Contribution of estrogen receptors alpha and beta to the effects of estradiol in the brain.

Clinical and experimental studies show a modulatory role of estrogens in the brain and suggest their beneficial action in mental and neurodegenerative diseases. The estrogen receptors ERalpha and ERbeta are present in the brain and their targeting could bring selectivity and reduced risk of cancer. Implication of ERs in the effect of estradiol on dopamine, opiate and glutamate neurotransmission is reviewed. The ERalpha agonist, PPT, is shown as estradiol to modulate hippocampal NMDA receptors and AMPA receptors in cortex and striatum of ovariectomized rats whereas the ERbeta agonist DPN is inactive. Striatal DPN activity suggests implication of ERbeta in estradiol modulation of D2 receptors and transporters in ovariectomized rats and is supported by the lack of effect of estradiol in ERbeta knockout (ERKObeta) mice. Both ERalpha and ERbeta agonists modulate striatal preproenkephalin (PPE) gene expression in ovariectomized rats. In male mice PPT protects against MPTP toxicity to striatal dopamine; this implicates Akt/GSK3beta signaling and the apoptotic regulators Bcl2 and Bad. This suggests a role for ERalpha in striatal dopamine neuroprotection. ERKOalpha mice are more susceptible to MPTP toxicity and not protected by estradiol; differences in ERKObeta mice are subtler. These results suggest therapeutic potential for the brain of ER specific agonists.

A sphingosine-1-phosphate receptor 1 agonist inhibits tertiary lymphoid tissue reactivation and hypersensitivity in the lung.

Hypersensitivity pneumonitis is characterized by pulmonary accumulation of B-cell-rich tertiary lymphoid tissues (TLTs), which are alleged sites of amplification for antigen-specific responses. The sphingosine-1-phosphate receptor 1 (S1P1) regulates key mechanisms underlying lymphoid tissue biology and its chemical modulation causes lymphocyte retention in lymph nodes. Given the putative immunopathogenic impact of lymphocyte accumulation in TLTs, we investigated whether or not chemical modulation of S1P1 caused lymphocyte retention within TLTs in a model of hypersensitivity pneumonitis. Mice were exposed subchronically to Methanosphaera stadtmanae (MSS) in order to induce an hypersensitivity pneumonitis-like disease. MSS exposure induced B-cell-rich TLTs surrounded by S1P1-positive microvessels. Upon MSS rechallenge, the S1P1 agonist RP001 prevented the pulmonary increase of CXCL13, a chief regulator of B-cell recruitment in lymphoid tissues. This was associated with a complete inhibition of MSS rechallenge-induced TLT enlargement and with a 2.3-fold reduction of MSS-specific antibody titers in the lung. Interference with TLT reactivation was associated with a 77% reduction of neutrophil accumulation and with full inhibition of protein-rich leakage in the airways. Thus, an S1P1 agonist hinders TLT enlargement upon antigenic rechallenge and inhibits key pathognomonic features of experimental hypersensitivity pneumonitis.

Dopamine-receptor stimulation: biobehavioral and biochemical consequences.

The MPTP monkey is a well-characterized animal model of parkinsonism and provides an exceptional tool for the study of dyskinesias induced by dopamine-like agents. Several such agents have been tested during the past 15 years, and it has been found that the duration of action of these compounds is the most reliable variable with which to predict their dyskinesiogenic profile. It is proposed that L-dopa-induced dyskinesias represent a form of pathological learning caused by chronic pulsatile (nonphysiological) stimulation of dopamine receptors, which activates a cascade of molecular and biochemical events. These events include defective regulation of Fos proteins that belong to the deltaFosB family, increased expression of neuropeptides, and defective GABA- and glutamate-mediated neurotransmission in the output structures of the basal ganglia.

Increased expression and activity of RhoA are associated with increased DNA synthesis and reduced p27(Kip1) expression in the vasculature of hypertensive rats.

We have previously shown that the function of the small G protein Rho is required for vascular smooth muscle cell proliferation and migration. We hypothesized that changes in Rho or Rho signaling might contribute to enhanced vascular proliferative responses associated with hypertension. Western blot analysis revealed that total RhoA expression was approximately 2-fold higher in aortas, tail arteries, and aortic smooth muscle cells (ASMCs) obtained from adult male spontaneously hypertensive rats (SHR) compared with those from Wistar Kyoto rats (WKY). An increase in active GTP-bound RhoA was detected in aortic homogenates by affinity precipitation with the RhoA effector rhotekin and by examining RhoA-[(35)S]GTPgammaS binding. RhoA protein and activity were also increased in vessels from rats treated with N-nitro-L-arginine methyl ester to increase blood pressure. Thrombin-stimulated RhoA activation was also significantly greater in ASMCs from SHR. As a functional correlate of these changes in Rho signaling, thrombin-stimulated DNA synthesis was enhanced in tail arteries and ASMCs from SHR. Expression of the cyclin-dependent kinase inhibitor p27(Kip1) was decreased by two thirds in SHR, and this decrease was mimicked in ASMCs by expression of a constitutively active (GTPase-deficient) mutant of RhoA. Wortmannin (10 nmol/L) fully inhibited the decrease in p27(Kip1) induced by RhoA, and a membrane-targeted catalytic subunit of phosphatidylinositol-3 kinase (PI3K [p110(CAAX)]) decreased p27(Kip1) expression, suggesting that RhoA signals through PI3K. These data provide evidence that RhoA brings about changes in DNA synthesis through reduced expression of p27(Kip1), mediated in part via PI3K, and suggest that increases in RhoA expression and activity contribute to the enhanced vascular responsiveness observed in hypertension.

Estrogen receptors modulate striatal metabotropic receptor type 5 in intact and MPTP male mice model of Parkinson's disease.

Glutamate is the most important brain excitatory neurotransmitter and glutamate overactivity is well documented in Parkinson's disease (PD). Metabotropic glutamate (mGlu) receptors are reported to interact with membrane estrogen receptors (ERs) and more specifically the mGlu5 receptor subtype. 17ß-estradiol and mGlu5 antagonists have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We previously reported that ERα and ERß are involved in neuroprotection following MPTP toxicity. The present study investigated the implication of ERs on the mGlu5 receptor adaptive response to MPTP toxicity in the brain of wild type (WT), ER knockout (ERKO)α and ERKOß male mice. Autoradiography of [(3)H]ABP688 specific binding to striatal mGlu5 receptors showed a dorsal/ventral gradient similar for WT, ERKOα and ERKOß mice with higher values ventrally. The lateral septum had highest [(3)H]ABP688 specific binding that remained unchanged in all experimental groups. ERKOα and ERKOß mice had similarly lower striatal [(3)H]ABP688 specific binding than WT mice as measured also by Western blots. MPTP dose-dependently decreased striatal [(3)H]ABP688 specific binding in WT but not in ERKOα and ERKOß mice; this correlated positively with striatal dopamine concentrations. A 17ß-estradiol treatment for 10 days left unchanged striatal [(3)H]ABP688 specific binding of unlesioned mice of the three genotypes. 17ß-estradiol treatment for 5 days before MPTP and for 5 days after partially prevented the mGlu5 receptor decrease only in WT MPTP mice and this was associated with higher BDNF striatal contents. These results thus show that in male mice ERs affect striatal mGlu5 receptor levels and their response to MPTP.

Oestrogens prevent loss of dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) in substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice.

Previous results from our laboratory have shown that 17beta-oestradiol prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) striatal dopamine depletion. 17beta-oestradiol, oestriol and oestrone are the naturally occurring oestogens in humans. Using various dopamine markers, the present study investigated whether oestrone and oestriol such as 17beta-oestradiol have neuroprotective activity in MPTP-treated mice. Male mice were treated with 17beta-oestradiol, oestriol or oestrone for 5 days before and after MPTP administration, and were compared with nonlesioned mice receiving the same treatment. Striatal concentrations of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were assayed by high-performance liquid chromatography. Dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) specific binding were measured by autoradiography. DAT, VMAT2 and tyrosine hydroxylase mRNA levels were measured by in situ hybridisation. MPTP induced a loss of DAT and VMAT2 specific binding in the striatum and substantia nigra, as well as a decrease of VMAT2 mRNA in the substantia nigra. 17beta-oestradiol treatment prevented the loss of these dopaminergic markers, as well as striatal concentrations of dopamine, DOPAC and HVA. Mice receiving oestriol and oestrone showed catecholamine concentrations comparable to MPTP mice. Oestriol treatment had no effect on dopaminergic markers in MPTP mice whereas oestrone prevented striatal DAT loss and the decrease of VMAT2 mRNA in the substantia nigra. In nonlesioned mice, 17beta-oestradiol, oestriol or oestrone had no effect on all the dopaminergic markers investigated. In conclusion, a weak or a lack of effect of oestriol and oestrone was observed compared to 17beta-oestradiol in MPTP mice and none of these steroids had an effect in nonlesioned mice. A DAT and VMAT2 specific binding decrease after MPTP in the striatum and substantia nigra, as well as a decrease of substantia nigra VMAT2 mRNA, was observed and could be prevented by oestradiol.

Sorption and desorption of diverse contaminants of varying polarity in wastewater sludge with and without alum.

Sewage sludge sorption and desorption measurements were conducted for nine diverse contaminants of varying polarity: caffeine, sulfamethoxazole, carbamazepine, atrazine, estradiol, ethinylestradiol, diclofenac, and, for the first time desethylatrazine and norethindrone. Two types of sorption behaviour were observed. Compounds with a log octanol-water partition coefficient, log Kow, below 3 showed little or no sorption over 48 hours of shaking, while compounds with log Kow over 3 showed 30 to 90% sorption within the first few minutes. After 6 hours of shaking, mass loss through suspected biotransformation became evident for some compounds. At the pH range considered (5.7-6.7), diclofenac (pKa 4.0, log Kow 4.5) was the only compound in which pH dependent sorption could be quantified. The log sewage sludge-water distribution coefficients, log Kd, ranged from 0.2 to 2.9, and, as expected, increased with increasing log Kow of the compound and organic carbon (OC) content of the sewage sludge. A sewage sludge precipitated with alum had a substantially lower Kd values, as well as lower OC content, compared to alum-free sludge. Desorption was studied by sequentially replacing supernatant water. With each water replacement, log Kd values tended to either remain similar (following a linear isotherm) or in some cases increase (following a Freundlich-type isotherm). The length of time required to restore equilibrium increased with each rinsing step. A literature review of reported Kd values compared well with the alum-free sludge data, but not the alum-sludge data. Sewage sludge Kd across the literature appear more consistent with increasing Kow.

A case of ganciclovir-resistant cytomegalovirus (CMV) retinitis in a patient with AIDS: longitudinal molecular analysis of the CMV viral load and viral mutations in blood compartments.

OBJECTIVE: To study the temporal relationships between cytomegalovirus (CMV) viral load and specific UL97 mutations in polymorphonuclear leukocytes (PMNL) and plasma samples from a patient with AIDS who developed ganciclovir-resistant CMV retinitis. METHODS: Sequential PMNL and plasma samples were analysed for determination of the CMV viral load using non-molecular methods and a quantitative polymerase chain reaction (PCR) assay. Screening of the same samples for the most common mutations conferring ganciclovir resistance was performed using nested PCR and restriction enzyme analysis. RESULTS: At the time of progression of CMV retinitis (after 6 months of ganciclovir), a rapid increase in the CMV DNA load was found in both PMNL and plasma samples. This increase paralleled the emergence of a specific mutation (V594) in the same samples and recovery of ganciclovir-resistant blood isolates. In this patient, however, the only tests that substantially predicted the progression of CMV disease were the quantitative PCR assay using PMNL and to a lesser extent the pp65 antigenemia assay. CONCLUSIONS: Quantitative evaluation of the CMV viral load in PMNL using sensitive assays such as PCR appears to be a promising approach for monitoring antiviral therapy in subjects with AIDS. In addition, common mutations conferring ganciclovir resistance can be detected directly in PMNL and plasma samples.

Drugs with estrogen-like potency and brain activity: potential therapeutic application for the CNS.

Numerous reports, ranging from molecular investigations to clinical studies, demonstrate the potency of estrogens to modulate brain function and their implications in schizophrenia and depression. Alterations of dopaminergic, cholinergic, GABAergic, glutamatergic and serotonergic neurotransmission through estrogen-mediated mechanisms have been consistently established. Moreover, studies using in vivo and in vitro models as well as epidemiological data suggest that estrogens provide neuroprotection of central nervous system (CNS) cells implicated in the etiology of neurodegenerative disorders such as Alzheimer s (AD) and Parkinson s (PD) diseases. Numerous genomic or non-genomic mechanisms of actions of estrogens in the brain have been documented implicating classical nuclear estrogen receptors as well as possible estrogen membrane receptors, antioxidant activity of steroids, their effect on fluidity as well as on antiapoptotic proteins and growth factors. Selective estrogen receptor modulators (SERMs) have estrogenic and/or antiestrogenic activity depending on the target tissue. Hence, SERMs have the same beneficial effect as estrogen in skeleton and cardiovascular systems but act as antagonists in breast and uterus. The finding of beneficial side effects of SERMs in the CNS might improve their risk-benefit ratio in traditional indications. In this review, we will survey schizophrenia and depression as examples of mental diseases and AD and PD as neurodegenerative diseases. We will review brain effects of estrogens, steroids possibly acting as pro-drugs of estrogens such as testosterone and dehydroepiandrosterone (DHEA) and present novel findings with SERMs. Drugs with estrogen activity in the brain may have therapeutic potential either by modulating brain neurotransmitter transmission or through neuroprotective activity.

Estrogen-like activity of tamoxifen and raloxifene on NMDA receptor binding and expression of its subunits in rat brain.

Hormonal specificity of modulation of N-methyl- D-aspartate (NMDA) receptors was investigated by comparing the effects of estradiol with tamoxifen or raloxifene, which display different responses in breast, bone, and uterus. Two weeks ovariectomy in rats decreased uterine weight, which was prevented by a two-week estradiol treatment; tamoxifen and raloxifene had weaker uterine stimulation than estradiol. Ovariectomy in rats decreased L-[3H]glutamate specific binding to NMDA receptors in CA1 and dentate gyrus but not CA2/3 regions of hippocampus and was without effect in cortex, striatum, nucleus accumbens, and olfactory tubercle. [3H]Ro 25-6981 (an NMDA antagonist selective for NR1/NR2B assembly) specific binding and mRNA levels of NMDA receptor subunits 1 and 2B decreased in CA1 after ovariectomy. Estradiol, tamoxifen, and raloxifene decreased L-[3H]glutamate specific binding to NMDA receptors and [3H]Ro 25-6981 specific binding in cortical area of ovariectomized rats and prevented the decrease of [3H]glutamate specific binding to NMDA receptors in CA1 and dentate gyrus, as well as [3H]Ro 25-6981 specific binding in CA1. Estradiol prevented the decrease of NMDA receptor subunits 1 and 2B mRNA levels in CA1 only; tamoxifen and raloxifene prevented the decrease of NMDA receptor subunit 1 mRNA levels in CA1. No effect of ovariectomy or treatments on L-[3H]CGP 39653 (an NMDA antagonist selective for NR1/NR2A assembly) specific binding and NMDA receptor subunit 2A mRNA levels was observed in all brain regions assayed. Our results showed brain regional and subunits specific agonist estrogenic activity of tamoxifen and raloxifene on NMDA receptors.

Relationship between colloid osmotic pressure and pulmonary artery wedge pressure in patients with acute cardiorespiratory failure.

Close relationships between progressive respiratory failure, roentgenographic signs of pulmonary opacification and decreases in the difference between colloid osmotic pressure of plasma and the pulmonary artery wedge pressure (colloid-hydrosatic pressure gradient) were demonstrated in 49 critically ill patients with multisystem failure, in patients in shock. The potential importance of this relationship is underscored by the observation that fatal progression of pulmonary edema was related to a critical reduction in the colloid-hydrostatic pressure gradient to levels of less than 0 mm Hg. More often, reduction in colloid osmotic pressure rather than increases in left ventricular filling pressure (pulmonary artery wedge pressure) accounted for the decline in colloid-hydrostatic pressure gradient. Routine measurement of colloid osmotic pressure, preferably in conjunction with pulmonary artery wedge pressure, is likely to improve understanding of the mechanisms of acute pulmonary edema.

Changes of rat striatal neuronal membrane morphology and steroid content during the estrous cycle.

It is well documented that sex steroids affect striatal dopamine systems. However, the mechanism(s) of these hormonal effects in the striatum is still not well understood. We now report that gonadal steroid hormones during the estrous cycle affect the morphology and steroid hormone content of the rat striatum. Rats displaying at least two consecutive estrous cycles were included in this study as well as a group of female rats ovariectomized two weeks before being killed. The striatum was dissected from one half of each brain and used for morphological studies. From the other half of each brain, the striatum was dissected and steroid hormone concentrations in striatum and the remainder of the brain were determined. Tissues and serum concentrations of 17 beta-estradiol, progesterone and prolactin were measured by specific radioimmunoassays. Serum 17 beta-estradiol and prolactin concentrations peaked in proestrus, while progesterone was high in diestrus and proestrus. 17 beta-Estradiol levels were higher in the striatum than in the rest of the brain; both were also shown to fluctuate during the estrous cycle and with a pattern similar to that observed in serum. Progesterone serum levels showed a similar pattern of changes during the estrous cycle to progesterone concentrations in the striatum and the rest of the brain. The ultrastructure of the striatal dendritic membranes was studied by freeze-fracture. A significant difference in the content of intramembranous particles in dendritic shafts, which are mainly contacted by dopaminergic synapses, was found during the estrous cycle. The numerical density of large (greater than 10 nm) intramembranous particles was increased in diestrus I and II and in the afternoon of proestrus compared to estrus, the morning of proestrus and ovariectomized rats. In contrast, the numerical density of small (less than 10 nm) intramembranous particles was decreased in cycling animals compared to ovariectomized rats and fell in the afternoon of proestrus and then progressively increased in the following days to peak in the morning of proestrus. A negative correlation between steroid concentrations and small intramembranous particle density was observed, while the correlation was positive for large particles. No changes were observed in the membranes of dendritic spines, the main postsynaptic target for cortical afferents. In summary, this is the first report that concentrations of 17 beta-estradiol and progesterone in the striatum fluctuate during the estrous cycle. This is associated with estrous cycle-dependent changes of intramembranous particle density of striatal dendritic membranes. Our data therefore indicate that the striatum is a brain region hormonally modulated under physiological conditions.

Dopaminergic activity in transgenic mice underexpressing glucocorticoid receptors: effect of antidepressants.

Transgenic mice bearing a transgene coding for a glucocorticoid receptor antisense mRNA, which partially blocks glucocorticoid receptor expression, were used to investigate the long-term effect of hypothalamic-pituitary-adrenal axis dysfunction on brain dopamine transmission. Compared to control mice, the transgenic animals showed increased amphetamine-induced locomotor activity and increased concentrations of striatal dopamine and its metabolites dihydroxyphenylacetic acid and homovanillic acid. Binding of [3H]SCH 23390 and [3H]spiperone to, respectively, D1 and D2 dopamine receptors was increased in transgenic mice. In contrast, autoradiography of striatal [3H]GBR 12935 binding to the dopamine transporter was decreased and the mRNA levels of this transporter, measured by in situ hybridization, remained unchanged in the substantia nigra pars compacta. The effect of chronic treatment for two weeks with amitriptyline or fluoxetine was compared in control and transgenic mice. No significant changes were observed in control mice following antidepressant treatment, whereas in transgenic mice both antidepressants reduced striatal [3H]SCH 23390 and [3H]raclopride specific binding to D1 and D2 receptors. Amitriptyline, but not fluoxetine, increased striatal [3H]GBR 12935 binding to the dopamine transporter, whereas its mRNA level in the substantia nigra pars compacta was decreased in fluoxetine, compared to vehicle- or amitriptyline-treated transgenic mice. From these results we suggest that hyperactive dopaminergic activity of the nigrostriatal pathway controls motor activity in the transgenic mice. Furthermore, antidepressant treatment corrected the increased striatal D1 and D2 receptors and decreased dopamine transporter levels in the transgenic mice.

Continuous or pulsatile chronic D2 dopamine receptor agonist (U91356A) treatment of drug-naive 4-phenyl-1,2,3,6-tetrahydropyridine monkeys differentially regulates brain D1 and D2 receptor expression: in situ hybridization histochemical analysis.

The effect of a chronic D2 dopamine receptor agonist (U91356A) treatment on dopamine receptor gene expression in the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys was investigated using quantitative in situ hybridization histochemistry. U91356A was administered to MPTP-monkeys for 27 days in a pulsatile (n=3) or continuous (n=3) schedule. Animals treated in a pulsatile mode showed progressive sensitization and developed dyskinesia; whereas with the continuous mode behavioural tolerance was observed but no dyskinesia developed. Untreated MPTP as well as naive control animals were also studied. The efficacy and uniformity of the MPTP effect was assessed by measures of dopamine concentrations by high performance liquid chromatography with electrochemical detection in the relevant brain areas. D1 and D2 receptor messenger RNAs levels were examined by in situ hybridization histochemistry using human complementary RNA probes. Intense specific labelling for D1 and D2 receptor messenger RNAs was measured in the caudate and putamen with a rostrocaudal gradient for D2 receptors and a lower density in the cortex for D1 receptors messenger RNA. D1 receptor mRNA levels in rostral striatum and cortex decreased whereas D2 receptor messenger RNA in caudal striatum increased in MPTP-monkeys compared to control animals. Continuous administration of U91356A reversed the MPTP-induced increase of D2 receptor messenger RNA, whereas the pulsatile administration did not significantly correct these messenger RNA changes. U91356A treatment whether continuous or pulsatile partially corrected the D1 receptor messenger RNA lesion-induced decrease in the striatum, whereas no correction was observed in the cortex. All MPTP-monkeys were extensively and similarly denervated suggesting that the D1 and D2 receptor expression changes following U91356A administration were treatment related. Our data show a lesion-induced imbalance of D1 (decrease) and D2 (increase) receptor messenger RNAs in the striatum of MPTP-monkeys. The response of these receptors to D1 agonist treatment showed receptor selectivity and was influenced by the time-course of drug delivery. Hence chronic continuous but not pulsatile administration of U91356A reversed the striatal D1 receptor messenger RNA increase.

Hemodynamic and coronary effects of intravenous labetalol in coronary artery disease.

Labetalol, an alpha and beta receptor blocking agent, was evaluated in 11 patients with documented coronary artery disease and stable angina. The mean dose of labetalol was 1.5 (range 1 to 2) mg/kg. Cardiovascular effects began within 1 minute after injection and were maximal within 10 minutes. Mean arterial pressure decreased from 105 +/- 13 to 81 +/- 10 mm Hg (p less than 0.0001), heart rate from 70 +/- 10 to 66 +/- 7 beats/min (p less than 0.05) and the pressure-rate product from 10,322 +/- 2,344 to 7,171 +/- 1,650 (p less than 0.001). Cardiac output and pulmonary wedge pressure did not change significantly. Mean pulmonary arterial pressure decreased from 20 +/- 3 to 16 +/- 2 mm Hg (p less than 0.005). Systemic and pulmonary resistances also decreased significantly (p less than 0.0001 and p less than 0.01, respectively). Coronary sinus flow increased from 107 +/- 26 to 118 +/- 25 ml/min (p less than 0.01) and coronary vascular resistance decreased from 1.0 +/- 0.2 to 0.77 +/- 0.1 mm Hg/ml per min (p less than 0.001). Labetalol may be a useful adjunct in the treatment of angina not only because it diminishes myocardial oxygen requirements but also because it improves coronary hemodynamics. Thus, labetalol appears to have some advantage compared with the usual beta blocking agents with their potentially detrimental effects on coronary hemodynamics.

Effects of a chronic lithium treatment on central dopamine neurotransporters.

The objectives of this study were to characterize the effects of a chronic lithium (Li+) treatment on dopamine (DA) uptake sites, as well as on the levels of mRNA encoding for these transporters, and to determine the eventual reversibility of the treatment. Quantitative autoradiography was carried out on sections from rat brain using 3beta-(4-[125I]iodophenyl)tropane-2beta-carboxylic acid isopropyl ester ([125I]RT1-121) to label DA transporters, and mRNA levels were measured by in situ hybridization. Following chronic Li+ treatment (28 days), the labelling to DA transporters increased (60-90%) in all sections of the rostral and caudal neostriatum, whereas no alteration was observed in the other regions studied, namely the substantia nigra, the ventral tegmental area, and the dorsal raphe nucleus. These effects were reversed completely following a withdrawal period of 2 days without Li+. Also, there were no modifications in the labelling of DA transporters after only 2 days of Li+ treatment. In addition, we measured the levels of mRNA encoding for DA transporters in the substantia nigra and the ventral tegmental area; however, no alterations were observed following a chronic Li+ treatment, and thus the hypothesis of an increased synthesis is not supported. This could mean that the Li+ treatment modified the affinity of DA transporters for the radioligand, possibly a consequence of conformational changes induced by the disruption of the nerve terminal membrane environment; however, a modification in the number of transporters could not be ruled out. The results of this study further support the hypothesis of the implication of central dopaminergic transmission in the pathology and treatment of affective disorders.

False aneurysm of the ascending aorta presenting as an acute myocardial infarction: a late complication of aortocoronary bypass.

After coronary bypass surgery, a 40-year-old man developed disruption of the site of cannulation of the ascending aorta. The false aneurysm which ensued presented as recurrent episodes of spontaneous angina and myocardial infarction ending in coronary death 48 days after surgery. the aortic origin of all three permeable coronary bypasses were strangulated by the hematoma. Awareness of this unusual potential hazard is essential, since an early suspicion would lead to proper diagnostic interventions and reoperation.

Preproenkephalin mRNA expression in the caudate-putamen of MPTP monkeys after chronic treatment with the D2 agonist U91356A in continuous or intermittent mode of administration: comparison with L-DOPA therapy.

The effect of chronic treatment with the D2 dopamine agonist U91356A or L-DOPA therapy on the regulation of preproenkephalin (PPE) mRNA was investigated in the caudate-putamen of previously drug-naive cynomolgus monkeys Macaca fascicularis rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In MPTP monkeys, pulsatile treatment with either L-DOPA or U91356A relieved parkinsonian symptoms but caused progressive sensitization to treatment and, as expected, induced choreic dyskinesias. In contrast, U91356A given in a continuous mode led to partial behavioral tolerance without appearance of dyskinesias. Using in situ hybridization histochemistry, lesioning was shown to produce elevation of PPE mRNA levels in the lateral and medial parts of the putamen and in the lateral part of the caudate nucleus compared to control animals at the three rostrocaudal regions analyzed. In general, no change of PPE mRNA levels were observed in the medial caudate after MPTP lesioning with or without L-DOPA or U91356A treatments in the three rostrocaudal regions measured except for an increase in the caudal part of L-DOPA-treated MPTP monkeys. In the putamen and lateral caudate nucleus, elevated PPE mRNA expression by MPTP generally was not corrected (or only partially corrected) by chronic L-DOPA treatment except for the rostral medial putamen where correction to control values was observed. In general, pulsatile administration of U91356A partially corrected the lesion-induced elevation of PPE mRNA levels in the putamen and lateral caudate nucleus whereas the correction was more pronounced and widespread when MPTP monkeys received the continuous administration of this drug. These results indicate that the mode of administration of a D2 dopamine receptor agonist, such as U91356A, although at a roughly equivalent dosage influences the extent of inhibition of the expression of PPE in the denervated striatum of monkeys. In addition, the general lack of correction of the MPTP-induced increase of PPE mRNA in the striatum of L-DOPA-treated monkeys compared to the decreases observed with the D2 agonist treatments suggest that the D1 agonist component of L-DOPA therapy opposes the D2 agonist activity. Hence, D1 receptor agonist activity would stimulate PPE mRNA expression whereas D2 receptor agonists inhibit the expression of this peptide. Increases in PPE expression in the striatum may be implicated in the induction of dyskinesias since both groups of treated MPTP monkeys displaying dyskinesias had elevated striatal PPE mRNA levels whereas the MPTP monkeys with the lowest striatal PPE mRNA levels developed tolerance without dyskinesias.

Lack of effect of testosterone and dihydrotestosterone compared to 17beta-oestradiol in 1-methyl-4-phenyl-1,2,3,6, tetrahydropyridine-mice.

Previous work from our laboratory has demonstrated prevention of 1-methyl-4-phenyl-1,2,3,6, tetrahydropyridine (MPTP)-induced striatal dopamine depletion in C57Bl/6 mice by 17beta-oestradiol, progesterone and raloxifene. The activity of androgenic compounds in MPTP mice has received less attention and was the object of the present investigation. The effects of 17beta-oestradiol (2 microg/day), testosterone (100 microg/day) and dihydrotestosterone (DHT) (2 microg/day or 100 microg/day) were studied during 5 days before and after an acute treatment of four MPTP (10 mg/kg) injections in male C57Bl/6 mice. Striatal concentrations of dopamine and its metabolites dihydroxyphenylacetic acid and homovanillic acid were measured by high-performance liquid chromatography. MPTP mice treated with saline showed large decreases in dopamine and its metabolites compared to control mice. 17beta-oestradiol partially spared this decrease whereas testosterone and DHT did not. Striatal specific binding to the dopamine transporter (DAT) and to the vesicular monoamine transporter (VMAT2) were measured using [125I] RTI-121 and [3H] dihydrotetrabenazine autoradiography, respectively. As with striatal dopamine concentrations, MPTP treatment caused a decrease in DAT and VMAT2 specific binding. 17beta-oestradiol partially spared this decrease, whereas androgens did not. In the substantia nigra, DAT mRNA was measured by in situ hybridization. MPTP treatment induced a significant, but smaller decrease in substantia nigra DAT mRNA than striatal DAT protein. In addition, 17beta-oestradiol completely prevented the MPTP-induced decrease of DAT mRNA, whereas androgens did not. The present results show that androgens are unable to protect against MPTP-induced dopaminergic toxicity.

Chronic D1 and D2 dopaminomimetic treatment of MPTP-denervated monkeys: effects on basal ganglia GABA(A)/benzodiazepine receptor complex and GABA content.

The effect of various chronic dopaminergic treatments in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys on the brain gamma-aminobutyric acid type A (GABA(A)) /benzodiazepine receptor complex and GABA content was investigated in order to assess the GABAergic involvement in dopaminomimetic-induced dyskinesia. Three MPTP monkeys received for one month pulsatile administrations of the D1 dopamine (DA) receptor agonist SKF 82958 whereas three others received the same dose of SKF 82958 by continuous infusion. A long acting D2 DA receptor agonist, cabergoline, was given to another three animals. Untreated MPTP as well as naive control animals were also included. Pulsatile SKF 82958 relieved parkinsonian symptoms but was also associated with dyskinesia in two of the three animals whereas animals treated continuously with SKF 82958 remained as untreated MPTP monkeys. Chronic cabergoline administration improved motor response with no persistent dyskinesia. MPTP treatment induced a decrease of 3H-flunitrazepam binding in the medial anterior part of caudate-putamen and an increase in the internal segment of globus pallidus (GPi) which was in general unchanged by pulsatile or continuous SKF 82958 administration. Throughout the striatum, binding of 3H-flunitrazepam remained reduced in MPTP monkeys treated with cabergoline but was not significantly lower than untreated MPTP monkeys. Moreover, cabergoline treatment reversed the MPTP-induced increase in 3H-flunitrazepam binding in the GPi. GABA concentrations remained unchanged in the striatum, external segment of globus pallidus and GPi following MPTP denervation. Pulsatile but not continuous SKF 82958 administration decreased putamen GABA content whereas cabergoline treatment decreased caudate GABA. No alteration in GABA levels were observed in the GPe and GPi following the experimental treatments. These results suggest that: (1) D2-like receptor stimulation with cabergoline modulates GABA(A) receptor density in striatal subregions anatomically related to associative cortical afferent and (2) the absence of dyskinesia in dopaminomimetic-treated monkeys might be associated with the reversal of the MPTP-induced upregulation of the GABA(A)/benzodiazepine receptor complex in the Gpi.