Simultaneous bilateral acute angle closure glaucoma following venlafaxine treatment.
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Acute Disease↗
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Upregulation of CB1 receptors and agonist-stimulated [35S]GTPgammaS binding in the prefrontal cortex of depressed suicide victims.
Endogenous and exogenous cannabinoids (CBs) acting through the CB(1) receptors have been implicated in the regulation of several behavioral and neuroendocrine functions. Modulation of endocannabinoidergic system by ethanol in mouse brain, and the association of suicide and mood disorders with alcoholism suggest possible involvement of the cannabinoidergic system in the pathophysiology of depression and suicide. Therefore, the present study was undertaken to examine the levels of CB(1) receptors and mediated signaling in the dorsolateral prefrontal cortex (DLPFC) of subjects with major depression who had died by suicides (depressed suicides, DS). [(3)H]CP-55,940 and CB(1) receptor-stimulated [(35)S]GTPgammaS binding sites were analyzed in membranes obtained from DLPFC of DS (10) and matched normal controls (10). Upregulation (24%, P<0.0001) of CB(1) receptor density (B(max)) was observed in DS (644.6+/-48.8 fmol/mg protein) compared with matched controls (493.3+/-52.7 fmol/mg protein). However, there was no significant alteration in the affinity of receptor (DS; 1.14+/-0.08 vs control; 1.12+/-0.10 nM). Higher density of CB(1) receptors in DS (38%, P<0.001) was also demonstrated by Western blot analysis. The CB(1) receptor-stimulated [(35)S]GTPgammaS binding was significantly greater (45%, P<0.001) in the DLPFC of DS compared with matched controls. The observed upregulation of CB(1) receptors with concomitant increase in the CB(1) receptor-mediated [(35)S]GTPgammaS binding suggests a role for enhanced cannabinoidergic signaling in the prefrontal cortex of DS. The cannabinoidergic system may be a novel therapeutic target in the treatment of depression and/or suicidal behavior.
Adolescent↗
Dose-related effects of chronic antidepressants on neuroprotective proteins BDNF, Bcl-2 and Cu/Zn-SOD in rat hippocampus.
It has been proposed that antidepressants have neuroprotective effects on hippocampal neurons. To further test this hypothesis, brain-derived neurotrophic factor (BDNF), B cell lymphoma protein-2 (Bcl-2), and copper-zinc superoxide dismutase (Cu/Zn-SOD) were examined immunohistochemically in hippocampal neurons of Sprague-Dawley rats following daily treatment with 5 or 10 mg/kg of amitriptyline or venlafaxine for 21 days. At 5 mg/kg, both amitriptyline and venlafaxine increased the intensity of BDNF immunostaining in hippocampal pyramidal neurons, and the intensity of Bcl-2 immunostaining in hippocampal mossy fibers, but did not alter the Cu/Zn-SOD immunoreactivity. The high dose of venlafaxine, however, decreased the intensity of BDNF immunostaining in all subareas of the hippocampus and increased the intensity of Cu/Zn-SOD immunostaining in the dentate granular cell layer. The high dose of amitriptyline increased the intensity of Cu/Zn-SOD immunostaining, but did not affect the immunoreactivity of Bcl-2 or BDNF. These findings suggest that the chronic administration of amitriptyline or venlafaxine at 5 mg/kg, but not 10 mg/kg, may be neuroprotective to hippocampal neurons. These dose-related effects of antidepressant drugs on hippocampal neurons may have relevance to disparate findings in the field.
Amitriptyline↗
Investigation of epistasis between the serotonin transporter and norepinephrine transporter genes in anorexia nervosa.
Weight-restored patients with anorexia nervosa (AN) respond favorably to the selective serotonin reuptake inhibitor fluoxetine, which justifies association studies of the serotonin transporter gene (SLC6A4, alias SERT) and AN. Case-control studies suggest that the least transcriptionally active allele of the SERT gene promoter polymorphism (5-HTTLPR) has an increased frequency in AN patients. However, this finding was not replicated with 55 trios (AN child+parents) and the transmission disequilibrium test (TDT). To clarify the role of the 5-HTTLPR in susceptibility to AN, we used the TDT and 106 Australian trios to provide 93% power to detect a genotypic relative risk (GRR) of 2.0. Our results were negative for this GRR (McNemar's chi(2)=0.01, df=1, p=0.921, odds ratio 1.0, 95% CI 0.7-1.5). Additionally, we found no association with AN females, AN subtype, age at onset, or minimum BMI. We then performed the first reported investigation of epistasis between the SERT gene and norepinephrine transporter gene (SLC6A2, alias NET) in AN, as an earlier study suggested that atypical AN responds to the dual serotonin-norepinephrine reuptake inhibitor venlafaxine. We observed no epistasis between the 5-HTTLPR and a polymorphism within the NET gene promoter polymorphic region (NETpPR) (chi(2)=0.48, df=1, p=0.490). Although 5-HTTLPR modulates serotonin reuptake by the serotonin transporter, our analyses provide no evidence that susceptibility to AN is modified by 5-HTTLPR alone, nor in concert with as yet undetermined functional effects of the NETpPR polymorphism.
Anorexia Nervosa↗
A critical interaction between dopamine D2 receptors and endocannabinoids mediates the effects of cocaine on striatal gabaergic Transmission.
Compelling evidence indicates that endocannabinoids are implicated in drug addiction. In the present study, we have addressed the interaction between cocaine and endocannabinoid system by means of neurochemical and neurophysiological experiments in rat brain slices. Using gas chromatography-electron impact mass spectrometry, we have found that cocaine increased the levels of the endocannabinoid anandamide in the striatum, a brain area primarily involved in the compulsive drug-seeking and drug-taking behaviors typical of addiction. This effect was attenuated by pharmacological inhibition of D2-like receptors but not D1-like receptors, and it was mimicked by D2-like but not D1-like receptor stimulation. The cocaine-induced increase in anandamide concentrations was attributable to both stimulation of its synthesis and inhibition of its degradation, as suggested by the ability of cocaine and quinpirole, a D2-like receptor agonist, to enhance the activity of NAPE-phospholipase D and to inhibit fatty acid amide hydrolase. By means of electrophysiological recordings from single striatal neurons, we have then observed that the ability of cocaine to inhibit, via D2-like receptors, GABA transmission was partially prevented following blockade of cannabinoid receptors, suggesting that endocannabinoids may act as downstream effectors in the action of cocaine in the striatum. Understanding the molecular and physiological effects of drugs of abuse in the brain is essential for the development of effective strategies against addiction.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Synergistic interactions between cannabinoids and environmental stress in the activation of the central amygdala.
Anxiety and panic are the most common adverse effects of cannabis intoxication; reactions potentiated by stress. Data suggest that cannabinoid (CB1) receptor modulation of amygdalar activity contributes to these phenomena. Using Fos as a marker, we tested the hypothesis that environmental stress and CB1 cannabinoid receptor activity interact in the regulation of amygdalar activation in male mice. Both 30 min of restraint and CB1 receptor agonist treatment (Delta9-tetrahydrocannabinol (2.5 mg/kg) or CP55940 (0.3 mg/kg); by i.p. injection) produced barely detectable increases in Fos expression within the central amygdala (CeA). However, the combination of restraint and CB1 agonist administration produced robust Fos induction within the CeA, indicating a synergistic interaction between environmental stress and CB1 receptor activation. An inhibitor of endocannabinoid transport, AM404 (10 mg/kg), produced an additive interaction with restraint within the CeA. In contrast, fatty acid amide hydrolase (FAAH) inhibitor-treated mice (URB597, 1 mg/kg) and FAAH-/- mice did not exhibit any differences in amygdalar activation in response to restraint compared to control mice. In the basolateral (BLA) and medial amygdala, restraint stress produced a low level of Fos induction, which was unaffected by cannabinoid treatment. Interestingly, the CB1 receptor antagonist SR141716 dose-dependently increased Fos expression in the BLA and CeA. These data suggest the CeA is an important neural substrate subserving the interactions between cannabinoids and environmental stress, and could be relevant to understanding the context-dependent emotional and affective changes induced by marijuana intoxication and the role of endocannabinoid signaling in the modulation of amygdalar activity.
Amygdala↗
Neurophysiologic correlates of side effects in normal subjects randomized to venlafaxine or placebo.
Adverse events reported in the context of medication administration may be due to pharmacodynamic and/or nonpharmacodynamic effects (eg, nocebo phenomena). Neurophysiological substrates of side effects may be examined in placebo-controlled antidepressant treatment trials. We explored the relationship between side effects and regional neurophysiologic changes in normal subjects receiving a 1-week placebo lead-in followed by 4 weeks randomized treatment with placebo (n = 15) or venlafaxine IR (n = 17). Quantitative electroencephalographic (QEEG) cordance measures were obtained before and during treatment, and side effects were assessed weekly using semistructured interviews. Side effect burden, characterized as the mean number of side effects per postrandomization visit, correlated significantly with neurophysiologic changes in the antidepressant group but not the placebo group. Medication group side effects were negatively correlated with changes in prefrontal cordance at end of placebo lead-in (r = -0.67, p < 0.003), at 2 weeks (r = -0.77, p < 0.002), and at 4 weeks (r = -0.77, p < 0.004) post randomization. After controlling for the prefrontal change at the end of placebo lead-in, postrandomization brain changes did not further explain side effect burden. Changes in prefrontal brain function associated with later antidepressant side effects were observed during placebo lead-in-prior to the administration of medication. Prefrontal brain function during brief placebo administration may help explain susceptibility to the development of antidepressant side effects. Results of these exploratory hypothesis-generating analyses should be considered tentative until replicated.
Adolescent↗
Recovery of hippocampal cell proliferation and BDNF levels, both of which are reduced by repeated restraint stress, is accelerated by chronic venlafaxine.
The present study investigated the poststress (PS) cellular and molecular changes in the hippocampus of rats subjected to repeated restraint stress (RS) and the effects of chronic administration of an antidepressant drug, venlafaxine, on these changes. It was found that RS suppressed hippocampal cell proliferation, decreased brain-derived neurotrophic factor (BDNF) levels, and increased both the levels of copper/zinc superoxide dismutase (Cu/Zn-SOD) and the number of Cu/Zn-SOD immunostained hippocampal interneurons. In venlafaxine-treated rats, the changes in cell proliferation, BDNF levels, and the number of Cu/Zn-SOD interneurons returned to control levels on PS Days 21, 14, 7, respectively. In vehicle-injected rats, BDNF and the number of Cu/Zn-SOD interneurons returned to control levels on PS Days 21 and 14, respectively, but cell proliferation was still suppressed on PS Day 21. The stress-induced elevation of Cu/Zn-SOD protein remained during the 3-week PS period, and it was further increased by about 20% after 3 weeks of venlafaxine administration.
Animals↗
The DRD2 TaqI-B polymorphism and its relationship to smoking abstinence and withdrawal symptoms.
The dopamine receptor D2 (DRD2) gene has polymorphisms that have been linked to regulation of the dopamine system and to an increased prevalence of smoking. The present study examined the relationship of the DRD2 TaqI-A and -B polymorphisms with short-term clinical outcome (abstinence and withdrawal symptoms), collected from daily (14 pre-quit and 42 post-quit) diary data among smokers (n=116) treated with the nicotine patch plus either venlafaxine or placebo. The results showed that B1/B1 or B1/B2 smokers were slightly less likely to be abstinent on a given day than those homozygous for the TaqI-B2 allele. Significant DRD2 TaqI-B x time interactions were found for several of the withdrawal scales, indicating that those smokers with the B1/B1 or B1/B2 genotypes tended to report more symptoms over time compared to those with the B2/B2 genotype. No interactions or main effects were found for the DRD2 TaqI-A polymorphism. The findings demonstrate that smokers homozygous for the TaqI-B2 allele experience progressive improvement in self-reported withdrawal symptoms while smokers with the TaqI-B1 allele showing little change.
Administration, Cutaneous↗
Cyclohexadiene-trans-diols as versatile starting material in natural product synthesis: short and efficient synthesis of iso-crotepoxide and ent-senepoxide.
A new synthesis of ent-senepoxide and iso-crotepoxide starting from microbially produced(+)-trans-2,3-dihydroxy-2,3-dihydrobenzoic acid via regio- and stereoselective epoxidation is described.
Biological Factors↗
Stereoselective synthesis of several azido/amino- and diazido/diamino-myo-inositols and their phosphates from p-benzoquinone.
A practical route is described for the preparation of azido-myo-inositols, amino-myo-inositols and azido-conduritol B derivatives. Starting from p-benzoquinone, optically pure compounds in both forms can be prepared via enzymatic resolution of a derived diacetoxy conduritol B derivative. Selective introduction of nitrogen-containing functional groups in four of the six possible positions in the cyclitol moiety is followed by further functionalization to yield the target compounds.
Amines↗
The deactivation pathways of the excited-states of the mycosporine-like amino acids shinorine and porphyra-334 in aqueous solution.
In vitro studies on the structurally related mycosporine-like amino acids (MAAs) porphyra-334 and shinorine in aqueous solutions were carried out aiming at their full photochemical and photophysical characterization and expanding the evidence on the assigned UV-photoprotective role of the molecules in vivo. The experiments on shinorine confirmed a high photostability and a poor fluorescence quantum yield, in concordance with previous results on porphyra-334. The estimation of triplet production quantum yields for both MAAs was achieved by laser-flash photolysis measurements. In particular, photosensitization experiments on porphyra-334 support the participation of the triplet state in the photodecomposition mechanism yielding a more precise value of [capital Phi](T). As well, photoacoustic calorimetry experiments allowed the first direct quantification of the nonradiative relaxation pathways of the excited MAAs in solution, corroborating that the vast majority (ca. 97%) of the absorbed energy is promptly delivered to the surroundings as heat, consistently with the low photodecomposition and emission yields observed.
Amino Acids↗
Biomimetic alcohol oxidations by an iron(III) porphyrin complex: relevance to cytochrome P-450 catalytic oxidation and involvement of the two-state radical rebound mechanism.
The systematic oxidation reactions of a wide range of alcohols have been carried out by using an iron porphyrin complex in order to understand their relation to cytochrome P-450 enzymes and to have a practical application to organic synthesis. The iron porphyrin complex catalyzed efficiently alcohol oxidation to the respective carbonyl compound via a high-valent iron-oxo porphyrin intermediate ((Porp)Fe=O+). Several mechanistic studies such as isotope 18O labeling, deuterium isotope effect, linear free energy relationship, and ring-opening of radical clock substrate, have suggested that the alcohol is oxidized by a sequence of reactions involving an alpha-hydroxyalkyl radical intermediate and oxygen rebound to form the gem-diol, dehydration of which yields the carbonyl compounds. Moreover, it has been proposed that a two-state reactivity mechanism can also be adopted for alcohol oxidation reactions in iron porphyrin model systems as exhibited by P-450 enzymes.
Alcohols↗
Mycosporines from freshwater yeasts: a trophic cul-de-sac?
Mycosporine-like amino-acids (MAAs) are found in aquatic bacteria, algae, and animals. A related compound, the mycosporine-glutaminol-glucoside (myc-glu-glu), has recently been reported in freshwater yeasts. Although animals depend on other organisms as their source of MAAs, they can efficiently accumulate them in their tissues. In this work we assessed the potential transfer of the yeast mycosporine myc-glu-glu from the diet into the copepod Boeckella antiqua and the ciliate Paramecium bursaria. For this purpose, we performed experiments to study the feeding of B. antiqua and P. bursaria on the yeast Rhodotorula minuta and their ability to bioaccumulate myc-glu-glu. Bioaccumulation of myc-glu-glu in B. antiqua was assessed through long-term factorial experiments manipulating the diet (Chlamydomonas reinhardii and C. reinhardii + yeasts) and radiation exposure (PAR and PAR + UVR). Shorter term experiments were designed in the case of P. bursaria. The composition and concentration of MAAs in the diet and in the consumers were determined by HPLC analyses. Our results showed that even though both consumers ingested yeast cells, they were unable to accumulate myc-glu-glu. Moreover, when exposed to conditions that stimulated the accumulation of photoprotective compounds (i.e. UVR exposure), an increase in MAAs concentration occurred in copepods fed C. reinhardii plus yeasts as well as in those fed only C. reinhardii. This suggests that the copepods were able to modify their tissue concentrations of MAAs in response to environmental clues but also that the contribution of yeast mycosporines to total MAAs concentration was negligible.
Animal Nutritional Physiological Phenomena↗
A concise synthetic route to the conduritols from pentoses.
A short synthetic strategy for preparation of the conduritols is described. The key step employs a zinc-mediated fragmentation of protected methyl 5-deoxy-5-iodo-d-pentofuranosides followed by an allylation of the intermediate aldehyde in the same pot. The allylation is performed with 3-bromopropenyl benzoate and occurs with good diastereoselectivity. An amino group can be introduced in the product by trapping the intermediate aldehyde as the imine prior to the allylation. The functionalised 1,7-octadienes, thus obtained, are converted into protected conduritols by ring-closing olefin metathesis.
Cyclization↗
Enantioselective synthesis of beta-amino esters and its application to the synthesis of the enantiomers of the antidepressant Venlafaxine.
Beta-amino esters are readily formed from the rhodium(II) prolinate-catalyzed intermolecular C-H insertion between methyl aryldiazoacetates and a bis-silyl protected methylamine.
Amines↗
cis-3,5-Cyclohexadiene-1,2-diol derivatives: facial selectivity in their Diels-Alder reactions with ethylenic, acetylenic and azo dienophiles.
The Diels-Alder reactions of maleimide with the acetonide derivative (6a) of cis-3,5-cyclohexadiene-1,2-diol (1a) in various solvents showed facial selectivities ranging from 1 : 1 to 1 : 9. The same derivative 6a reacted in benzene with ethylenic dienophiles with generally modest facial selectivity, but acetylenic dienophiles added exclusively anti to the oxygen functions of 6a. Dimerization of cyclic acetals 6a and 7 was mainly, but for 6a not exclusively, by anti addition with respect to both the diene and the dienophile partners. Reactions of azo dienophiles with derivatives of 1a were predominantly by anti addition, but the diol itself (1a) gave the syn adduct as the major product.
Acetylene↗
Calciferol and its relatives. XII. (S)-3-Ethynyl-4-methylcyclohex-3-en-1-ol.
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Alcohols↗