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The dopamine system is a primary treatment target for cocaine dependence (CD), but research on dopaminergic abnormalities (eg, D2 receptor system deficiencies) has so far failed to translate into effective treatment strategies. The D3 receptor system has recently attracted considerable clinical interest, and D3 antagonism is now under investigation as a novel avenue for addiction treatment. The objective here was to evaluate the status and behavioral relevance of the D3 receptor system in CD, using the positron emission tomography (PET) radiotracer [11C]-(+)-PHNO. Fifteen CD subjects (many actively using, but all abstinent 7-240 days on scan day) and fifteen matched healthy control (HC) subjects completed two PET scans: one with [11C]-(+)-PHNO to assess D3 receptor binding (BPND; calculated regionally using the simplified reference tissue model), and for comparison, a second scan with [11C]raclopride to assess D2/3 binding. CD subjects also completed a behavioral battery to characterize the addiction behavioral phenotype. CD subjects showed higher [11C]-(+)-PHNO BPND than HC in the substantia nigra, which correlated with behavioral impulsiveness and risky decision making. In contrast, [11C]raclopride BPND was lower across the striatum in CD, consistent with previous literature in 2 week abstinence. The data suggest that in contrast to a D2 deficiency, CD individuals may have heightened D3 receptor levels, which could contribute to addiction-relevant traits. D3 upregulation is emerging as a biomarker in preclinical models of addiction, and human PET studies of this receptor system can help guide novel pharmacological strategies for treatment. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) imaging of monoamine oxidases (MAO-A: [11C]harmine, [11C]clorgyline, and [11C]befloxatone; MAO-B: [11C]deprenyl-D2) has been actively pursued given clinical importance of MAOs in human neuropsychiatric disorders. However, it is unknown how well PET outcome measures for the different radiotracers are quantitatively related to actual MAO protein levels. We measured regional distribution (n=38) and developmental/aging changes (21 hours to 99 years) of both MAOs by quantitative immunoblotting in autopsied normal human brain. MAO-A was more abundant than MAO-B in infants, which was reversed as MAO-B levels increased faster before 1 year and, unlike MAO-A, kept increasing steadily to senescence. In adults, regional protein levels of both MAOs were positively and proportionally correlated with literature postmortem data of MAO activities and binding densities. With the exception of [11C]befloxatone (binding potential (BP), r=0.61, P=0.15), correlations between regional PET outcome measures of binding in the literature and MAO protein levels were good (P<0.01) for [11C]harmine (distribution volume, r=0.86), [11C]clorgyline (λk3, r=0.82), and [11C]deprenyl-D2 (λk3 or modified Patlak slope, r=0.78 to 0.87), supporting validity of the latter imaging measures. However, compared with in vitro data, the latter PET measures underestimated regional contrast by ∼2-fold. Further studies are needed to address cause of the in vivo vs. in vitro nonproportionality. [ABSTRACT FROM AUTHOR]

Aims Pathological gambling ( PG) shares diagnostic features with substance use disorder ( SUD), but the neurochemical mechanisms underlying PG are poorly understood. Because dopamine ( DA), a neurotransmitter implicated in reward and reinforcement, is probably involved, we used positron emission tomography ( PET) to test whether PG is associated with abnormalities in D2 and D3 receptor levels, as observed in SUD. Design Case-control study comparing PG to healthy control ( HC) subjects. Setting Academic research imaging centre. Participants Thirteen non-treatment-seeking males meeting DSM- IV criteria for PG, and 12 matched HC (11 of whom completed PET). Measurements Two PET scans (one with the D3 receptor preferring agonist [11 C]-(+)-propyl-hexahydro-naphtho-oxazin ( PHNO) and the other with [11 C]raclopride) to assess D2/3 DA receptor availability, and behavioural measures (self-report questionnaires and slot-machine game) to assess subjective effects and relationships to PET measures. Findings Binding of both radiotracers did not differ between groups in striatum or substantia nigra ( SN) (all P > 0.1). Across PG, [11 C]-(+)- PHNO binding in SN, where the signal is attributable primarily to D3 receptors, correlated with gambling severity ( r = 0.57, P = 0.04) and impulsiveness ( r = 0.65, P = 0.03). In HC, [11 C]raclopride binding in dorsal striatum correlated inversely with subjective effects of gambling ( r = −0.70, P = 0.03) and impulsiveness ( r = −0.70, P = 0.03). Conclusions Unlike with substance use disorder, there appear to be no marked differences in D2/ D3 levels between healthy subjects and pathological gamblers, suggesting that low receptor availability may not be a necessary feature of addiction. However, relationships between [11 C]-(+)- PHNO binding and gambling severity/impulsiveness suggests involvement of the D3 receptor in impulsive/compulsive behaviours. [ABSTRACT FROM AUTHOR]

The thalamus occupies a pivotal position within the corticobasal ganglia-cortical circuits. In Parkinson's disease (PD), the thalamus exhibits pathological neuronal discharge patterns, foremost increased bursting and oscillatory activity, which are thought to perturb the faithful transfer of basal ganglia impulse flow to the cortex. Analogous abnormal thalamic discharge patterns develop in animals with experimentally reduced thalamic noradrenaline; conversely, added to thalamic neuronal preparations, noradrenaline exhibits marked antioscillatory and antibursting activity. Our study is based on this experimentally established link between noradrenaline and the quality of thalamic neuronal discharges. We analyzed 14 thalamic nuclei from all functionally relevant territories of 9 patients with PD and 8 controls, and measured noradrenaline with high-performance liquid chromatography with electrochemical detection. In PD, noradrenaline was profoundly reduced in all nuclei of the motor (pallidonigral and cerebellar) thalamus (ventroanterior: −86%, P = .0011; ventrolateral oral: −87%, P = .0010; ventrolateral caudal: −89%, P = .0014): Also, marked noradrenaline losses, ranging from 68% to 91% of controls, were found in other thalamic territories, including associative, limbic and intralaminar regions; the primary sensory regions were only mildly affected. The marked noradrenergic deafferentiation of the thalamus discloses a strategically located noradrenergic component in the overall pathophysiology of PD, suggesting a role in the complex mechanisms involved with the genesis of the motor and non-motor symptoms. Our study thus significantly contributes to the knowledge of the extrastriatal nondopaminergic mechanisms of PD with direct relevance to treatment of this disorder. © 2012 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Monoamine oxidase A (MAO-A) is an important target in the pathophysiology and therapeutics of major depressive disorder, aggression, and neurodegenerative conditions. We measured the effect of changes in MAO-A substrate on MAO-A binding in regions implicated in affective and neurodegenerative disease with [11C]-harmine positron emission tomography in healthy volunteers. Monoamine oxidase A VT, an index of MAO-A density, was decreased (mean: 14%±9%) following tryptophan depletion in prefrontal cortex (P<0.031), and elevated (mean: 17%±11%) in striatum following carbidopa-levodopa administration (P<0.007). These findings suggest an adaptive role for MAO-A in maintaining monoamine neurotransmitter homeostasis by rapidly compensating fluctuating monoamine levels. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) findings suggesting lower D2-type dopamine receptors and dopamine concentration in brains of stimulant users have prompted speculation that increasing dopamine signaling might help in drug treatment. However, this strategy needs to consider the possibility, based on animal and postmortem human data, that dopaminergic activity at the related D3 receptor might, in contrast, be elevated and thereby contribute to drug-taking behavior.Wetested the hypothesis thatD3 receptor binding is above normal in methamphetamine (MA) polydrug users, using PET and the D3-preferring ligand [11C]-(+)-propyl-hexahydro-naphthooxazin ([11C]-(+)-PHNO). Sixteen control subjects and 16 polydrug users reporting MA as their primary drug of abuse underwent PET scanning after [11C]-(+)-PHNO. Compared with control subjects, drug users had higher [11C]-(+)-PHNO binding in the D3-rich midbrain substantia nigra (SN;+46%; p<0.02) and in the globus pallidus (+9%; p=0.06) and ventral pallidum (+11%; p=0.1), whereas binding was slightly lower in the D2-rich dorsal striatum (approximately -4%, NS; -12% in heavy users, p = 0.01) and related to drug-use severity. The [11C]-(+)-PHNO binding ratio in D3-rich SN versus D2-rich dorsal striatum was 55% higher in MA users (p = 0.004), with heavy but not moderate users having ratios significantly different from controls. [11C]-(+)-PHNO binding in SN was related to self-reported "drug wanting." We conclude that the dopamine D3 receptor, unlike the D2 receptor, might be upregulated in brains of MA polydrug users, although lower dopamine levels in MA users could have contributed to the finding. Pharmacological studies are needed to establish whether normalization of D3 receptor function could reduce vulnerability to relapse in stimulant abuse. [ABSTRACT FROM AUTHOR]

The choice of reference region in positron emission tomography (PET) human brain imaging of the vesicular monoamine transporter 2 (VMAT2), a marker of striatal dopamine innervation, has been arbitrary, with cerebellar, whole cerebral, frontal, or occipital cortices used. To establish whether levels of VMAT2 are in fact low in these cortical areas, we measured VMAT2 protein distribution by quantitative immunoblotting in autopsied normal human brain (n=6). Four or five species of VMAT2 immunoreactivity (75, 55, 52, 45, 35 kDa) were detected, which were all markedly reduced in intensity in nigrostriatal regions of patients with parkinsonian conditions versus matched controls (n=9 to 10 each). Using the intact VMAT2 immunoreactivity, cerebellar and cerebral neocortices had levels of the transporter >100-fold lower than the VMAT2-rich striatum and with no significant differences among the cortical regions. We conclude that human cerebellar and cerebral cortices contain negligible VMAT2 protein versus the striatum and, in this respect, all satisfy a criterion for a useful reference region for VMAT2 imaging. The slightly lower PET signal for VMAT2 binding in occipital (the currently preferred reference region) versus cerebellar cortex might not therefore be explained by differences in VMAT2 protein itself but possibly by other imaging variables, for example, partial volume effects. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined prefrontal and anterior cingulate cortex monoamine oxidase (MAO-A) binding during acute cigarette withdrawal. A number of healthy nonsmoking and smoking individuals served as subjects in this study. Results of the study showed that prefrontal and anterior cingulate cortex MAO-A was greater during withdrawal in heavy-smoking individuals. It also found that depression severity was associated with a change in MAO-A beween withdrawal and heavy smoking.

Because methamphetamine exposure to experimental animals can damage brain dopamine neurones, we examined whether hospital patients diagnosed with methamphetamine-related disorders might have greater risk of subsequent admission with a Parkinson's disease diagnosis. This was a population-based cohort study using all statewide inpatient hospital discharge records from July 1, 1990, through June 30, 2000, in California, USA, in which subjects aged at least 50 years were followed for up to 10 years. Individuals with reported methamphetamine-related conditions (n = 1,863; ICD-9 codes 304.4, 305.7, 969.7, and E854.2) were matched on demographic variables and follow-up time with those with primary appendicitis conditions (n = 9,315). The appendicitis group had a Parkinson's disease incidence rate no different than the rate found among members of a large health maintenance organization in California. Cox regression procedures were used to estimate group differences in the rates of receiving a subsequent inpatient diagnosis of Parkinson's disease (ICD-9 332.0). The methamphetamine group showed increased risk of a subsequent admission with Parkinson's disease compared with that of the matched appendicitis group (adjusted hazard ratio = 2.65, 95% CI, 1.17-5.98, P= 0.019). Study limitations include a population limited to hospital admissions, an uncertainty regarding diagnostic validity of the ICD-9 code 332.0 (Parkinson's disease), and a small number of incident cases with suspected Parkinson's disease. We strongly emphasize the preliminary nature of the findings. Nevertheless, these data, requiring replication, provide some evidence that methamphetamine users might be at greater than normal risk for developing Parkinson's disease. © 2010 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Animal data indicate that the recreational drug ecstasy (3,4-methylenedioxymethamphetamine) can damage brain serotonin neurons. However, human neuroimaging measurements of serotonin transporter binding, a serotonin neuron marker, remain contradictory, especially regarding brain areas affected; and the possibility that structural brain differences might account for serotonin transporter binding changes has not been explored. We measured brain serotonin transporter binding using [11C] N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine in 50 control subjects and in 49 chronic (mean 4 years) ecstasy users (typically one to two tablets bi-monthly) withdrawn from the drug (mean 45 days). A magnetic resonance image for positron emission tomography image co-registration and structural analyses was acquired. Hair toxicology confirmed group allocation but also indicated use of other psychoactive drugs in most users. Serotonin transporter binding in ecstasy users was significantly decreased throughout all cerebral cortices (range -19 to -46%) and hippocampus (-21%) and related to the extent of drug use (years, maximum dose), but was normal in basal ganglia and midbrain. Substantial overlap was observed between control and user values except for insular cortex, in which 51% of ecstasy user values fell below the lower limit of the control range. Voxel-based analyses confirmed a caudorostral gradient of cortical serotonin transporter binding loss with occipital cortex most severely affected. Magnetic resonance image measurement revealed no overall regional volume differences between groups; however, a slight left-hemispheric biased cortical thinning was detected in methamphetamine-using ecstasy users. The serotonin transporter binding loss was not related to structural changes or partial volume effect, use of other stimulant drugs, blood testosterone or oestradiol levels, major serotonin transporter gene promoter polymorphisms, gender, psychiatric status, or self-reported hyperthermia or tolerance. The ecstasy group, although grossly behaviourally normal', reported subnormal mood and demonstrated generally modest deficits on some tests of attention, executive function and memory, with the latter associated with serotonin transporter decrease. Our findings suggest that the 'typical'/low dose (one to two tablets/ session) chronic ecstasy-polydrug user might display a highly selective mild to marked loss of serotonin transporter in cerebral cortex/hippocampus in the range of that observed in Parkinson's disease, which is not gender-specific or completely accounted for by structural brain changes, recent use of other drugs (as assessed by hair analyses) or other potential confounds that we could address. The striking sparing of serotonin transporter-rich striatum (although possibly affected in 'heavier' users) suggests that serotonergic neurons innervating cerebral cortex are more susceptible, for unknown reasons, to ecstasy than those innervating subcortical regions and that behavioural problems in some ecstasy users during abstinence might be related to serotonin transporter changes limited to cortical regions. [ABSTRACT FROM AUTHOR]

We previously reported increased binding of (+)[11C]DTBZ (dihydrotetrabenazine), the vesicular monoamine transporter (VMAT2) positron emission tomography (PET) radioligand, in striatum of some methamphetamine users. This finding might be explained by stimulant-induced vesicular DA depletion resulting in decreased DA (+)[11C]DTBZ competition at VMAT2. In a prospective PET study, we now find that administration of an acute oral dose of amphetamine (0.4 mg/kg) to humans does not cause increased striatal (+)[11C]DTBZ binding but a slight 5% decrease. Our data suggest that a low amphetamine dose is unlikely to cause sufficient DA depletion to detect increased (+)[11C]DTBZ binding and that a higher dose might be required. Synapse 64:417-420, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

α-Synuclein is a major component of Lewy bodies and glial cytoplasmic inclusions, pathological hallmarks of idiopathic Parkinson's disease and multiple system atrophy, and it is assumed to be aetiologically involved in these conditions. However, the quantitative status of brain α-synuclein in different Parkinsonian disorders is still unresolved and it is uncertain whether α-synuclein accumulation is restricted to regions of pathology. We compared membrane-associated, sodium dodecyl sulfate-soluble α-synuclein, both the full-length 17 kDa and high molecular weight species, by western blotting in autopsied brain of patients with Parkinson's disease (brainstem-predominant Lewy body disease: n = 9), multiple system atrophy (n = 11), progressive supranuclear palsy (n = 16), and of normal controls (n = 13). Brain of a patient with familial Parkinsonism-dementia due to α-synuclein locus triplication (as positive control) showed increased membrane-associated, sodium dodecyl sulfate-soluble α-synuclein levels with abundant high molecular weight immunoreactivity. In multiple system atrophy, a massive increase in 17 kDa membrane-associated, sodium dodecyl sulfate-soluble α-synuclein was observed in highly pathologically affected regions, including putamen (+1760%, range +625–2900%), substantia nigra [+1000% (+356–1850%)], and white matter of internal capsule [+2210% (+430–6830%)] together with numerous high molecular weight species. Levels of 17 kDa membrane-associated, sodium dodecyl sulfate-soluble α-synuclein were only modestly increased in less affected areas (cerebellar cortex, +95%; caudate, +30%; with both also showing numerous high molecular weight species) and were generally normal in cerebral cortices. In both Parkinson's disease and progressive supranuclear palsy, membrane-associated, sodium dodecyl sulfate-soluble α-synuclein levels were normal in putamen and frontal cortex whereas a trend was observed for variably increased 17 kDa membrane-associated, sodium dodecyl sulfate-soluble α-synuclein concentrations [+184% (−60% to +618%)] with additional high molecular weight species in Parkinson's disease substantia nigra. No obvious correlation was observed between nigral membrane-associated, sodium dodecyl sulfate-soluble α-synuclein accumulation and Lewy body density in Parkinson's disease. Two progressive supranuclear palsy cases had membrane-associated, sodium dodecyl sulfate-soluble α-synuclein accumulation in substantia nigra similar to multiple system atrophy. Several Parkinson's disease patients had very modest high molecular weight membrane-associated, sodium dodecyl sulfate-soluble α-synuclein accumulation in putamen. Levels of 17-kDa membrane-associated, sodium dodecyl sulfate-soluble α-synuclein were generally positively correlated with those of high molecular weight membrane-associated, sodium dodecyl sulfate-soluble α-synuclein and there was a trend for a positive correlation between striatal dopamine loss and 17-kDa membrane-associated, sodium dodecyl sulfate-soluble α-synuclein concentrations in multiple system atrophy. Brain membrane-associated, sodium dodecyl sulfate-soluble α-synuclein accumulations in Parkinson's disease and multiple system atrophy are regionally specific, suggesting that these sporadic α-synucleinopathies, unlike familial Parkinsonism-dementia, are not associated with a simple global over-expression of the protein. Despite a similar extent of dopamine depletion, the magnitude of brain membrane-associated, sodium dodecyl sulfate-soluble α-synuclein changes is disease specific, with multiple system atrophy clearly having the most severe accumulation. Literature discrepancies on α-synuclein status in ‘Parkinson's disease’ might be explained by inclusion of cases not having classic ... [ABSTRACT FROM PUBLISHER]

The D3 dopamine (DA) receptor is a member of the D2-like DA receptor family. While the D2 receptor is abundant especially in motor-regions of the striatum, the D3 receptor shows a relative abundance in limbic regions and globus pallidus. This receptor is of current interest in neurology because of its potential involvement in psychiatric and motor complications in Parkinsons disease and the possibility that dopamine D3-preferring agonist therapy might delay progression of the disorder. Preclinical data indicate that striatal levels of the D3 (but not the D2) DA receptor are decreased following lesion of nigrostriatal DA neurons; at present, there are no in vivo data on this receptor subtype in Parkinsons disease. The objective of this positron emission tomography study was to compare [11C]-(+)-PHNO (D3 versus D2 preferring) and [11C]raclopride (D3 = D2) binding in brain of non-depressed, non-demented, dopaminergic drug-naïve patients with early-stage Parkinsons disease (n = 10), relative to matched-controls (n = 9). Parkinsons disease was associated with a trend for bilaterally decreased [11C]-(+)-PHNO (but not [11C]raclopride) binding in the D3-rich ventral striatum (−11%, P = 0.07) and significantly decreased binding in globus pallidus (−42%, P = 0.02). In contrast, in the primarily D2-populated putamen, both [11C]-(+)-PHNO (25%, P = 0.02) and [11C]raclopride (25%, P 3 receptors localized to the substantia nigra, [11C]-(+)-PHNO binding was normal. Decreased [11C]-(+)-PHNO to [11C]raclopride ratio correlated with motor deficits and lowered-mood (P 2 and D3 receptors with D3 receptor ‘downregulation’ possibly related to some motor and mood problems in Parkinson disease. D3 receptor levels might be a determinant vulnerability factor underlying side-effects associated with treatment; hence, these initial findings provide valuable baseline information to understand the role of D3 receptors in response to Parkinsons disease medication. [ABSTRACT FROM AUTHOR]

Binding of (+)-[11C]DTBZ (dihydrotetrabenazine) to the striatal vesicular monoamine transporter (VMAT2) is widely considered to be a stable marker of dopamine neurone integrity. However, we now find that specific binding of a tracer dose of (+)-[11C]DTBZ is modestly increased in rat striatum following dopamine depletion with α-methyl- p-tyrosine (α-MPT, +14%) or d-amphetamine (d-AMPH, 20 mg/kg, +12%) and decreased following dopamine elevation with γ-hydroxybutyrate (GHB, −16%) or levodopa (−20%). We suggest that in vivo (+)-[11C]DTBZ binding in imaging studies is subject to competition by vesicular dopamine and, in this respect, is not a 'stable' dopamine biomarker as is generally assumed. Synapse 62:873-876, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Animal data indicate that methamphetamine can damage striatal dopamine terminals. Efforts to document dopamine neuron damage in living brain of methamphetamine users have focused on the binding of [ 11C]dihydrotetrabenazine (DTBZ), a vesicular monoamine transporter (VMAT2) positron emission tomography (PET) radioligand, as a stable dopamine neuron biomarker. Previous PET data report a slight decrease in striatal [ 11C]DTBZ binding in human methamphetamine users after prolonged (mean, 3 years) abstinence, suggesting that the reduction would likely be substantial in early abstinence. We measured striatal VMAT2 binding in 16 recently withdrawn (mean, 19 d; range, 1—90 d) methamphetamine users and in 14 healthy matched-control subjects during a PET scan with (+)[ 11C]DTBZ. Unexpectedly, striatal (+)[ 11C]DTBZ binding was increased in methamphetamine users relative to controls ( +22%, caudate; +12%, putamen; +11%, ventral striatum). Increased (+)[ 11C]DTBZ binding in caudate was most marked in methamphetamine users abstinent for 1—3 d (+41%), relative to the 7-21 d (+15%) and >21 d (+9%) groups. Above-normal VMAT2 binding in some drug users suggests that any toxic effect of methamphetamine on dopamine neurons might be masked by an increased (+)[ 11C]DTBZ binding and that VMAT2 radioligand binding might not be, as is generally assumed, a "stable" index of dopamine neuron integrity in vivo. One potential explanation for increased (+)[ 11C]DTBZ binding is that VMAT2 binding is sensitive to changes in vesicular dopamine storage levels, presumably low in drug users. If correct, (+)[ 11C]DTBZ might be a useful imaging probe to correlate changes in brain dopamine stores and behavior in users of methamphetamine. [ABSTRACT FROM AUTHOR]