[show abstract][hide abstract] ABSTRACT: Although various brain regions have been shown to respond to the presentation of visual sexual stimuli (VSS), whether these regions are specifically mediating sexual arousal or whether they mediate general emotional or motivational arousal is unknown. To clarify this issue, our purpose was to map the regions where the response to VSS was related to plasma testosterone. Specific objectives were (i) to identify regions that respond differentially to VSS in untreated hypogonadal patients compared with healthy controls and (ii) to identify in hypogonadal patients the regions that respond differentially to VSS as a function of therapeutically induced increased testosterone levels.
In nine male hypogonadal patients, in the same patients under treatment, and in eight healthy males, we used Positron Emission Tomography to investigate responses of regional cerebral blood flow to VSS. Statistical Parametric Mapping was used to locate regions that demonstrated a differential response.
Regions responding differentially both in untreated patients compared with controls and in untreated patients compared with themselves under treatment were the right orbitofrontal cortex, insula and claustrum, where the activation was higher in controls than in untreated patients and where activation increased under treatment, and the left inferior frontal gyrus, that demonstrated a deactivation only in controls and in patients under treatment. That these responses appear to depend on testosterone indicates that these regions mediate sexual arousal and not only a process of general emotional or motivational arousal.
[show abstract][hide abstract] ABSTRACT: The selectivity of [18F]MPPF (fluorine-18-labeled 4-(2;-methoxyphenyl)-1-[2;-(N-2"-pirydynyl)-p-fluorobenzamido]ethylpiperazine) for serotonergic 5-hydroxytryptamine(1A) (5-HT1A) receptors has been established in animals and humans. The authors quantified the parameters of ligand-receptor exchanges using a double-injection protocol. After injection of a tracer and a coinjection dose of [18F]MPPF, dynamic positron emission tomography (PET) data were acquired during a 160-minute session in five healthy males. These PET and magnetic resonance imaging data were coregistered for anatomical identification. A three-compartment model was used to determine six parameters: Fv (vascular fraction), K1, k2 (plasma/free compartment exchange rate), koff, kon/Vr (association and dissociation rate), Bmax (receptor concentration), and to deduce Kd (apparent equilibrium dissociation rate). The model was fitted with regional PET kinetics and arterial input function corrected for metabolites. Analytical distribution volume and binding potential were compared with indices generated by Logan-Patlak graphical analysis. The 5HT1A specificity for MPPF was evidenced. A Bmax of 2.9 pmol/mL and a Kd of 2.8 nmol/L were found in hippocampal regions, Kd and distribution volume in the free compartment were regionally stable, and the Logan binding potential was linearly correlated to Bmax. This study confirms the value of MPPF in the investigation of normal and pathologic systems involving the limbic network and 5-HT1A receptors. Standard values can be used for the simulation of simplified protocols.
[show abstract][hide abstract] ABSTRACT: Changes in tissue and extracellular serotonin (5-HT) in raphe dorsalis, raphe medialis and in their main projections areas (hippocampus, striatum and frontal cortex) were investigated at short and long-term times after single injection (5 mg/kg ip) of a novel tryptophan hydroxylase inhibitor, p-ethynylphenylalanine (p-EPA). The 5-HT tissue concentration decreased significantly in raphe nuclei, 30 min post-injection and for 4 days, whereas it decreased from 24 hours post-injection in the 5-HT projections. Normal 5-HT levels reappeared after 12 days post-injection in all areas. Moreover, in the projection areas, the extracellular 5-HT levels decreased rapidly, 90, 40 and 30 min after p-EPA injection, in hippocampus, striatum and frontal cortex, respectively. Decreased accumulation of 5-hydroxytryptophan (5-HTP) under NSD-101 perfusion in the serotoninergic projections after p-EPA injection, confirmed the direct inhibitory effect of the drug on the tryptophan hydroxylase activity. These results demonstrated that p-EPA is a useful pharmacological tool which powerfully, acutely and irreversibly reduces the 5-HT levels.
Neurochemical Research 05/2002; 27(4):269-75. · 2.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: Our aim was to show the ability of a recently developed beta(+)-range-sensitive intracerebral probe (SIC) to measure, in vivo, the binding of radioligands in small animals.
The potential of the device for pharmacokinetic studies was evaluated by measurement of the dynamic striatal binding of (11)C-raclopride, a well-documented D(2) dopaminergic receptor ligand, in rat brain after intravenous injection of the labeled compound. The effects of preinjection of the unlabeled ligand (raclopride, 2 mg/kg intravenously) and of increasing the synaptic dopamine level (amphetamine treatment, 1 mg/kg intravenously) or of depleting synaptic dopamine (reserpine pretreatment, 5 mg/kg intraperitoneally) on in vivo (11)C-raclopride binding were monitored by SIC.
The radioactivity curves measured as a function of time were reproducible and consistent with previous studies using PET imaging (ratio of striatum to cerebellum, 2.6 +/- 0.3 after 20 min). Further studies showed significant displacement of (11)C-raclopride by its stable analog. Finally, the device proved its capacity to accurately detect changes in (11)C-raclopride binding after a sudden (amphetamine) or a gradual (reserpine) modulation of endogenous dopamine levels.
These results show that the new device can monitor binding of PET ligands in anesthetized rodents in vivo, with high temporal resolution.
Journal of Nuclear Medicine 03/2002; 43(2):227-33. · 5.77 Impact Factor
[show abstract][hide abstract] ABSTRACT: By using a combination of an original beta+-sensitive intracerebral probe and microdialysis, the effect of increased endogenous serotonin on specific binding of 18F-MPPF [4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-fluorobenzamido]ethyl]piperazine] to the serotonin-1A (5-HT1A) receptors was investigated in the hippocampus of the anaesthetized rat. Our beta-sensitive probe prototype was sensitive enough to obtain specific 18F-MPPF time-activity curves in the rodent (hippocampus/cerebellum ratio approximately 2). The serotonin neuronal release was pharmacologically enhanced using fenfluramine at three different doses (1, 2 and 10 mg/kg intravenous) multiplying by 2-15 the extracellular serotonin in the hippocampus. These extracellular variations of extracellular serotonin resulted in dose-ranging decreases in 18F-MPPF-specific binding in the same rat. Our results showed for the first time that 18F-MPPF binding could be modulated by modifications of extracellular serotonin in the rat hippocampus. These results were confirmed by the enhancement of extracellular radioactivity collected in dialysates after the displacement of 18F-MPPF by fenfluramine. After modelization, 18F-MPPF binding could constitute an interesting radiotracer for positron emission tomography in evaluating the serotonin endogenous levels in limbic areas of the human brain.
Journal of Neurochemistry 02/2002; 80(2):278-86. · 3.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: Biochemical approaches were used in freely moving rats to determine, under steady-state conditions, the brain/arterial plasma partition coefficients of L-tryptophan and α-[3H]methyl-L-tryptophan, from which the lumped constant for the α-methyl-L-tryptophan method of estimating the rate of brain serotonin synthesis is calculated. The lumped constants were significantly different in the various structures examined: 0.149 ± 0.003 in the raphe dorsalis, 0.103 ± 0.002 in the raphe centralis, 0.087 ± 0.003 in the reticular formation, and 0.62 ± 0.08 in the pineal gland. From these data we proposed a two-compartment model to calculate the rate of serotonin synthesis by quantitative autoradiography using a three-time point experiment. Rates of synthesis for the raphe dorsalis and the reticular formation (620 ± 57 and 80 ± 35 pmol/g of tissue/min, respectively) were similar to those measured simultaneously by biochemical means, but rates were 50% higher for the raphe centralis (568 ± 90 vs. 381 ± 31 pmol/g of tissue/min). The lack of dynamic equilibrium of the tracer between plasma and tissue pools may explain the discrepancy between the two methods. Our findings did not confirm previous data, indicating that the application of the autoradiographic method to measure the rate of brain serotonin synthesis using α-methyl-L-tryptophan as tracer has limitations.
Journal of Neurochemistry 01/2002; 72(6):2593-2600. · 3.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: The in vivo behavior of 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-[(18)F]fluorobenzamido ]ethyl]-piperazine (p-[(18)F]MPPF), a new serotonin 5-HT(1A) antagonist, was studied in awake, freely moving rats. Biodistribution studies showed that the carbon-fluorine bond was stable in vivo, that this compound was able to cross the blood-brain barrier, and that a general diffusion equilibrium could account for the availability of the tracer. The great quantity of highly polar metabolites found in plasma did not contribute to the small amounts of metabolites found in hippocampus, frontal cortex, and cerebellum. Exvivo p-[(18)F]MPPF and in vitro 8-hydroxy-2-(di-n-[(3)H]propylamino)tetralin autoradiography were compared both qualitatively and quantitatively. Qualitative evaluation proved that the same brain regions were labeled and that the p-[(18)F]MPPF labeling is (a) in total agreement with the known distribution of 5-HT(1A) receptors in rats and (b) characterized by very low nonspecific binding. Quantitative comparison demonstrated that the in vivo labeling pattern obtained with p-[(18)F]MPPF cannot be explained by differences in regional blood flow, capillary density, or permeability. The 5-HT(1A) specificity of p-[(18)F]MPPF and binding reversibility were confirmed in vivo with displacement experiments. Thus, this compound can be used to evaluate parameters characterizing 5-HT(1A) binding sites in the brain.
Journal of Neurochemistry 09/2000; 75(2):803-11. · 3.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: By using a combination of an original b + -sensitive intracerebral probe and microdialysis, the effect of increased endogenous serotonin on specific binding of 18 F-MPPF (4-(2¢-methoxy- phenyl)-1-(2¢-(N-(2¢¢-pyridinyl)-p-fluorobenzamido)ethyl)piper- azine) to the serotonin-1A (5-HT1A) receptors was investigated in the hippocampus of the anaesthetized rat. Our b-sensitive probe prototype was sensitive enough to obtain specific 18 F-MPPF time-activity curves in the rodent (hippo- campus/cerebellum ratio 2). The serotonin neuronal release was pharmacologically enhanced using fenfluramine at three different doses (1, 2 and 10 mg/kg intravenous) multiplying by 2-15 the extracellular serotonin in the hippocampus. These extracellular variations of extracellular serotonin resulted in dose-ranging decreases in 18 F-MPPF-specific binding in the same rat. Our results showed for the first time that 18 F-MPPF binding could be modulated by modifications of extracellular serotonin in the rat hippocampus. These results were con- firmed by the enhancement of extracellular radioactivity col- lected in dialysates after the displacement of 18 F-MPPF by