5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man--a PET study with [11C]raclopride.

The modulating effects of serotonin on dopamine neurotransmission are not well understood, particularly in acute psychotic states. Positron emission tomography was used to examine the effect of psilocybin on the in vivo binding of [11C]raclopride to D2-dopamine receptors in the striatum in healthy volunteers after placebo and a psychotomimetic dose of psilocybin (n = 7). Psilocybin is a potent indoleamine hallucinogen and a mixed 5-HT2A and 5-HT1A receptor agonist. Psilocybin administration (0.25 mg/kg p.o.) produced changes in mood, disturbances in thinking, illusions, elementary and complex visual hallucinations and impaired ego-functioning. Psilocybin significantly decreased [11C]raclopride receptor binding potential (BP) bilaterally in the caudate nucleus (19%) and putamen (20%) consistent with an increase in endogenous dopamine. Changes in [11C]raclopride BP in the ventral striatum correlated with depersonalization associated with euphoria. Together with previous reports of 5-HT receptor involvement in striatal dopamine release, it is concluded that stimulation of both 5-HT2A and 5-HT1A receptors may be important for the modulation of striatal dopamine release in acute psychoses. The present results indirectly support the hypothesis of a serotonin-dopamine dysbalance in schizophrenia and suggest that psilocybin is a valuable tool in the analysis of serotonin-dopamine interactions in acute psychotic states.     

Effects of fluoxetine on dopamine D2 receptors in the human brain: a positron emission tomography study with [11C]raclopride

We have previously reported that repeated dosing with the selective serotonin reuptake inhibitor (SSRI) citalopram decreases striatal [11C]raclopride binding in healthy volunteers. As the SSRI-class antidepressant drugs are believed to have a similar mechanism of action, we wanted to explore whether the prototype SSRI drug, fluoxetine, shares the effects of citalopram on subcortical dopamine neurotransmission. Eight healthy male volunteers were studied using a randomized double-blind placebo-controlled study design. Striatal and thalamic D2-receptor binding was measured at baseline, after a single oral dose (20 mg) of fluoxetine, and after repeated dosing (2 wk, 20 mg/d). The D2-receptor binding potential (BP) was assessed using [11C]raclopride and 3D positron emission tomography. Repeated dosing of fluoxetine decreased BP in the right medial thalamus (p=0.022). Fluoxetine did not decrease striatal BP, but there was a trend (p=0.090) towards increased BP in the left putamen after repeated dosing. A single dose of fluoxetine did not affect BP in the thalamus or striatum. Fluoxetine appears to have a regionally selective effect on the dopaminergic neurotransmission in various areas of the brain. The current results after fluoxetine together with our previous data on citalopram suggest that the modulatory effects of these drugs on striatal dopaminergic neurotransmission are different upon repeated dosing and further substantiates pharmacological differences between SSRI-class drugs.     

Antipsychotic-associated mental side effects and their relationship to dopamine D2 receptor occupancy in striatal subdivisions: a high-resolution PET study with [11C]raclopride

We examined the relationship between antipsychotic-associated mental side effects and dopamine D2 receptor occupancy in striatal subdivisions using high-resolution positron emission tomography with [11C]raclopride to better characterize the neurochemical mechanism underlying these adverse effects. Twenty-one patients with schizophrenia receiving stable doses of antipsychotics and 24 age- and sex-matched healthy controls completed 3-Tesla magnetic resonance imaging and high-resolution positron emission tomography scans with [11C]raclopride to measure D2 receptor binding potential (BP ND) in the striatum. The D2 receptor BP ND was obtained using a Logan plot, and receptor occupancy was calculated as the percentage reduction of receptor BP ND with drug treatment relative to baseline. The data obtained from age- and sex-matched healthy controls were used as an estimate of the patients' baseline, as previously proposed. Antipsychotic-associated mental side effects were measured with the Liverpool University Neuroleptic Side Effect Rating Scale. The whole striatal D2 receptor occupancy ranged from 54% to 95%. The analysis revealed that the Liverpool University Neuroleptic Side Effect Rating Scale score had significant positive associations with D2 occupancy in the precommissural dorsal caudate, postcommissural caudate, and ventral striatum. The results suggest that mental side effects of antipsychotics are associated with D2 receptor blockade in the associative and limbic subdivisions of the striatum, which are considered to play a crucial role in cognition and reward motivation.     

Beer Flavor Provokes Striatal Dopamine Release in Male Drinkers: Mediation by Family History of Alcoholism

Striatal dopamine (DA) is increased by virtually all drugs of abuse, including alcohol. However, drug-associated cues are also known to provoke striatal DA transmission- a phenomenon linked to the motivated behaviors associated with addiction. To our knowledge, no one has tested if alcohol''s classically conditioned flavor cues, in the absence of a significant pharmacologic effect, are capable of eliciting striatal DA release in humans. Employing positron emission tomography (PET), we hypothesized that beer''s flavor alone can reduce the binding potential (BP) of [¹¹C]raclopride (RAC; a reflection of striatal DA release) in the ventral striatum, relative to an appetitive flavor control. Forty-nine men, ranging from social to heavy drinking, mean age 25, with a varied family history of alcoholism underwent two [¹¹C]RAC PET scans: one while tasting beer, and one while tasting Gatorade. Relative to the control flavor of Gatorade, beer flavor significantly increased self-reported desire to drink, and reduced [¹¹C]RAC BP, indicating that the alcohol-associated flavor cues induced DA release. BP reductions were strongest in subjects with first-degree alcoholic relatives. These results demonstrate that alcohol-conditioned flavor cues can provoke ventral striatal DA release, absent significant pharmacologic effects, and that the response is strongest in subjects with a greater genetic risk for alcoholism. Striatal DA responses to salient alcohol cues may thus be an inherited risk factor for alcoholism.     

Dopamine transporter density in patients with tardive dyskinesia: a single photon emission computed tomography study

RATIONALE: Tardive dyskinesia occurs frequently in schizophrenic patients chronically treated with classical antipsychotic medication. It may be caused by loss of dopaminergic cells, due to free radicals as a product of high synaptic dopamine levels. OBJECTIVE: To evaluate dopamine transporter density in the striatum in patients with tardive dyskinesia. METHODS: Striatal [123I]FP-CIT binding was measured with SPECT in seven schizophrenic patients with tardive dyskinesia and eight healthy controls. RESULTS: No significant difference was found between striatal [123I]FP-CIT binding ratios in patients with tardive dyskinesia and controls. CONCLUSIONS: This preliminary study indicates no change in striatal dopamine transporter density in schizophrenic patients with tardive dyskinesia. This finding does not support the hypothesis that tardive dyskinesia is caused by dopaminergic cell loss.     

Effects of age on dopamine D2 receptor availability in striatal subdivisions: A high-resolution positron emission tomography study

The purpose of the present study was to examine the relationship between age and dopamine D₂ receptor availability in striatal subdivisions of young and middle-aged healthy subjects using high-resolution positron emission tomography (PET) with [¹¹C]raclopride to better characterize the nature of age-related decrements in striatal D₂ receptor availability. Twenty-four healthy volunteers completed 3-Tesla magnetic resonance imaging and high-resolution [¹¹C]raclopride PET scans. The analyses using linear and exponential models revealed that age had a significant negative correlation with D₂ receptor availability in the post-commissural putamen (postPU) and that D₂ receptor binding in the postPU decreased significantly more with age than in the ventral striatum, suggesting subregional differences in age-related changes in D₂ receptor binding. The postPU, which belongs to the sensorimotor striatum, may be particularly vulnerable to the effects of age in young and middle-aged subjects.     

Reduction of dopamine uptake and cocaine binding in mouse striatum by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP) (daily injections of 8 mg/kg for 5 days via tail vein) reduced [3H]dopamine uptake in striatal synaptosomes by 63% and reduced [3H]cocaine binding to striatal membranes by 61%. [3H]Cocaine binding was not affected in olfactory tubercle, suggesting a selective effect of NMPTP on the nigro-striatal but not on the mesolimbic dopaminergic system. The destruction of dopamine terminals in the striatum did not alter (up-regulate) [3H]spiroperidol binding. The results suggest that NMPTP causes a degenerative destruction of the striatal dopamine pathway and that NMPTP may be useful in developing a rodent model of Parkinson's disease.     

Amphetamine-Induced Dopamine Release and Neurocognitive Function in Treatment-Naive Adults with ADHD

Converging evidence from clinical, preclinical, neuroimaging, and genetic research implicates dopamine neurotransmission in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The in vivo neuroreceptor imaging evidence also suggests alterations in the dopamine system in ADHD; however, the nature and behavioral significance of those have not yet been established. Here, we investigated striatal dopaminergic function in ADHD using [¹¹C]raclopride PET with a d-amphetamine challenge. We also examined the relationship of striatal dopamine responses to ADHD symptoms and neurocognitive function. A total of 15 treatment-free, noncomorbid adult males with ADHD (age: 29.87±8.65) and 18 healthy male controls (age: 25.44±6.77) underwent two PET scans: one following a lactose placebo and the other following d-amphetamine (0.3 mg/kg, p.o.), administered double blind and in random order counterbalanced across groups. In a separate session without a drug, participants performed a battery of neurocognitive tests. Relative to the healthy controls, the ADHD patients, as a group, showed greater d-amphetamine-induced decreases in striatal [¹¹C]raclopride binding and performed more poorly on measures of response inhibition. Across groups, a greater magnitude of d-amphetamine-induced change in [¹¹C]raclopride binding potential was associated with poorer performance on measures of response inhibition and ADHD symptoms. Our findings suggest an augmented striatal dopaminergic response in treatment-naive ADHD. Though in contrast to results of a previous study, this finding appears consistent with a model proposing exaggerated phasic dopamine release in ADHD. A susceptibility to increased phasic dopamine responsivity may contribute to such characteristics of ADHD as poor inhibition and impulsivity.     

Decreased thalamic D2/D3 receptor binding in drug-naive patients with schizophrenia: a PET study with [11C]FLB 457

The thalamus is a neuroanatomic structure that has reciprocal connections with several brain regions suggested to be involved in the pathophysiology of schizophrenia. Recent studies have reported structural as well as functional abnormalities of the thalamus in schizophrenia. The aim of the present exploratory study was to examine D2/D3 dopamine receptors in the thalamus as well as the anterior cingulate and the frontal and temporal cortices by using the high-affinity radioligand [11C]FLB 457 and positron emission tomography (3D PET) and to explore the data in relation to disease, age and psychopathology. Nine drug-naive patients with schizophrenia and eight control subjects were examined. Regional binding potential (BP) values were calculated using the simplified reference tissue model. The D2/D3 receptor binding was significantly lower in the right medial thalamus in the schizophrenia patients compared to control subjects. In addition, we found a significant negative age effect on the D2/D3 BP in the frontal and temporal cortex for both groups. There was no significant age effect on the D2/D3 BP in the thalamus or in the anterior cingulate. The result provides additional support to the view that the age effect on D2/D3 receptors differ between brain regions. The preliminary finding of low thalamic D2/D3 BP in patients strengthens the hypothesis that the thalamus is a key region in the pathophysiology of schizophrenia.     

The striatal dopamine transporter in first-episode, drug-naive schizophrenic patients: evaluation by the new SPECT-ligand[99mTc]TRODAT-1

Following the current hypothesis that acute schizophrenic psychotic illness is associated with a striatal 'hyperdopaminergic state', presynaptic integrity and dopamine transporter (DAT) density in first-episode, neuroleptic-naive schizophrenic patients was measured by single-photon-emission-tomography (SPECT) and compared with that in healthy control subjects. A new SPECT-ligand for assessment of the striatal DAT, the Technetium-99m-labelled tropane TRODAT-1 ([99mTc]TRODAT-1), was used. Ten inpatients suffering from a first acute schizophrenic episode and 10 age- and sex-matched healthy control subjects underwent SPECT with [99mTc]TRODAT-1. On the day of SPECT, psychopathological ratings were performed with the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS) and Schedule for Assessment of Negative Symptoms (SANS). Patients had not previously received any neuroleptic or antidepressant medication. Mean specific TRODAT-1 binding in the striatum did not differ significantly between the patient and the age- and sex-matched control group (1.25 vs. 1.28). Variance was significantly higher in the patient group. The data obtained with the new ligand in first-episode, drug-naive schizophrenic patients are in line with the PET results from the group of Laakso et al. in a comparable patient sample. [99mTc]TRODAT-1 seems to be a valuable new SPECT-ligand in the evaluation of the presynaptic site of the striatal dopaminergic synapse in schizophrenia.     

Regional brain distribution of [18F]GBR 13119, a dopamine uptake inhibitor, in CD-1 and C57BL/6 mice

We have examined the regional brain distribution of [18F]GBR 13119 (18F: beta +, T1/2 = 110 min), a dopamine uptake inhibitor, in CD-1 and C57BL/6 mice. High levels of binding are observed in the striatum of both species, with striatum/cerebellum ratios of 3-4 at 60 min after injection of the radiotracer. Striatum radioactivity and striatum/cerebellum ratios are more than 50% reduced in C57BL/6 mice treated chronically with the neurotoxin MPTP. We conclude mice are an appropriate model for the in vivo study of the dopamine uptake system, and that [18F]GBR 13119 may be a suitable in vivo marker for degeneration of striatal dopaminergic neurons.     

Binding characteristics of the dopamine uptake inhibitor [3H]nomifensine to striatal membranes

Binding of the radiolabeled antidepressant [3H]nomifensine to rat and rabbit striatal membranes has been characterized. The specific binding of [3H]nomifensine to striatal membranes was stable, reversible and saturable. Saturation experiments indicated that [3H]nomifensine labeled a single site with an affinity (Kd) of 80 nM and a total number of binding sites (Bmax) of 6.5 pmoles/mg protein both in rat and rabbit striatal membranes. The affinity constants obtained from kinetic analyses and competition experiments were in fairly good agreement with those obtained in saturation experiments. Compounds known to inhibit [3H]dopamine uptake in vitro, such as nomifensine, 4-hydroxy-nomifensine, mazindol, amfonelic acid and benztropine, were the most potent competitors of nomifensine binding. Additionally, the absolute potencies of various drugs in competing for [3H]nomifensine binding to rat and rabbit striatal membranes correlated closely with their potencies in inhibiting [3H]dopamine uptake into striatal synaptosomes. Specific [3H]nomifensine binding was dependent on the presence of NaCl which is also consistent with its association with the dopamine uptake pump. The number, but not the affinity, of striatal [3H]nomifensine binding sites was reduced significantly following in vivo lesions with 6-hydroxydopamine. The number of [3H]nomifensine binding sites was found to be highest in areas rich in dopamine nerve terminals such as the striatum and olfactory tubercle. These results suggest that [3H]nomifensine binds to a site on dopaminergic nerve terminals associated with the dopamine uptake pump.     

Serotonergic modulation of striatal D2 dopamine receptor binding in humans measured with positron emission tomography

The modulating effect of serotonergic drugs on the striatal dopamine neurotransmission has remained controversial, and there are no published data on serotonin-dopamine interaction obtained from living human brain. Citalopram is a selective serotonin reuptake inhibitor widely used in the treatment of depression (20–40 mg/day). We measured the effects of acute (20 mg, per os) and chronic (20 mg/day for 14 days) doses of citalopram and placebo intake on [¹¹C]-raclopride binding to striatal D₂-receptors in eight healthy volunteers by using positron emission tomography. Although the effect magnitude was not large, the results indicate that chronic citalopram intake slightly decreases the raclopride binding which may reflect increased dopamine release in the striatum. In addition, after 14 days there was a high correlation between the citalopam plasma levels and the decrease in the [¹¹C]-raclopride binding in both the caudate and the putamen, although statistically significant effect in the raclopride binding potential was more pronounced in the putamen. This report suggests functional interaction of brain dopaminergic and serotonergic systems in vivo in man.     

Dopamine depletion and in vivo binding of PET D1 receptor radioligands: implications for imaging studies in schizophrenia.

Recent positron emission tomography (PET) studies have assessed the level of dopamine (DA) D1 receptors in the prefrontal cortex (PFC) in patients with schizophrenia and have generated contradictory findings. In the PFC of patients with schizophrenia, the binding potential (BP) of [11C]NNC 112 has been reported as increased, while the BP of [11C]SCH 23390 was reported as decreased or unchanged. In this study, the effect of acute and subchronic DA depletion on the in vivo binding of [11C]NNC 112 and [3H]SCH 23390 was evaluated in rats. Acute DA depletion did not affect [11C]NNC 112 in vivo binding, but paradoxically decreased [3H]SCH 23390 in vivo binding. Subchronic DA depletion was associated with increased [11C]NNC 112 in vivo binding and decreased [3H]SCH 23390 in vivo binding. Together, these data demonstrate that the in vivo binding of these radiotracers is differentially affected by changes in endogenous DA tone, and suggest that alterations in the binding of these tracers in the PFC of patients with schizophrenia might reflect changes in D1 receptors secondary to sustained deficit in prefrontal DA function.     

Effects of acute metabolic stress on striatal dopamine release in healthy volunteers.

Several lines of evidence indicate that a variety of metabolic stressors, including acute glucose deprivation are associated with dopamine release. Pharmacologic doses of the glucose analogue, 2-deoxyglucose (2DG) cause acute glucoprivation and are associated with enhanced dopamine turnover in preclinical studies. In this study, we utilized [11C]raclopride PET to examine 2DG-induced striatal dopamine release in healthy volunteers. Six healthy volunteers underwent PET scans involving assessment of 2DG-induced (40 mg/kg) decrements in striatal binding of the D(2)/D(3) receptor radioligand [11C]raclopride. Decreases in [11C]raclopride specific binding reflect 2DG-induced changes in synaptic dopamine. Specific binding significantly decreased following 2DG administration, reflecting enhanced synaptic dopamine concentrations (p =.02). The administration of 2DG is associated with significant striatal dopamine release in healthy volunteers. Implications of these data for investigations of the role of stress in psychiatric disorders are discussed.     

The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of striatal dopamine in schizophrenia.

Schizophrenia has been linked to abnormal dopamine function, recently to excessive amphetamine-induced release of striatal dopamine, and also to pathology of prefrontal cortical neurons. It has been hypothesized that prefrontal pathology is a primary condition that leads to dopamine dysregulation. We evaluated in vivo the relationship between neuronal integrity in dorsolateral prefrontal cortex, assessed as N-acetylaspartate (NAA) relative concentrations measured with proton magnetic resonance spectroscopic imaging, and amphetamine-induced release of striatal dopamine, assessed with 11C-raclopride Positron Emission Tomography (PET) in patients with schizophrenia and in healthy subjects. In the patients, NAA measures in dorsolateral prefrontal cortex selectively predicted striatal displacement of 11C-raclopride after amphetamine infusions (rho = -0.76, p < .02). In contrast, NAA measures in other cortical regions and in healthy subjects did not show any correlation. These results support the hypothesis that in schizophrenia neuronal pathology of dorsolateral prefrontal cortex is directly related to abnormal subcortical dopamine function.     

History of cannabis use is not associated with alterations in striatal dopamine D2/D3 receptor availability

Cannabis use in adolescence is emerging as a risk factor for the development of psychosis. In animal studies, Δ9-tetrahydrocannabinol (THC), the psychoactive component of cannabis, modulates striatal dopaminergic neurotransmission. Alterations in human striatal dopaminergic function have also been reported both in psychosis and in stimulant use. We sought to examine whether striatal dopamine D(2)/D(3) receptor availability was altered in volunteers with a history of cannabis use using a database of previously acquired [(11)C]-raclopride positron emission tomography (PET) scans. Ten [(11)C]-raclopride scans from volunteers with a history of cannabis use were compared to ten control scans using a functional striatal subdivision region of interest (ROI) analysis. No significant differences in either overall striatal BP(ND) values or BP(ND) values in any functional striatal subdivision were found between the two groups. There was also no correlation between lifetime frequency of cannabis use and BP(ND) values. Limbic striatal BP(ND) values were ten percent lower in current nicotine cigarette smokers. These findings suggest that, unlike other drugs of abuse, a history of cannabis use is not associated with alterations in striatal dopamine D(2)/D(3) receptor availability.     

Stress-Induced Dopamine Response in Subjects at Clinical High Risk for Schizophrenia with and without Concurrent Cannabis Use

Research on the environmental risk factors for schizophrenia has focused on either psychosocial stress or drug exposure, with limited investigation of their interaction. A heightened dopaminergic stress response in patients with schizophrenia and individuals at clinical high risk (CHR) supports the dopaminergic sensitization hypothesis. Cannabis is believed to contribute to the development of schizophrenia, possibly through a cross-sensitization with stress. Twelve CHR and 12 cannabis-using CHR (CHR-CU, 11 dependent) subjects underwent [¹¹C]-(+)-PHNO positron emission tomography scans, while performing a Sensorimotor Control Task (SMCT) and a stress condition (Montreal Imaging Stress task). The simplified reference tissue model was used to obtain binding potential relative to non-displaceable binding (BP_ND) in the whole striatum, its functional subdivisions (limbic striatum (LST), associative striatum (AST), and sensorimotor striatum (SMST)), globus pallidus (GP), and substantia nigra (SN). Changes in BP_ND, reflecting alterations in synaptic dopamine (DA) levels, were tested with analysis of variance. SMCT BP_ND was not significantly different between groups in any brain region (p>0.21). Although stress elicited a significant reduction in BP_ND in the CHR group, CHR-CU group exhibited an increase in BP_ND. Stress-induced changes in regional BP_ND between CHR-CU and CHR were significantly different in AST (p<0.001), LST (p=0.007), SMST (p=0.002), SN (p=0.021), and whole striatum (p=0.001), with trend level in the GP (p=0.099). All subjects experienced an increase in positive (attenuated) psychotic symptoms (p=0.001) following the stress task. Our results suggest altered DA stress reactivity in CHR subjects who concurrently use cannabis, as compared with CHR subjects. Our finding does not support the cross-sensitization hypothesis, which posits greater dopaminergic reactivity to stress in CHR cannabis users, but adds to the growing body of literature showing reduced DA (stress) response in addiction.     

Striatal dopamine D2/3 receptor binding following dopamine depletion in subjects at Ultra High Risk for psychosis

Altered striatal dopaminergic neurotransmission is thought to be fundamental to schizophrenia. Increased presynaptic dopaminergic activity ([¹⁸F]–DOPA PET) may predate the onset of psychotic symptoms and correlates to clinical symptoms in subjects at Ultra High Risk (UHR) for developing psychosis. Postsynaptic dopaminergic neurotransmission has not been investigated yet in UHR patients. We hypothesized that synaptic dopamine concentration would be increased in UHR patients, and that synaptic dopamine concentration would be related to symptom severity. 14 UHR patients and 15 age and IQ matched controls completed an [¹²³I]–IBZM SPECT scan at baseline and again after dopamine depletion with alpha-methyl-para-tyrosine (AMPT). We measured changes in radiotracer binding potential, compared these between UHR patients and controls, and correlated these to symptom severity. The UHR group as a whole did not differ significantly from controls. AMPT significantly reduced symptom severity in the UHR group (p=0.014). Higher synaptic dopamine concentration predicted larger reduction of positive symptoms following depletion in the UHR group (p=0.01). In UHR patients, positive symptoms responded to dopamine depletion, comparable to observations in schizophrenia, suggesting a similar mechanism. Higher synaptic dopamine concentration was associated with more severe positive symptoms and a greater reduction of these symptoms following depletion.     

Decreasing amphetamine-induced dopamine release by acute phenylalanine/tyrosine depletion: A PET/[11C]raclopride study in healthy men.

Acute phenylalanine/tyrosine depletion (APTD) has been proposed as a new method to decrease catecholamine neurotransmission safely, rapidly, and transiently. Validation studies in animals are encouraging, but direct evidence in human brain is lacking. In the present study, we tested the hypothesis that APTD would reduce stimulated dopamine (DA) release, as assessed by positron emission tomography (PET) and changes in [(11)C]raclopride binding potential (BP), a measure of DA D2/D3 receptor availability. Eight healthy men received two PET scans, both following d-amphetamine, 0.3 mg/kg, p.o., an oral dose known to decrease [(11)C]raclopride BP in ventral striatum. On the morning before each scan, subjects ingested, in counter-balanced order, an amino-acid mixture deficient in the catecholamine precursors, phenylalanine, and tyrosine, or a nutritionally balanced mixture. Brain parametric images were generated by calculating [(11)C]raclopride BP at each voxel. BP values were extracted from the t-map (threshold: t=4.2, equivalent to p<0.05, Bonferroni corrected) and a priori identified regions of interest from each individual's coregistered magnetic resonance images. Both receptor parametric mapping and region of interest analyses indicated that [(11)C]raclopride binding was significantly different on the two test days in the ventral striatum (peak t=6.31; x=-25, y=-8, and z=0.1). In the t-map defined cluster, [(11)C]raclopride BP values were 11.8+/-11.9% higher during the APTD session (p<0.05). The reduction in d-amphetamine-induced DA release exhibited a linear association with the reduction in plasma tyrosine levels (r=-0.82, p<0.05). Together, the results provide the first direct evidence that APTD decreases stimulated DA release in human brain. APTD may be a suitable new tool for human neuropsychopharmacology research.