Dopamine Synthesis Rate Research Articles

Normal database of dopaminergic neurotransmission system in human brain measured by positron emission tomography

The central dopaminergic system is of interest in the pathophysiology of schizophrenia and other neuropsychiatric disorders. Both pre- and postsynaptic dopaminergic functions can be estimated by positron emission tomography (PET) with different radiotracers. However, an integrated database of both pre- and postsynaptic dopaminergic neurotransmission components including receptors, transporter, and endogenous neurotransmitter synthesis has not yet been reported. In the present study, we constructed a normal database for the pre- and postsynaptic dopaminergic functions in the living human brain using PET. To measure striatal and extrastriatal dopamine D(1) and D(2) receptor bindings, dopamine transporter binding, and endogenous dopamine synthesis rate, PET scans were performed on healthy men after intravenous injection of [(11)C]SCH23390, [(11)C]raclopride, [(11)C]FLB457, [(11)C]PE2I, or L-[beta-(11)C]DOPA. All PET images were anatomically standardized using SPM2, and a database was built for each radiotracer. Gray matter images were segmented and extracted from all anatomically standardized magnetic resonance images using SPM2, and they were used for partial volume correction. These databases allow the comparison of regional distributions of striatal and extrastriatal dopamine D(1) and D(2) receptors, dopamine transporter, and endogenous dopamine synthesis capability. These distributions were in good agreement with those from human postmortem studies. This database can be used in various researches to understand the physiology of dopaminergic functions in the living human brain. This database could also be used to investigate regional abnormalities of dopaminergic neurotransmission in neuropsychiatric disorders.

Mapping of central dopamine synthesis in man, using positron emission tomography with l-[β-11C]DOPA

To estimate the presynaptic function of the central dopaminergic system, positron emission tomography measurement of the endogenous dopamine synthesis rate was performed with L-[beta-11C]DOPA. In the present study, we developed a simple method for calculating an indicator of the dopamine synthesis rate with L-[beta-11C]DOPA on a voxel-by-voxel basis for parametric mapping. After intravenous injection of L-[beta-11C]DOPA, dynamic scanning was performed on ten healthy men for 89 min. The dopamine synthesis ratio was calculated on a voxel-by-voxel basis as the ratio of the area under the time-activity curves of brain regions to the reference brain region, that is, occipital cortex. The overall uptake rate constant as an indicator of dopamine synthesis was also calculated by kinetic and graphical analyses. The dopamine synthesis ratio calculated by the present method was in good agreement with the indicators of dopamine synthesis calculated by kinetic and graphical analyses, although a systemic underestimation was observed, especially when the integration interval was set in the early phase of the scan duration. In particular, underestimations were prominent in brain regions with relatively lower influx rate constant K1. By this method, regional dopamine synthesis could be estimated on a voxel-by-voxel basis. This method does not need an arterial input function and should prove to be useful for clinical research.

A small dopamine permeability of storage vesicle membranes and end product inhibition of tyrosine hydroxylase are sufficient to explain changes occurring in dopamine synthesis and storage after inhibition of neuron firing

Computer simulations of dopamine (DA) regulation at a striatal varicosity were developed to determine basic principles that explain the pattern of changes in level of neurotransmitter and its rate of synthesis and metabolism when DA neuron firing is inhibited. The models suggest that DA synthesis is normally at a slower rate because of end-product inhibition of tyrosine hydroxylase (TH) by cytosolic DA. The vast majority of DA in the cytosol arrives there via "recycling"--DA that was released during an exocytotic event is moved into the cytosol via the dopamine transporter (DAT). When neuronal firing is inhibited, the amount of cytosolic DA markedly decreases as there is no recycling. The rate of DA synthesis then increases because of the loss of end-product inhibition of TH. The newly synthesized DA is stored in vesicles, thus increasing the total amount of DA in the vesicles. A small amount of DA is continually leaking out of vesicles, and the amount leaking out increases proportionally to the amount of DA in vesicles. When the amount of DA leaking out balances the amount being stored by the vesicular monoamine transporter, DA accumulates in the cytosol. The accumulating DA inhibits TH activity, and the system enters a steady state condition characterized by approximately double the normal amount of DA in vesicles and approximately normal rate of DA synthesis and metabolism.

Pharmacokinetics and Pharmacodynamics of γ-Hydroxybutyric Acid during Tolerance in Rats: Effects on Extracellular Dopamine

gamma-Hydroxybutyrate (GHB) is a potent sedative/hypnotic and drug of abuse. Tolerance develops to GHB's sedative/hypnotic effects. It is hypothesized that GHB tolerance may be mediated by alterations in central nervous system pharmacokinetics or neurotransmitter response. Rats were dosed daily with GHB (548 mg/kg s.c. q.d. for 5 days), and sleep time was measured as an index of behavioral tolerance. Plasma and brain GHB pharmacokinetics on days 1 and 5 were monitored using blood and microdialysis sampling. Extracellular (ECF) striatal dopamine levels were measured by microdialysis as a pharmacodynamic endpoint of tolerance. Pharmacokinetic (PK)/pharmacodynamic (PD) modeling was performed to describe the plasma and brain disposition using an indirect response model with inhibition of dopamine synthesis rate to describe the pharmacodynamic response. GHB plasma and brain ECF concentration versus time profiles following acute or chronic exposure were not significantly different. GHB sedative/hypnotic tolerance was observed by day 5. Acute GHB administration resulted in a decrease in striatal ECF dopamine (DA) levels compared with baseline levels. GHB tolerance was reflected by a 60% decrease in dopamine area under the curve (effect and baseline): acute, 10.1 +/- 15.3% basal DA/min/10(-3) versus chronic, 4.73 +/- 1.49% basal DA/min/10(-3) (p < 0.05, n = 5; unpaired Student's t test). The PK/PD model revealed an increase in the IC50 following chronic exposure indicating decreased dopaminergic sensitivity toward the inhibitory effects of GHB. Our findings indicate that GHB pharmacokinetics do not contribute to behavioral tolerance; however, changes in neurotransmitter responsiveness may suggest specific neurochemical pathways involved in the development and expression of tolerance.

Quantitative analysis of dopamine synthesis in human brain using positron emission tomography with L-[β-11C]DOPA

To estimate the presynaptic function of the central dopaminergic system, the rate of endogenous dopamine synthesis has been measured by using L-[beta-C]DOPA or 6-[F]fluoro-L-DOPA with positron emission tomography. However, the regional kinetics of L-[beta-C]DOPA in human brain have not been investigated in detail. In the present study, the regional kinetics of L-[beta-C]DOPA in normal human brain and the accuracy of the method for quantifying L-[beta-C]DOPA kinetics, employing reference regions, were investigated. After intravenous injection of L-[beta-C]DOPA, dynamic scanning was performed on ten healthy subjects for 89 min. The overall uptake rate constant K was calculated by the kinetic and graphical approaches, in which the occipital cortex was used as a reference brain region. Regional distribution of K was similar to those of dopamine D2 receptor. A significant negative correlation was observed between the neutral amino acid concentration in plasma and the influx rate constant through the blood-brain barrier (K1). The K values calculated by graphical approach were in good agreement with the values calculated by kinetic approach for both experimental and simulated data. The regional distribution of K corresponds to that of the nigrostriatal and mesolimbic dopaminergic system. Negative correlation between neutral amino acid concentration and K1 supports the suggestion that L-DOPA is transported in a competitive fashion via the same carrier system as neutral amino acids at the blood-brain barrier. Because the graphical approach can obviate the need for an arterial input function, it is useful for investigating the rate of regional dopamine synthesis in neuropsychiatric and neurodegenerative diseases.

Increased striatal dopamine synthesis is associated with decreased tissue levels of tyrosine

Tyrosine levels do not generally affect indices of dopamine (DA) synthesis or efflux under basal conditions, but can do so when DA synthesis is increased. One possibility is that a high rate of DA synthesis depletes the normally adequate pool of endogenous tyrosine. To study this, we administered drugs known to preferentially increase striatal DA synthesis and examined DOPA levels in striatal microdialysate during perfusion with NSD-1015. In additional groups, we also measured DA, tyrosine and large neutral amino acids in striatal microdialysate, as well as in tissue from striatum and medial prefrontal cortex (MPFC). γ-butyrolactone (GBL) (750 mg/kg i.p.) increased DOPA levels in striatal microdialysate, increased tissue DA levels in the MPFC and striatum, but lowered tissue tyrosine levels only in striatum. In striatal microdialysate, GBL markedly lowered DA levels; tyrosine levels were only marginally lower. Haloperidol (HAL) (1.0 mg/kg s.c.) ± amfonelic acid (AFA) (5 mg/kg i.p.) increased striatal DOPA accumulation, increased striatal DA efflux, lowered striatal tissue tyrosine levels, but did not affect microdialysate tyrosine levels. There were no consistent changes in levels of other large neutral amino acids. We conclude that increased tyrosine hydroxylation can significantly deplete the endogenous pool of tyrosine. Under such conditions, near normal extracellular tyrosine levels are maintained despite lower tissue levels. The data are consistent with a net transfer of tyrosine from non-DAergic cells to DA terminals in support of DA synthesis.

Age-related differences in levodopa dynamics in Parkinson's: implications for motor complications

Treatment-related motor complications in Parkinson's disease have been previously linked to disease-induced pre-synaptic alterations: dopaminergic denervation and changes in dopamine (DA) release patterns. The occurrence of such complications is also known to be partly dependent on the age of disease onset, occurring more frequently in patients with disease onset at a younger age. Using positron emission tomography (PET) and 4-h-long 18F-fluorodopa (FD) scans we have investigated in vivo an age dependence of disease-induced changes in DA turnover as a possible contributing factor to the age-related differences in treatment-related motor complications. We evaluated the relative changes in DA turnover (measured by its direct inverse, effective DA distribution volume--EDV) and DA synthesis and vesicular storage capacity (quantified by the plasma input uptake rate constant Ki) in Parkinson's disease patients as a function of age (n = 27, age range 38-79 years). After correcting for disease severity, a significant negative correlation was found between age and magnitude of disease-induced decrease in EDV and in Ki in the putamen (P < 0.001, P = 0.02, respectively). However, the difference between the disease-induced decrease in EDV and that in Ki also exhibited an age dependence (P < 0.001), indicating a relatively higher disease-induced increase in DA turnover (inverse of EDV) compared with the decrease in DA synthesis and storage rate in patients of younger age compared with older patients. This finding implies that DA turnover in younger-onset patients undergoes a relatively greater alteration and thus likely contributes to a greater imbalance between DA synthesis, storage and release, which could lead to larger swings in synaptic DA levels. It has indeed been suggested on theoretical grounds that such imbalance may contribute to the greater propensity for motor fluctuations. These results provide one possible explanation for the age-dependent occurrence of complications and support the existence of a pre-synaptic contribution to the occurrence of motor complications.

Local effects of acute ethanol on dopamine neurotransmission in the ventral striatum in C57BL/6 mice

In this study, fast-scan cyclic voltammetry in brain slices was used to evaluate the effects of acute ethanol on dopamine terminal release and uptake in the nucleus accumbens of C57BL/6 mice. We found that pharmacologically relevant concentrations of ethanol (20 and 100 mM) did not alter electrically evoked dopamine release, while the highest concentration (200 mM) significantly decreased release (∼45%). No significant changes were observed in the rate of dopamine uptake after ethanol (20, 100 or 200 mM). In addition, it was established that a moderate dose (2 g/kg, i.p.) of ethanol did not alter the rate of dopamine synthesis, measured as L-dihydroxyphenylalanine (L-DOPA) accumulation. However, a high dose (5 g/kg, i.p.) of ethanol significantly increased the levels of L-DOPA to 60% above the control value. These data are consistent with earlier findings obtained in brain slices from rats; dopamine release, but not clearance, is affected by acute ethanol.

The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L-amino acid decarboxylase in healthy subjects

The A1 allele of the TaqI restriction fragment length polymorphism (RFLP) of the human dopamine D2 receptor gene (DRD2) is associated with a low density of D2 dopamine receptors in the striatum. Because of the important role of D2 autoreceptors in regulating dopamine synthesis, we aimed to examine whether subjects with the A1 allele have altered presynaptic dopamine function in the brain. We also studied the effects of two other DRD2 polymorphisms, C957 T and--141C Ins/Del, which have been suggested to affect D2 receptor levels in brain. The relationships between the TaqIA RFLP, C957 T and--141C Ins/Del polymorphisms and striatal dopamine synthesis in 33 healthy Finnish volunteers were studied using positron emission tomography and [18F]fluorodopa ([18F]FDOPA), a radiolabelled analog of the dopamine precursor L-DOPA. Heterozygous carriers of the A1 allele (A1/A2; 10 subjects) had significantly higher (18%) [18F]FDOPA uptake in the putamen than subjects without the A1 allele (A2/A2; 23 subjects). C957 T and--141C Ins/Del polymorphisms did not significantly affect [18F]FDOPA Ki values. These results demonstrate that the A1 allele of DRD2 gene is associated with increased striatal activity of aromatic L-amino acid decarboxylase, the final enzyme in the biosynthesis of dopamine and the rate-limiting enzyme for trace amine (e.g. beta-phenylethylamine) synthesis. The finding can be explained by lower D2 receptor expression leading to decreased autoreceptor function, and suggests that dopamine and/or trace amine synthesis rate is increased in the brains of A1 allele carriers.

Positron emission tomography to quantify brain nicotine abstinence

Background The hypothesis for this research was that brain dopamine (DA) utilization would decrease during abstinence from repeated nicotine administration. Methods Six young Macaca mulatta monkeys were given 0.9% NaCl or nicotine in doses of 32 or 100 μg/kg i.m. bid for 9 days. On the 10th day, PET measurements were repeated before and after nicotine. The PET studies were done in habituated, trained, and fully conscious animals. Results Compared to the control condition, the binding potential (k3/k4) of[11C]raclopride in dorsal or ventral striatum did not change with either dose following acute repeated nicotine, or in the nicotine abstinent state. Compared to control, acute nicotine in either dose did not affect the DA utilization rate constant (k3) in dorsal or ventral striatum as measured by[Beta-11C]L-DOPA. However, in monkeys given nicotine repeatedly, after overnight nicotine abstinence, DA utilization was reduced significantly. A subsequent nicotine dose increased DA utilization to slightly above control levels. The ventral striatum showed greater changes than the dorsal striatum. Conclusions The reduced rate of DA synthesis as assayed with[Beta-11C]L-DOPA during nicotine abstinence and its reversal by nicotine provides an important PET measure of brain nicotine dependence and withdrawal. Clinical Pharmacology & Therapeutics (2005) 77, P98–P98; doi: 10.1016/j.clpt.2005.01.003

Nicotine modulates dopamine synthesis rate as determined by L-[β-11C]DOPA: PET studies compared with [11C]raclopride binding in the conscious monkey brain

SynapseVolume 57, Issue 2 p. 120-122 Short Communication Nicotine modulates dopamine synthesis rate as determined by L-[β-11C]DOPA: PET studies compared with [11C]raclopride binding in the conscious monkey brain Hideo Tsukada, Corresponding Author Hideo Tsukada tsukada@crl.hpk.co.jp Central Research Laboratory, Hamamatsu Photonics K.K., Hamakita, Shizuoka 434-8601, JapanCentral Research Laboratory, Hamamatsu Photonics K.K., 5000 Hirakuchi, Hamakita, Shizuoka 434-8601, JapanSearch for more papers by this authorKatsumasa Miyasato, Katsumasa Miyasato School of Medicine, Saint Marianna University, Kawasaki 216-8511, Kanagawa, JapanSearch for more papers by this authorNorihiro Harada, Norihiro Harada Central Research Laboratory, Hamamatsu Photonics K.K., Hamakita, Shizuoka 434-8601, JapanSearch for more papers by this authorShingo Nishiyama, Shingo Nishiyama Central Research Laboratory, Hamamatsu Photonics K.K., Hamakita, Shizuoka 434-8601, JapanSearch for more papers by this authorDai Fukumoto, Dai Fukumoto Central Research Laboratory, Hamamatsu Photonics K.K., Hamakita, Shizuoka 434-8601, JapanSearch for more papers by this authorTakeharu Kakiuchi, Takeharu Kakiuchi Central Research Laboratory, Hamamatsu Photonics K.K., Hamakita, Shizuoka 434-8601, JapanSearch for more papers by this author Hideo Tsukada, Corresponding Author Hideo Tsukada tsukada@crl.hpk.co.jp Central Research Laboratory, Hamamatsu Photonics K.K., Hamakita, Shizuoka 434-8601, JapanCentral Research Laboratory, Hamamatsu Photonics K.K., 5000 Hirakuchi, Hamakita, Shizuoka 434-8601, JapanSearch for more papers by this authorKatsumasa Miyasato, Katsumasa Miyasato School of Medicine, Saint Marianna University, Kawasaki 216-8511, Kanagawa, JapanSearch for more papers by this authorNorihiro Harada, Norihiro Harada Central Research Laboratory, Hamamatsu Photonics K.K., Hamakita, Shizuoka 434-8601, JapanSearch for more papers by this authorShingo Nishiyama, Shingo Nishiyama Central Research Laboratory, Hamamatsu Photonics K.K., Hamakita, Shizuoka 434-8601, JapanSearch for more papers by this authorDai Fukumoto, Dai Fukumoto Central Research Laboratory, Hamamatsu Photonics K.K., Hamakita, Shizuoka 434-8601, JapanSearch for more papers by this authorTakeharu Kakiuchi, Takeharu Kakiuchi Central Research Laboratory, Hamamatsu Photonics K.K., Hamakita, Shizuoka 434-8601, JapanSearch for more papers by this author First published: 19 May 2005 https://doi.org/10.1002/syn.20157Citations: 11AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume57, Issue2August 2005Pages 120-122 RelatedInformation

Over-expression of renal LAT1 and LAT2 and enhanced L-DOPA uptake in SHR immortalized renal proximal tubular cells

Spontaneously hypertensive rats (SHR) may have an increased renal production of dopamine. LAT2 promotes L-DOPA renal uptake, and this may determine the rate of dopamine synthesis. The present study evaluated L-DOPA inward and outward transfer in immortalized renal proximal tubular epithelial cells of SHR and Wistar-Kyoto rats (WKY). Uptake of [(14)C]-L-DOPA was initiated by the addition of 1 mL Hanks' medium with a given concentration of the substrate. The apical fractional outflow of intracellular [(14)C]-L-DOPA was evaluated in cells loaded with [(14)C]-L-DOPA for 6 minutes, and then the corresponding efflux was monitored over 12 minutes. The presence of LAT1 and LAT2 transcripts and protein in WKY and SHR cells was examined, respectively, by reverse transcription-polymerase chain reaction (RT-PCR) and immunobloting. LAT2 in WKY cells contributed almost exclusively for [(14)C]-L-DOPA uptake. In SHR cells [(14)C]-L-DOPA uptake was 25% through system B(0), 25% through LAT2 (resulting from inhibition by 1 mmol/L glycine, L-alanine, L-serine, and L-threonine), and the remaining 50% through LAT1. The efflux of [(14)C]-L-DOPA from WKY and SHR cells corresponded to approximately 65% and approximately 25%, respectively, of the amount accumulated in the cells. The LAT1 and LAT2 transcripts were present in both SHR and WKY cells, but the abundance of both LAT1 and LAT2 proteins in SHR cells was greater than in WKY cells. Differences in L-DOPA handling between SHR and WKY cells may result from over-expression of LAT1 and LAT2 transporters in the former. The unique role of Na(+)-dependent transporters (system B(0)) in SHR cells also contributes to the enhanced L-DOPA uptake in these cells.

Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1

Mutations in the parkin gene are linked to autosomal-recessive juvenile parkinsonism (AR-JP). Parkin functions as a ubiquitin protein ligase in the degradation of several proteins, including the neuron-specific septin CDCrel-1. AR-JP-associated parkin mutations inhibit ubiquitination and degradation of CDCrel-1 and other parkin target proteins. Here we show that recombinant adeno-associated virus-mediated CDCrel-1 gene transfer to the substantia nigra of rats results in a rapid onset (6-10 days) of nigral and striatal CDCrel-1 expression that is followed by a progressive loss of nigral dopaminergic neurons and a decline of the striatal dopamine levels. In contrast, neurons of the globus pallidus are spared from CDCrel-1 toxicity. Furthermore, CDCrel-1 inhibits the release of dopamine from stably-transfected PC12 cells, and pharmacological inhibition of tyrosine hydroxylase and dopamine synthesis in rats prevents CDCrel-1-induced nigral neurodegeneration. These results show that CDCrel-1 overexpression exerts dopamine-dependent neurotoxicity and suggest that inhibition of dopamine secretion by CDCrel-1 may contribute to the development of AR-JP.

Effect of dopamine loss and the metabolite 3-O-methyl-[18F]fluoro-dopa on the relation between the 18F-fluorodopa tissue input uptake rate constant Kocc and the [18F]fluorodopa plasma input uptake rate constant Ki.

Parkinson disease is characterized by the loss of dopaminergic neurons, thus decreasing the system's ability to produce and store dopamine (DA). Such ability is often investigated using 18F-fluorodopa (FD) positron emission tomography. A commonly used model to investigate the DA synthesis and storage rate is the modified Patlak graphical approach. This approach allows for both plasma and tissue input functions, yielding the respective uptake rate constants K(i) and K(occ). This method requires the presence of an irreversible compartment and the absence of any nontrapped tracer metabolite. In the case of K(occ), this last assumption is violated by the presence of the FD metabolite 3-O-methyl-[18F]fluoro-dopa (3OMFD), which makes the K(occ) evaluation susceptible to a downward bias. It was found that both K(i) and K(occ) are influenced by DA loss and thus are not pure measures of DA synthesis and storage. In the case of K(occ), the presence of 3OMFD exacerbates the effect of DA egress, thus introducing a disease-dependent bias in the K(occ) determination. These findings imply that K(i) and K(occ) provide different assessments of disease severity and that, as disease progresses, K(i) and especially K(occ) become more related to DA storage capacity and less to the DA synthesis rate.

Positron emission tomography and brain monoamine neurotransmission -- entries for study of drug interactions.

Monoamine neurotransmission is a complicated process with interactions between individual neurotransmitter pathways, multiple receptors with different responses and a variety of feedback loops regulating neurotransmitter synthesis, release, reuptake and effect on receptors. The system is further affected by a range of enzymes with co-factors controlling synthesis and degradation of monoamines. Positron emission tomography (PET) has evolved to a very versatile tool for the in vivo imaging and characterisation of physiology and biochemistry. The basis for its expansion during the last years has been a rapid development of labelling methods, allowing a range of tracer molecules to be generated and used in human and research animal studies. The most important PET radionuclide is (11)C with a short half-life of approximately 20 minutes. This radionuclide is ideal for the labelling of organic molecules and for multi-tracer applications in research and drug development studies. PET has been used for a range of explorative studies on the monoamine neurotransmission, as exemplified by studies on the expression of dopamine and serotonin receptors as well as the rate of dopamine and serotonin synthesis. The present article gives examples of studies where PET has been used for the characterization of monoamine transmitter systems in experimental animals and in humans, both in healthy individuals and in patients with diseases affecting neurotransmission.

Dopamine synthesis rate in prefrontal cortex in schizophrenia by use of PET

Dopamine synthesis rate in prefrontal cortex in schizophrenia by use of PET

Age-related changes in the striatal dopaminergic system in the living brain: a multiparametric PET study in conscious monkeys.

In the present study, age-related changes in the striatal dopaminergic system were examined in the living brains of conscious young (6.2 +/- 1.5 years old) and aged (20.2 +/- 2.6 years old) monkeys (Macaca mulatta) using positron emission tomography (PET). L-[beta-(11)C]DOPA and [(11)C]beta-CFT were applied to determine dopamine presynaptic functions such as synthesis rate and transporter (DAT) availability, respectively. Striatal dopamine D(1)- (D(1)R) and D(2)-like receptor (D(2)R) binding were measured with [(11)C]SCH23390 and [(11)C]raclopride, respectively. Although the markers of presynaptic terminals showed parallel age-related declines, the reduction of dopamine synthesis rate measured with L-[beta-(11)C]DOPA was slightly smaller than that of DAT determined with [(11)C]beta-CFT. The binding of [(11)C]raclopride to D(2)R in vivo was significantly reduced with aging, while that of [(11)C]SCH23390 to D(1)R showed no such marked age-related reduction. When the DAT inhibitor GBR12909 (0.5 and 5 mg/kg) was administered, DAT availability, dopamine synthesis, and D(2)R binding were significantly decreased in a dose-dependent manner in both age groups; however, the degrees of the decreases in these parameters were significantly higher in young rather than in aged animals. Dopamine concentration in the striatal extracellular fluid (ECF), as measured by microdialysis, was increased by administration of GBR12909 in a dose-dependent manner and the degree of the increase in dopamine level decreased with age. These results demonstrate that age-related changes of dopamine neuronal functions were not limited to the resting condition but were also seen in the functional responses to the neurotransmitter modulation.

Increase in dopamine turnover occurs early in Parkinson's disease: evidence from a new modeling approach to PET 18 F-fluorodopa data.

An increase in dopamine turnover has been hypothesized to occur early in Parkinson's disease (PD) as a compensatory mechanism for dopaminergic neuronal loss. A new approach to the determination of dopamine turnover was developed using 4-hour-long 18 F-fluorodopa (FD) positron emission tomography (PET) data. An effective dopamine turnover, an estimate of dopamine turnover, has been measured using its inverse, the effective dopamine distribution volume (EDV). This new method is based on a reversible tracer approach and determines the EDV using a graphical method. Six healthy subjects and 10 subjects with very early PD underwent a 4-hour-long FD scan. The EDV and the plasma uptake rate constant K(i), a marker of dopamine synthesis and storage, were compared according to their ability to separate the PD group from the healthy group. The EDV was the better discriminator (93.8% correct classification versus 81.3% for K(i)). Effective dopamine distribution volume decreased by 65% in the PD group relative to the healthy group, whereas the decrease in K(i) was 39%. These results show that changes in EDV are measurable with PET earlier than changes in the dopamine synthesis and storage rate, indicating that EDV is a sensitive marker for early PD and that a dopamine turnover increase likely serves as an early compensatory mechanism.

Differential responses in central dopaminergic activity induced by apomorphine in IPL nude rat

The IPL nude rat, derived by spontaneous mutation from the Sprague–Dawley strain, presents alterations in the prolactin synthesis and secretion due to an increased dopaminergic inhibition. However, there are no reports concerned to central dopamine activity. The corpus striatum is a brain area involved in the development of stereotyped behavior after the activation of mesolimbic and/or nigro-striatal dopamine pathways. In order to identify possible mesolimbic and/or nigro-striatal dysfunctions in the IPL nude rat, we study the spontaneous oral behaviors and the effects of apomorphine-induced dopaminergic activation on stereotyped behavior and neurochemical changes. Males from both strains were injected with saline or apomorphine (2 and 5 mg/kg s.c.) and evaluated during 30 min in a stereotypes oral tests. The corpus striatum and nucleus accumbens were used to measure dopamine (DA), 3,4-dihydroxyphenylalanine (DOPA) and 3,4-dihydroxyphenylacetic acid (DOPAC) by HPLC. The concentrations were expressed as synthesis rate (DA/DOPA) and turnover rate (DOPAC/DA). We observed that the spontaneous gnaw movements were significantly different between the untreated IPL nude and Sprague–Dawley (SD) rats. Apomophine injection decreased the amount of stereotyped gnawing in IPL nude rats at the two doses used, but it induced an increase in SD rats. Apomorphine also caused an enhancement in the number of biting and sniffing without modifying the licking behavior. In addition, modifications of the dopaminergic activity were also observed. Synthesis rate in the striatum of IPL nude rats was higher than in SD rats after the injection of saline. Apomorphine caused a reduction of the synthesis rate in both strains. Turnover rate was significantly lower in the striatum of IPL nude rats than in the SD rats injected with saline. Apomorphine caused an increase in the turnover rate in both strains. Contrary to observed in the striatum, the 2 mg/kg dose of apomorphine caused a significant increase in the DA synthesis rate in nucleus accumbens, while 5 mg/kg decrease it in both strains. The DA turnover rate in the same area was lower in IPL nude than in SD rats after saline injection. Apomorphine enhances the DA turnover rate in both strains. We conclude that the modifications of the oral spontaneous and induced stereotypical patterns observed in the IPL nude rats could be related to the differential responses in dopaminergic activity in the two brain areas examined.

Dopaminergic transmission in the rat striatum in vivo in conditions of pharmacological modulation.

The effects of pharmacological modulation of striatal dopaminergic neurotransmission were studied in freely mobile rats by intracerebral microdialysis and HPLC to assay dopamine and dopamine metabolite levels and the rate of dopamine synthesis, in combination with observations of stereotypical behavior. Inhibition of catechol O-methyltransferase (COMT) with tolcapone led to increases in extracellular dopamine levels only when the baseline dopamine level was elevated by administration of L-3,4-dihydroxyphenylalanine in combination with the decarboxylation inhibitor carbidopa. Increases in dopamine levels in striatal dialysates by blockade of reuptake were enhanced by inhibition of metabolic degradation of dopamine by tolcapone, a selective catechol O-methyltransferase inhibitor. GBR-12909, a blocker of the dopamine transporter, increased extracellular dopamine and induced motor stereotypy. Both of these effects were potentiated by tolcapone. The rate of dopamine biosynthesis decreased when reuptake was inhibited. These data provide evidence for the key role of the dopamine transporter in maintaining neurochemical homeostasis at the synaptic level.