18F alpha-methyl tyrosine PET studies in patients with brain tumors. (1/126)

We have developed 18F-labeled alpha-methyl tyrosine (FMT) for PET imaging. The aim of this study was to evaluate the clinical application potential of FMT for patients with brain tumors. METHODS: Eleven healthy volunteers and 20 patients with brain tumors were injected with 185 MBq (5 mCi) FMT. In 3 healthy volunteers, whole-body imaging and urinary and plasma analysis were conducted for the assessment of the biodistribution of FMT. The normal range of cortical standardized uptake value (SUV) as a reference for comparing tumor SUV of FMT was estimated by using PET data obtained at 30 min postinjection in 8 healthy volunteers. Dynamic PET scans were conducted for 100 min in 4 healthy volunteers and for 30 min in 15 patients with brain tumors. The 10-min static images in another 4 volunteers and all patients were obtained at 30 min postinjection. In 13 patients, FMT uptake in the brain tumor was compared with 18F-fluorodeoxyglucose (FDG). Tumor-to-normal cortex count (T/N) ratio and tumor-to-white matter count (T/W) ratio and SUVs of brain tumors were determined on FMT and FDG PET images. RESULTS: Approximately 1480 MBq (40 mCi) FMT were produced in one radiosynthesis. Percentage injected dose (%ID) of FMT in the brain ranged from 2.8% to 4.9%, and approximately 50%ID of FMT was excreted in urine during 60 min postinjection, of which 86.6% was unmetabolized FMT. A faint physiological brain uptake with SUV of 1.61 +/- 0.32 (mean +/- SD, n = 8) was observed in healthy volunteers. Tumor SUV of FMT ranged from 1.2 to 8.2, with mean value of 2.83 +/- 1.57 (n = 23), which was significantly higher than that of the cortical area in healthy volunteers (P < 0.01). T/N and T/W ratios of FMT were significantly higher than those of FDG (2.53 +/- 1.31 versus 1.32 +/- 1.46, P < 0.001; 3.99 +/- 2.10 versus 1.39 +/- 0.65, P < 0.0001, respectively). CONCLUSION: FMT, like other radiolabeled amino acids, can provide high-contrast PET images of brain tumors.  (+info)

Increased methamphetamine neurotoxicity in heterozygous vesicular monoamine transporter 2 knock-out mice. (2/126)

Methamphetamine (METH) is a powerful psychostimulant that is increasingly abused worldwide. Although it is commonly accepted that the dopaminergic system and oxidation of dopamine (DA) play pivotal roles in the neurotoxicity produced by this phenylethylamine, the primary source of DA responsible for this effect has remained elusive. In this study, we used mice heterozygous for vesicular monoamine transporter 2 (VMAT2 +/- mice) to determine whether impaired vesicular function alters the effects of METH. METH-induced dopaminergic neurotoxicity was increased in striatum of VMAT2 +/- mice compared with wild-type mice as revealed by a more consistent DA and metabolite depletion and a greater decrease in dopamine transporter expression. Interestingly, increased METH neurotoxicity in VMAT2 +/- mice was accompanied by less pronounced increase in extracellular DA and indices of free radical formation compared with wild-type mice. These results indicate that disruption of vesicular monoamine transport potentiates METH-induced neurotoxicity in vivo and point, albeit indirectly, to a greater contribution of intraneuronal DA redistribution rather than extraneuronal overflow on mediating this effect.  (+info)

alpha2C adrenoceptors inhibit adenylyl cyclase in mouse striatum: potential activation by dopamine. (3/126)

alpha2C adrenoceptors occur in high density in the striatum, but the functional role of these receptors is uncertain. Mice with targeted inactivation of the alpha2C adrenoceptor gene (Adra2c-/-) and genetically related control mice expressing the wild-type alpha2C adrenoceptor (Adra2c+/+) were used to determine whether striatal alpha2C adrenoceptors modulate adenylyl cyclase activation. In striatal slices from Adra2c+/+ mice, the alpha2 adrenoceptor antagonist RX821002 facilitated forskolin-stimulated cyclic AMP accumulation in a concentration-dependent manner. In contrast, RX821002 had no effect on forskolin-stimulated cAMP accumulation in striatal slices from Adra2c-/- mice or in striatal slices from Adra2c+/+ mice treated with reserpine and alpha-methyl-rho-tyrosine to deplete monoamine neurotransmitters. Given the sparse innervation of the striatum by noradrenergic neurons, the possibility that dopamine can activate the mouse alpha2C adrenoceptor at physiologically relevant concentrations was investigated using normal rat kidney (NRK) cells transfected with the mouse alpha2A or alpha2C adrenoceptor cDNA (NRK-alpha2A or NRK-alpha2C cells). Inhibition of [3H]RX821002 binding by agonists in homogenates of transfected cells revealed an affinity of dopamine for alpha2C adrenoceptors that was higher than the affinity of norepinephrine for its cognate receptor, the alpha2A adrenoceptor. Both norepinephrine and dopamine inhibited forskolin-stimulated cAMP accumulation in intact NRK-alpha2C cells. In NRK-alpha2A cells, norepinephrine facilitated forskolin-stimulated cAMP accumulation, an effect not observed for dopamine. Together, these data demonstrate that the alpha2C adrenoceptor is negatively coupled to adenylyl cyclase and is tonically activated in mouse striatal slices. The endogenous activator of the striatal alpha2C adrenoceptor may be dopamine, as well as norepinephrine.  (+info)

Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. (4/126)

The classical dopamine hypothesis of schizophrenia postulates a hyperactivity of dopaminergic transmission at the D(2) receptor. We measured in vivo occupancy of striatal D(2) receptors by dopamine in 18 untreated patients with schizophrenia and 18 matched controls, by comparing D(2) receptor availability before and during pharmacologically induced acute dopamine depletion. Acute depletion of intrasynaptic dopamine resulted in a larger increase in D(2) receptor availability in patients with schizophrenia (19% +/- 11%) compared with control subjects (9% +/- 7%, P = 0.003). The increased occupancy of D(2) receptors by dopamine occurred both in first-episode neuroleptic-naive patients and in previously treated chronic patients experiencing an episode of illness exacerbation. In addition, elevated synaptic dopamine was predictive of good treatment response of positive symptoms to antipsychotic drugs. This finding provides direct evidence of increased stimulation of D(2) receptors by dopamine in schizophrenia, consistent with increased phasic activity of dopaminergic neurons.  (+info)

Involvement of tyrosine hydroxylase upregulation in cyclosporine-induced hypertension. (5/126)

To identify the mechanism of cyclosporine-induced hypertension, we studied the effect of cyclosporine on the catecholamine synthetic pathway in rats. We administered cyclosporine (10 mg/kg per day, s.c.) for 3 days to 10-week-old male Wistar rats. Systolic blood pressure increased significantly in the cyclosporine-treated group in comparison to that in the control group. Norepinephrine and epinephrine levels in the adrenal medulla and plasma of cyclosporine-treated rats were also significantly higher than levels in the control rats. Moreover, tyrosine hydroxylase (TH) activity and TH mRNA expression in the adrenal medulla of cyclosporine-treated rats were significantly elevated. Administration of the TH inhibitor alphamethyl-p-tyrosine (200 mg/kg, b.i.d., s.c.) for 3 days significantly suppressed cyclosporine-induced increases in systolic blood pressure. Phosphorylation of cyclic AMP responsive element-binding protein (CREB) and its binding activity to DNA in the nuclear fraction from the adrenal medulla of cyclosporine-treated rats were much higher than that of the control rats. Calcineurin protein expression of cyclosporine-treated rats was less than that of the control rats. These results suggest that cyclosporine increased blood pressure via activation of the catecholamine synthetic pathway due to the activation of transcription factor CREB.  (+info)

A simple method to measure baseline occupancy of neostriatal dopamine D2 receptors by dopamine in vivo in healthy subjects. (6/126)

The effect of endogenous dopamine (DA) on measurement of neostriatal DA D(2) receptor binding potential (D(2)RBP) in vivo was evaluated with positron emission tomography (PET) and the radiotracer [11C]raclopride by comparing the D(2)RBP before and after acute DA depletion. DA depletion was achieved by per-oral administration of 4.5 g alpha-methyl-para-tyrosine (AMPT) given in 25 h. Six healthy subjects completed the protocol. The AMPT treatment increased D(2)RBP significantly from 3.11 +/- 0.25 to 3.68 +/- 0.23 and decreased plasma levels of the DA metabolite homovanillic acid by 71 +/- 11% and levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenethyleneglycol by 53 +/- 7%. Increase in D(2)RBP correlated with decrease in attentiveness and with increase in errors of commission from Conners' Continuous Performance Test. On AMPT, a significant decrease in subjective happiness scores was observed. The results imply that a noninvasive [11C]raclopride PET protocol coupled with relatively brief administration of a rather low total dose of AMPT resulted in measurable acute DA depletion that might provide estimates of synaptic neostriatal DA concentration.  (+info)

Antidepressant-like behavioral effects in 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) receptor mutant mice. (7/126)

The development of serotonin receptor knockout mice has provided an opportunity to study antidepressant drug effects in animals with targeted genetic deletion of receptors involved in antidepressant responses. In the current study, the effects of two types of antidepressant drugs, the selective serotonin reuptake inhibitors fluoxetine and paroxetine and the selective norepinephrine reuptake inhibitor desipramine, were examined in 5-hydroxytryptamine (5-HT)(1A) and 5-HT(1B) receptor mutant mice using the tail suspension test (TST). Under baseline conditions, the immobility of 5-HT(1A) receptor mutant mice, but not 5-HT(1B) receptor mutant mice, was significantly lower than that of wild-type mice. The decreased baseline immobility in 5-HT(1A) receptor mutant mice was reversed by pretreatment with alpha-methyl-para-tyrosine, but not by para-chlorophenylalanine, suggesting mediation by enhanced catecholamine function. In wild-type mice, fluoxetine (10.0--20.0 mg/kg i.p.) and desipramine (5.0--20.0 mg/kg i.p.) both significantly decreased immobility in the TST. In 5-HT(1A) receptor mutant mice, desipramine (20.0 mg/kg i.p.) significantly decreased immobility, whereas fluoxetine (20.0 mg/kg i.p.) and paroxetine (20.0 mg/kg i.p.) had no effect. The immobility of 5-HT(1B) receptor mutant mice was decreased similarly by desipramine (5.0--20.0 mg/kg i.p.). However, the effect of low doses of fluoxetine were significantly augmented in the 5-HT(1B) receptor mutant mice (2.5--20.0 mg/kg i.p.) compared with wild-type mice. Administration of selective 5-HT receptor antagonists in wild-type mice partially reproduced the phenotypes of the mutant mice. These results suggest that 5-HT(1A) and 5-HT(1B) receptors have different roles in the modulation of the response to antidepressant drugs in the TST.  (+info)

Subjective effects of AMPT-induced dopamine depletion in schizophrenia: correlation between dysphoric responses and striatal D(2) binding ratios on SPECT imaging. (8/126)

Approximately one third of schizophrenic patients treated with neuroleptic drugs experience unpleasant subjective responses, that are collectively known as neuroleptic dysphoria. Experimental research in animals indicates that drug induced dopaminergic blockade in mesolimbic circuits, especially the nucleus accumbens, leads to impaired pleasure responsivity and dysphoria. The present study tested this putative mechanism in drug-free schizophrenic patients (n = 12), through inducing dysphoric responses with alphamethyl paratyrosine (AMPT) and simultaneously quantifying their baseline striatal dopmine (D(2)) function with (123)IBZM-SPECT imaging. Results showed a wide variability in the occurrence and severity of dysphoric responses, clearly distinguishing a dysphoric group from non-dysphoric responders. Severity of dysphoric responses, measured by standardized rating scales, correlated inversely with changes in D(2) receptor binding ratios (r = +0.82, p <.01). These results support the notion that striatal dopaminergic activity is not uniformly elevated in all schizophrenic patients, and the sub-group of individuals with lower baseline dopamine function are at an increased risk for dysphoric responses during antipsychotic therapy with dopaminergic blocking drugs.  (+info)