCMRglu was measured, there was a trend (p < 0.03) toward an inverse association between brain glucose metabolism and MAO B activity in the frontal and parietal cortices. Although the age-related increase in brain MAO B in living subjects is consistent with postmortem reports, the degree of increase is generally lower.

Chiral drugs: comparison of the pharmacokinetics of [11C]d-threo and L-threo-methylphenidate in the human and baboon brain.

Abstract  Methylphenidate (Ritalin) is the most commonly prescribed psychoactive medication for children in the US where it is used for the treatment of attention deficit hyperactivity disorder. Methylphenidate is marketed as a racemic mixture of the d-threo and l-threo enantiomers. It is believed that the d enantiomer is responsible for the therapeutic effect of methylphenidate. In this study we labeled the individual enantiomers with carbon-11 and compared their binding and pharmacokinetics in the human and baboon brain. Microdialysis studies in the rat were performed to compare their potency in elevating striatal dopamine concentration. Positron emission tomographic (PET) studies with [11C]d-threo-methylphenidate ([11C]d-threo-MP) demonstrated highest regional uptake in basal ganglia. In contrast, [11C]l-threo-methylphenidate ([11C]l-threo-MP) displayed similar uptakes in all brain regions. The ratios of distribution volumes at the steady-state for the basal ganglia to cerebellum (DVBG/DVCB) ranged from 2.2 to 3.3 for [11C]d-threo-MP in baboon and human, and only 1.1 for [11C]l-threo-MP. Pretreatment with unlabeled methylphenidate (0.5 mg/kg) or GBR12909 (1.5 mg/kg) markedly reduced the striatal but not the cerebellar uptake of [11C]d-threo-MP, whereas there was no effect on DVBG/DVCB for [11C]l-threo-MP. In the rat, d-threo-MP increased extracellular dopamine concentration by 650% whereas l-threo-MP did not affect dopamine levels. These results indicate that pharmacological specificity of MP resides entirely in the d-threo isomer and directly show that binding of the l-isomer in human brain is mostly non-specific.

Enhanced resting activity of the oral somatosensory cortex in obese subjects.

The cerebral mechanisms underlying excess food intake in obese subjects are poorly understood. We used PET and 2-deoxy-2[18F]fluoro-D-glucose to assess differences in regional brain metabolism between obese and lean subjects at rest. Brain metabolic images were analyzed using statistical parameter maps. We found that obese subjects have significantly higher metabolic activity in the bilateral parietal somatosensory cortex in the regions where sensation to the mouth, lips and tongue are located. The enhanced activity in somatosensory regions involved with sensory processing of food in the obese subjects could make them more sensitive to the rewarding properties of food related to palatability and could be one of the variables contributing to their excess food consumption.

Cardiovascular effects of methylphenidate in humans are associated with increases of dopamine in brain and of epinephrine in plasma

RationaleThe cardiovascular effects of psychostimulant drugs (methylphenidate, amphetamine, cocaine) have been mostly associated with their noradrenergic effects. However, there is some evidence that dopaminergic effects are involved in the cardiovascular actions of these drugs. Here, we evaluated this association in humans.MethodsPositron emission tomography (PET) and [11C]raclopride, a dopamine (DA) D2 receptor radioligand that competes with endogenous DA for occupancy of the D2 receptors, were used to measure changes in brain DA after different doses of intravenous methylphenidate in 14 healthy subjects. Cardiovascular (heart rate and blood pressure) and catecholamine (plasma epinephrine and norepineprhine) responses were determined in parallel to assess their relationships to methylphenidate-induced changes in brain DA.ResultsMethylphenidate administration significantly increased heart rate, systolic and diastolic blood pressures and epinephrine concentration in plasma. The increases in blood pressure were significantly correlated with methylphenidate-induced increases of DA in striatum (r>0.78, P<0.001) and of plasma epinephrine levels (r>0.82, P<0.0005). In turn methylphenidate-induced DA increases in striatum were correlated with increases of epinephrine in plasma (r=0.85, P<0.0001). Subjects in whom methylphenidate did not increase DA had no change in blood pressure or in plasma epinephrine concentration.DiscussionThese results are consistent with the hypothesis that methylphenidate-induced increases in blood pressure are in part due to its central dopaminergic effects. They also suggest that methylphenidates pressor effects may be in part mediated by DA-induced increases in peripheral epinephrine.

Comparable changes in synaptic dopamine induced by methylphenidate and by cocaine in the baboon brain.

Though the blockade of dopamine transporters (DAT) is associated with cocaines and methylphenidates reinforcing effects, it is the stimulation of dopamine (DA) receptors, achieved by increases in synaptic DA, that enables these effects to occur. Positron emission tomography (PET) and [11C]raclopride were used to assess the levels of occupancy of DA D2 receptors by dopamine achieved by doses of cocaine or methylphenidate previously documented to block over 70% of DAT. Studies were performed in five baboons using a paired scan protocol designed to measure DA D2 receptor availability (Bmax/Kd) at baseline conditions and after intravenous administration of either cocaine or methylphenidate. Cocaine (1–2 mg/kg) or methylphenidate (0.5 mg/kg) administered 5 min prior to [11C]raclopride decreased Bmax/Kd by 29 ± 3% and 32 ± 4%, respectively. Smaller reductions in Bmax/Kd (13% for cocaine given 30 min before [11C]raclopride and 25 ± 10% for methylphenidate given 40 min before [11C]raclopride) were seen with longer periods between drug and radioligand. These observations are consistent with the slower striatal clearance kinetics of [11C]methylphenidate than [11C]cocaine observed in previous PET experiments and with the approximately twofold higher potency of methylphenidate than cocaine in in vitro experiments. Though the elevation of synaptic DA induced by >70% occupancy of DAT by these drugs lead to a modest increase in occupancy of D2 receptors (25–30%), further studies are required to assess if this is an underestimation because of differences in D2 receptor binding kinetics between raclopride and DA. Synapse 31:59–66, 1999.

Alcohol intoxication induces greater reductions in brain metabolism in male than in female subjects.

BACKGROUND The mechanisms underlying the gender differences in alcohol drinking behavior and alcohols effects are poorly understood and may reflect gender differences in brain neurochemistry. Alcohol decreases glucose metabolism in the human brain in a pattern that is consistent with its facilitation of GABAergic neurotransmission. We compared the regional changes in brain glucose metabolism during alcohol intoxication between female and male subjects. METHODS Ten female and 10 male healthy controls were scanned with positron emission tomography and 2-deoxy-2[18F]fluoro-D-glucose twice: 40 min after placebo (diet soda) or alcohol (0.75 g/kg mixed with diet soda). RESULTS Alcohol significantly and consistently decreased whole-brain metabolism. The magnitude of these changes was significantly larger in male (-25 +/- 6%) than in female (-14 +/- 11%; p < 0.005) subjects. Half of the female subjects had reductions in metabolism during intoxication that were significantly lower than those in male subjects. This blunted response in the female subjects was not due to differences in alcohol concentration in plasma, because these did not differ between the genders. In contrast, the self-reports for the perception of intoxication were significantly greater in female than in male subjects. The cognitive deterioration during alcohol intoxication, although not significant, tended to be worse in female subjects. CONCLUSIONS This study shows a markedly blunted sensitivity to the effects of acute alcohol on brain glucose metabolism in female subjects that may reflect gender differences in alcohols modulation of GABAergic neurotransmission. The greater behavioral effects of alcohol in female subjects despite the blunted metabolic responses could reflect other effects of alcohol, for which the regional metabolic signal may be hidden within the large decrements in metabolism that occur during alcohol intoxication.

Cocaine abusers do not show loss of dopamine transporters with age

Cocaine blocks dopamine transporters (DAT) and this effect is crucial to its reinforcing properties. To assess the effects of chronic cocaine on DAT we evaluated 20 current cocaine abusers and 20 age matched controls using PET and [C-11]cocaine as a DAT ligand. Though there were no differences in DAT availability between groups, current cocaine abusers (and 12 detoxified cocaine abusers studied previously) did not show the typical age-related decline in DAT seen in controls. Though further studies are required to rule out sampling effects and to control for confounding variables (i.e. smoking), one could speculate that chronic DAT blockade by cocaine has a protective effect on the loss of DAT with age.

Non-MAO A binding of clorgyline in white matter in human brain

Clorgyline is an irreversible inhibitor of monoamine oxidase (MAO A) which has been labeled with carbon‐11 (C‐11) and used to measure human brain MAO A with positron emission tomography (PET). In this study we compared [11C]clorgyline and deuterium‐substituted [11C]clorgyline ([11C]clorgyline‐D2) to better understand the molecular link between [11C]clorgyline binding and MAO A. In PET studies of five normal healthy volunteers scanned with [11C]clorgyline and [11C]clorgyline‐D2 2 h apart, deuterium substitution generally produced the expected reductions in the brain uptake of [11C]clorgyline. However, the reduction was not uniform with the C‐11 binding in white matter being significantly less sensitive to deuterium substitution than other brain regions. The percentages of the total binding attributable to MAO A is largest for the thalamus and smallest for the white matter and this is clearly seen in PET images with [11C]clorgyline‐D2. Thus deuterium‐substituted [11C]clorgyline selectively reduces the MAO A binding component of clorgyline in the human brain revealing non‐MAO A binding which is most apparent in the white matter. The characterization of the non‐MAO A binding component of this widely used MAO A inhibitor merits further investigation.

Evidence that l-deprenyl treatment for one week does not inhibit mao a or the dopamine transporter in the human brain

In this study, we investigated whether treatment with L-deprenyl, a selective monoamine oxidase B (MAO B) inhibitor, also inhibits MAO A or the dopamine transporter in the human brain. Six normal volunteers (age 46+/-6 yrs) had two PET sessions, one at baseline and one following L-deprenyl (10 mg/day) for 1 week. Each session included one scan with [11C]clorgyline (to assess MAO A) and one scan 2 hours later with [11C]cocaine (to assess dopamine transporter availability). A 3-compartment model was used to compare the plasma-to-brain transfer constant, K1 (a function of blood flow) and lambdak3 (a kinetic term proportional to brain MAO A) before and after treatment. Dopamine transporter availability was measured as the ratio of distribution volumes of the striatum to cerebellum (DVR) which is equal to Bmax/KD +1. L-Deprenyl treatment for 1 week did not affect either brain MAO A activity or dopamine transporter availability. There was a non-significant trend for an increase in K1 after L-deprenyl. These results confirm that L-deprenyl after one week of treatment at doses typically used clinically is selective for MAO B and that it does not produce a measurable affect on the dopamine transporter, suggesting that MAO A inhibition and dopamine transporter blockade do not contribute to its pharmacological effects.