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Antidepressants are among the most commonly detected pharmaceuticals in aqueous systems, and, as emerging organic pollutants, may exert negative effects on non-target aquatic organisms. Previously, it has been revealed that antidepressant exposure significantly inhibits the growth and development of fish during their early developmental stages. Thus, in the present study, we aimed to identify and compare the underlying mechanisms of action of different antidepressants at the transcriptional level using zebrafish (Danio rerio) embryos. Through high-throughput RNA sequencing (RNA-Seq) data analysis, 32, 34, and 130 differentially expressed genes (DEGs) were obtained from zebrafish larvae after 120h of embryonic exposure to sublethal concentrations of amitriptyline, fluoxetine, and mianserin, respectively. The expression profiles of the identified DEGs showed similar trends in response to the three antidepressant treatments, suggesting consistent toxic effects of low concentrations of these three drugs on the regulation of gene expression in fish. Several metabolic and signaling pathways, including glycolysis/gluconeogenesis and the insulin pathway, were affected in the exposed fish larvae. The expression profiles of selected DEGs were then verified by the qRT-PCR method, which indicated significant positive correlations with the RNA-Seq results. Next, we determined the concentration-dependent expression patterns of 6 selected DEGs in fish larvae exposed to three antidepressants at a series of environmentally relevant concentrations. The results revealed a significant concentration-dependent reduction in the levels of dual-specificity phosphatase 5 (dusp5) mRNA, as well as a non-concentration-dependent gene expression inhibition of prostaglandin D2 synthase b (ptgdsb); the circadian rhythm-related genes, i.e. those encoding nuclear receptor subfamily 1, group D, member 1 (nr1d1) and period 2 (per2); and genes encoding early growth response factors (egr1 and egr4), in the antidepressant-treated fish larvae. In summary, to our knowledge, our findings demonstrate, for the first time, that the three different categories of antidepressants have common effects on the gene expression involved in multiple biological processes and signaling pathways during the early development of fish and thus provide information for characterizing the adverse outcome pathways and on the ecological risk assessment of these pharmaceutical pollutants in the aquatic environment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Levels of autophagy markers rise upon treatment of cells with antidepressants. However, it was not known whether this phenomenon might be linked to other antidepressant pathways or to any physiological effect. In this punctum, we summarize and discuss our recent findings that provide evidence for a role of the cochaperone FKBP5/FKBP51 (FK506 binding protein 5) in autophagy as a prerequisite for antidepressant action in cells, mice, and humans. FKBP5 associates with BECN1, changes its phosphorylation and protein levels and enhances markers of autophagy and autophagic flux. The effects of antidepressants on autophagy as well as their physiological effects in mice and human depend on FKBP5.

The (+)-isomer of indeloxazine AS1069562 exerts multiple pharmacological actions including the inhibition of serotonin (5-HT) and norepinephrine reuptake and analgesia in experimental animal pain models. Here, we evaluated the antinociceptive effects of AS1069562 and the antidepressants duloxetine and amitriptyline in mouse models of prostaglandin-induced spinal hypersensitivity. Prostaglandin E2 (PGE2) and F2α (PGF2α) were intrathecally administered to induce spinal hypersensitivity, causing tactile allodynia in mice. Allodynia induced by PGF2α but not by PGE2 was suppressed by desensitization of C-fibers with systemic pretreatment with resiniferatoxin. C-fiber hyperexcitability might therefore play a role in allodynia induced by PGF2α but not PGE2. In the PGE2-induced allodynia model, AS1069562 and duloxetine significantly suppressed allodynia, whereas amitriptyline did not. In the PGF2α-induced allodynia model, AS1069562 and amitriptyline significantly ameliorated allodynia, whereas duloxetine did not. To demonstrate the broad effects of AS1069562 compared to duloxetine, additional studies were conducted to elucidate other target mechanisms of AS1069562 beyond 5-HT and norepinephrine reuptake inhibition. AS1069562 exhibited affinity for both 5-HT1A and 5-HT3 receptors, and the analgesic effect of AS1069562 on PGF2α-induced allodynia was significantly blocked by the 5-HT1A receptor antagonist (S)-WAY100135 and the 5-HT3 receptor agonist SR57227. Taken together, these results indicate that AS1069562 inhibits both C-fiber- and non-C-fiber-dependent prostaglandin-induced allodynia, while duloxetine inhibits only non-C-fiber-triggered allodynia, and amitriptyline inhibits only C-fiber-triggered allodynia. These broad antinociceptive effects of AS1069562 may be due not only to 5-HT and norepinephrine reuptake inhibition but also to its effects on 5-HT receptors such as 5-HT1A and 5-HT3 receptors., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Intravenous lipid emulsion is a recommended treatment for local anesthetic intoxication. The lipid sink theory hypothesizes that the mechanism behind the lipid treatment is the entrapment of toxic drugs in plasma, preventing them from reaching target receptors. Lipid sink treatment has also been used as a last refuge treatment for severe tricyclic antidepressant intoxication with seemingly beneficial results. We selected three drugs, i.e. amiodarone, ketamine, and amitriptyline, that can cause severe intoxication and compared their interactions with two commercial fat emulsions (Intralipid® and ClinOleic®) and one synthetic liposome (80:20 mol% phosphatidylcholine/phosphatidylglycerol) dispersion. The interaction studies were carried out by capillary electrokinetic chromatography and the retention factors and distributions constants of the drugs were calculated. The results demonstrate that there is stronger interaction between the drugs and the synthetic liposome dispersion than with the commercial emulsions., (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In the present work, the interaction between an antidepressant drug amitriptyline hydrochloride and nonionic polyoxyethylene surfactants, with special attention to the possible contribution from the ion-dipole type of interaction, has been investigated by using multitechnique approach. Tensiometric and conductometric studies show steeper decrease on the critical micellar concentration gradient of the drug in the presence of electrolyte (NaCl) as well as nonionic surfactants. Critical assessments by applying Clint, Rubingh, Rosen, Motomura and other thermodynamic models confirm strong interactions in the mixed monolayer at the surface and in mixed micelle in the bulk of aqueous electrolytic solution. The structural difference in the drug and nonionic surfactants also plays a role in tuning the aggregational behavior of the drug-surfactant mixtures. Finally, it is shown by DLS measurements that the micellar growth of drug-surfactant aggregates is favored in terms of increase in hydrodynamic radii in the presence of electrolyte. However, the nonionic surfactants provide sufficient steric crowding causing dissociation of larger micelles into smaller ones with small radii., (Copyright © 2012 Elsevier B.V. All rights reserved.)

In the present study, we report the micellization and clouding behavior of an amphiphilic antidepressant drug viz., amitriptyline hydrochloride (AMT) at different fixed temperatures and KCl concentrations in aqueous solutions. The critical micelle concentration (cmc) of AMT, as measured by conductivity method, increases with increasing temperature and decreasing with KCl concentration. The thermodynamic parameters viz., standard Gibbs energy (ΔG(m)(0)), standard enthalpy (ΔH(m)(0)), and standard entropy (ΔS(m)(0)) of micellization of AMT are evaluated. The values clearly indicate more stability of the AMT solution in presence of KCl. Like surfactant, AMT also shows phase separation behavior. The cloud point (CP) of AMT in water decreases with increase in pH of the medium because of the deprotonation of the drug molecule. The CP values increase with increasing KCl concentration and AMT concentrations, clearly indicating the micellar growth at higher concentration. Furthermore, for better understanding of the behavior of drug molecule in water, we evaluated various thermodynamic parameters of the above drug molecule at CP., (Copyright © 2011 Elsevier B.V. All rights reserved.)

A cationic antidepressant drug, amitriptylene (AMT), was successfully incorporated into core-shell-corona micelles of poly[styrene-b-sodium 2-(acrylamido)-2-methyl-1-propanesulfonate-b-ethylene oxide] (PS-b-PAMPS-b-PEO). Zeta-potential measurements revealed that both electrostatic and hydrophobic interactions contributed to the binding of the drug to the polymer. The AMT/PS-b-PAMPS-b-PEO nanocomplexes were characterized by dynamic light scattering, scanning electron microscopy, and transmission electron microscopy. The hydrodynamic diameter of the AMT loaded nanocomplexes decreased from 80 to 40nm depending on the amount of the drug loaded on the polymer. This is attributed to the cancellation of the negative charge of the PAMPS group by the cationic drug. The AMT/PS-b-PAMPS-b-PEO nanocomplexes were stable in aqueous solution exhibiting no aggregation or no precipitation for several months. Release of the AMT from the nanocomplexes was investigated in vitro in salt-free and 0.1M NaCl solutions. The drug was released faster in the 0.1M NaCl solution than in the salt-free solution. This is due to the shielding effect of the salt on the electrostatic interaction. However, in both cases, the drug release mainly occurs by the Fickian diffusion mechanism., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The surface tension measurements have been carried out on aqueous solutions of antidepressant drug amitriptyline hydrochloride with six cationic surfactants (decyl-, dodecyl-, tetradecyl-, cetyltrimethylammonium bromide, cetylpyridinium bromide and cetylpyridinium chloride) at different mole fractions to study the surface and micellar properties at the interface as well as in the micelles. The properties studied include critical micelle concentration (cmc), Gibbs surface excess (Gamma(max)), minimum head group area at the air/water interface (A(min)), free energy of micellization (DeltaG(m)( composite function)), and standard Gibbs energy of adsorption (DeltaG(ads)( composite function)), while synergistic behavior of drug-surfactant binary mixtures was analysed using Clint's and Rubingh's models. Deviations of cmc from cmc(*) and X(1)(m) from X(1)(ideal) indicate the synergistic behavior (i.e., non-ideal behavior) for the drug-surfactant binary mixtures. The values of interaction parameters beta and activity coefficients f(1) and f(2) (for both, in mixed monolayer as well as in mixed micelles) also indicate the synergistic behavior. The excess free energy (DeltaG(ex)) for the drug-surfactant binary mixtures explains stability of mixed micelles in comparison to micelles of pure drug and variation with alkyl chain length of surfactants., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)