To further understand the role of ovarian hormones in the function of the serotonin neural system, we investigated the effects of estradiol (E), progesterone (P), and raloxifene on <em>5HT</em> 1A and 2C receptor protein expression in the dorsal raphe region using Western blot analysis. Adult rhesus macaques (Macaca mulatta) were ovariectomized (Ovx) and implanted with Silastic capsules containing E or P. In the first paradigm, animals that had been Ovx for 6-16 months were treated for 1 month with E (El) or E + P (EP1) and compared to animals that were untreated and Ovx for 5 months (n = 4 per group). In the second paradigm, comparisons were made between animals that were Ovx and untreated for 5 months, or Ovx and immediately implanted with Silastic capsules containing E or E + P for 5 months (E5, EP5), or administered raloxifene in the diet for 5 months (Ral5) (n = 4 per group). The dorsal raphe region was harvested, homogenized and a crude membrane fraction was obtained for examination of receptor proteins. In the first paradigm, <em>5HT</em>1A receptor protein expression was significantly lower in E1 and EPI treatment groups compared to the Ovx-control group (ANOVA P = 0.01; posthoc P < 0.03), but <em>5HT</em>2C receptor expression was unaffected by 1 month of E or EP treatment. In the second paradigm, there was no difference in <em>5HT</em>1A receptor expression between the Ovx-control group and the E5 group, but <em>5HT</em>1A receptor expression was significantly suppressed in the EP5 group (ANOVA P = 0.04; posthoc P < 0.05). In addition, <em>5HT</em>2C expression increased in the E5 treatment group relative to the Ovx-control group. Addition of P to the E5 regimen prevented the E5-induced increase in <em>5HT</em>2C receptor expression and significantly reduced <em>5HT</em>2C receptor expression to a level below that observed in the Ovx-control group (ANOVA P = 0.001; posthoc P < 0.05). Thus, <em>5HT</em>1A receptor may lose sensitivity to the suppressive effect of E after 5 months, whereas the <em>5HT</em>2C receptor increases. However, addition of P in the EP5 regimen maintains the regulatory effects observed with 1 month of treatment. <em>5HT</em>1A receptor protein levels were higher with raloxifene treatment than in Ovx-control animals (P < 0.01), suggesting that raloxifene may antagonize residual E in Ovx animals.

Elicitation of delayed-type hypersensitivity (DTH) responses is due to the required sequential action of two different antigen (Ag)-specific Thy-1+ cells: early acting, DTH-initiating cells and locally recruited CD4+, alpha beta-TCR+, DTH effector T cells. DTH-initiating cells have an unusual phenotype for Ag-specific cells (Thy-1+, CD5+, CD4-, CD8-, CD3-, sIg-, B220+ (CD45RA+), Mac 1+, IL-2R- and IL-3R+) and act by producing Ag-specific non-IgE factors that sensitize mast cells for release of the vasoactive amine serotonin (<em>5HT</em>) at the local site of elicitation of DTH by challenge. Another mechanism of DTH initiation involves Ag-specific IgE antibodies that also can sensitize mast cells for local serotonin release. Serotonin initiates DTH by activating the local endothelial cells to allow recruitment of DTH effector T cells, and also by activating <em>5HT</em>-2 receptors on these recruited T cells.

Monoamine transporters playing major roles in regulating normal and abnormal synaptic activity are associated with various neuropsychological disorders. In spite of the discovery of a series of structurally different monoamine transporter antagonists for the therapy approach, no practical pharmaceutical can act as a transporter activator. Here, we isolated luteolin and apigenin from the fruit of Perilla frutescens (L.) Britt by using an activity-guided extraction technique, and proved that the two compounds possess actions of enhancing monoamine uptake either upon monoamine-transporter transgenic Chinese hamster ovary (CHO) cells or upon wild dopaminergic cell lines, with higher specificity for dopamine (DA) uptake than for norepinephrine (NE)- and serotonin (<em>5HT</em>)-uptake, as well as with more potency and greater efficacy for luteolin than for apigenin. Further, in the transgenic cells, the principal NE/DA uptake activation by luteolin was significantly prevented by respective transporter inhibitor, and the transmitter-uptake-enhancing action was independent of its ligands, which is in support of the compounds as monoamine transporter activators. Furthermore, luteolin evoked a marked disinhibition of cocaine-targeted effect in CHO cells overexpressing dopamine transporter. Thus, luteolin and apigenin function as monoamine transporter activators, which would improve several hypermonoaminergic neuropsychological disorders, especially cocaine dependence, through up-regulating monoamine transporter activity.

BACKGROUND

The C-terminus of the serotonin transporter (SERT) contains binding domains for different proteins and is critical for its functional expression. In endogenous and heterologous expression systems, our proteomic and biochemical analysis demonstrated that an intermediate filament, vimentin, binds to the C-terminus of SERT. It has been reported that <em>5HT</em>-stimulation of cells leads to disassembly and spatial reorientation of vimentin filaments.

RESULTS

We tested the impact of <em>5HT</em>-stimulation on vimentin-SERT association and found that <em>5HT</em>-stimulation accelerates the translocation of SERT from the plasma membrane via enhancing the level of association between phosphovimentin and SERT. Furthermore a progressive truncation of the C-terminus of SERT was performed to map the vimentin-SERT association domain. Deletion of up to 20, but not 14 amino acids arrested the transporters at intracellular locations. Although, truncation of the last 14 amino acids, did not alter <em>5HT</em> uptake rates of transporter but abolished its association with vimentin. To understand the involvement of <em>5HT</em> in phosphovimentin-SERT association from the plasma membrane, we further investigated the six amino acids between Delta14 and Delta20, i.e., the SITPET sequence of SERT. While the triple mutation on the possible kinase action sites, S(611), T(613), and T(616) arrested the transporter at intracellular locations, replacing the residues with aspartic acid one at a time altered neither the <em>5HT</em> uptake rates nor the vimentin association of these mutants. However, replacing the three target sites with alanine, either simultaneously or one at a time, had no significant effect on <em>5HT</em> uptake rates or the vimentin association with transporter.

CONCLUSIONS

Based on our findings, we propose that phosphate modification of the SITPET sequence differentially, one at a time exposes the vimentin binding domain on the C-terminus of SERT. Conversely, following <em>5HT</em> stimulation, the association between vimentin-SERT is enhanced which changes the cellular distribution of SERT on an altered vimentin network.

The treatment of bipolar depression is one of the most challenging issues in contemporary psychiatry. Currently only quetiapine and the olanzapine-fluoxetine combination are officially approved by the FDA against this condition. The neurobiology of bipolar depression and the possible targets of bipolar antidepressant therapy remain relatively elusive. We performed a complete and systematic review to identify agents with definite positive or negative results concerning efficacy followed by a second systematic review to identify the pharmacodynamic properties of these agents. The comparison of properties suggests that the stronger predictors for antidepressant efficacy in bipolar depression were norepinephrine alpha-1, dopamine D1 and histamine antagonism, followed by 5-HT2A, muscarinic and dopamine D2 and D3 antagonism and eventually by norepinephrine reuptake inhibition and <em>5HT</em>-1A agonism. Serotonin reuptake which constitutes the cornerstone in unipolar depression treatment does not seem to play a significant role for bipolar depression. Our exhaustive review is compatible with a complex model with multiple levels of interaction between the major neurotransmitter systems without a single target being either necessary or sufficient to elicit the antidepressant effect in bipolar depression.

Serotonin [5-hydroxytryptamine (<em>5HT</em>)] acts through multiple G protein-coupled 5-HT receptors, and its activity is also regulated by the 5-HT transporter. The current studies report the expression and localization of the 5-HT receptors and transporter in the kidney. In addition, the enzymatic pathway mediating 5-HT synthesis is present in renal cortex, especially in the proximal tubules and glomerular epithelial cells and mesangial cells. Expression of the 5-HT receptors and 5-HT transporter was detected by RT-PCR in cell lines of these cell types. In cultured proximal tubule cells and podocytes, 5-HT activated ERK1/2 and increased the expression of connective tissue growth factor and transforming growth factor-beta, two key mediators of extracellular matrix accumulation. Immunohistochemistry and real-time RT-PCR studies also indicated that 5-HT stimulated expression of vascular endothelial growth factor in podocytes in vitro and in vivo. Therefore, these results indicate the presence of an integrated intrarenal serotonergic system and suggest a possible role for 5-HT as a mediator of renal fibrosis in the kidney.

BACKGROUND

A robust association between "suicidality" and deficits of the serotoninergic neurotransmission has been claimed in the past. However, many studies having investigated the relationship between suicidality and peripheral indicators of serotoninergic neurotransmission suffer from considering only one or a very small number of potentially useful serotoninergic parameters, whereas a synoptic multidimensional approach appears to be more appropriate. Furthermore, the psychiatric context within which suicidal behaviour occurs should be considered when interpreting biochemical findings of patients with suicidal ideation and suicide attempts.

METHODS

In the present study 5 peripheral serotonergic markers, (platelet <em>5HT</em> concentration, <em>5HT</em> uptake activity, <em>5HT</em>(2A) receptor binding characteristics, MAO-B activity and tryptophan concentration in plasma) were assessed simultaneously. Of the 60 acutely suicidal inpatients (ICD-10: F43.xx, n = 52; F31/32/33, n = 8), 45 were suicide attempters. Data of 28 nonsuicidal patients with major depression (F31, n = 4; F32, n = 14; F33, n = 10) and 123 healthy volunteers represented the control groups.

RESULTS

Mean platelet <em>5HT</em> concentration was significantly lower in suicidal inpatients when compared to nonsuicidal depressed patients, but did not differ from the figure in healthy subjects. Nonsuicidal depressed patients showed significantly higher mean platelet-<em>5HT</em> concentration than healthy controls. Mean V(max) of <em>5HT</em> uptake in washed platelets, but not in platelet-rich plasma, was significantly higher in suicidal patients than in healthy controls, not, however, when compared to nonsuicidal depressed patients. Mean K(D) for the platelet <em>5HT</em>(2A) receptor and MAO-B activity were significantly lower in suicidal patients as compared to nonsuicidal depressed patients and healthy controls. The observed differences in peripheral serotonergic markers between groups are partially due to a significant gender effect. A lower MAO-B activity was observed only in suicidal females, while the higher V(max) of <em>5HT</em> uptake in washed platelets of suicidal patients was due to suicidal males.

CONCLUSIONS

In view of conflicting observations made by other authors and the present findings on suicidal patients with adjustment disorder it remains doubtful whether and if so to which extent platelet studies can provide valid information on serotonergic mechanisms related to suicidal behaviour.

In this paper, the granule laden cells localizing around fine vessels in cerebral cortex were investigated with fluorescent, light and electron microscopes using Wistar rats. These cells were designated as fluorescent granular perithelial cells (F.G.P.). The findings obtained in this study were summarized as follows; 1. The F.G.P. were one of essential components of cerebral vessels and separated clearly from nervous tissue by a basal lamina. They were often observed at bifurcating regions of fine vessels. 2. The F.G.P. seemed to differentiate morphologically around birth, and the specific granules to them began to emit yellow fluorescence at second week and attained to a definite level of fluorescence intensity at eighth week. Microfluorometrically, the peak of emission stood at 530 micrometer. Accompanying with a growth of animals, eosinophilia of granules became strong. Sudanophilic areas in the F.G.P. were limited to a periphery of granules. Anisogranularity was evident in old rats age second and third year. 3. Electronmicroscopically, the specific cytoplasmic organelles in the F.G.P. were round electron opaque bodies and vesico-tubular system or sac shaped smooth surfaced endoplasmic reticula. The electron opaque bodies appeared clearly at second week after birth, and changed their profiles and contents with aging of rats. In old rats, they looked porous and honeycomb like structure, and sometimes, whole cytoplasm of the F.G.P. was occupied with these structures. Some sac shaped endoplasmic reticula contained less intense material in one side and seemed to be associated with a formation of electron opaque bodies. Further, it was very interesting that the extensions of some F.G.P. encircled completely the entire circumferences of cerebral vessels. It looked as if fine vessels would penetrate into the F.G.P. 4. After administration of major tranquilizers and prednisolone, fluorescence and eosinophilia of intracellular granules decreased moderately, and the other drugs, - vitamins E and B - enhanced the both. <em>5HT</em> and <em>5HT</em>P enhanced the fluorescence, but suppressed the eosinophilia. From the findings mentioned above, the F.G.P. were expected to play an important role in a transport of nourish substance from fine vessels to neurons, and in a removal of some products in the extracellular spaces of central nervous system.

Serotonin modulates agonistic and reproductive behavior across vertebrate species. <em>5HT</em>(1A) and <em>5HT</em>(1B) receptors mediate many serotonergic effects on social behavior, but other receptors, including <em>5HT</em>(2) receptors, may also contribute. We investigated serotonergic regulation of electrocommunication signals in the weakly electric fish Apteronotus leptorhynchus. During social interactions, these fish modulate their electric organ discharges (EODs) to produce signals known as chirps. Males chirp more than females and produce two chirp types. Males produce high-frequency chirps as courtship signals; whereas both sexes produce low-frequency chirps during same-sex interactions. Serotonergic innervation of the prepacemaker nucleus, which controls chirping, is more robust in females than males. Serotonin inhibits chirping and may contribute to sexual dimorphism and individual variation in chirping. We elicited chirps with EOD playbacks and pharmacologically manipulated serotonin receptors to determine which receptors regulated chirping. We also asked whether serotonin receptor activation generally modulated chirping or more specifically targeted particular chirp types. Agonists and antagonists of <em>5HT</em>(1B/1D) receptors (CP-94253 and GR-125743) did not affect chirping. The <em>5HT</em>(1A) receptor agonist 8OH-DPAT specifically increased production of high-frequency chirps. The <em>5HT</em>(2) receptor agonist DOI decreased chirping. Receptor antagonists (WAY-100635 and MDL-11939) opposed the effects of their corresponding agonists. These results suggest that serotonergic inhibition of chirping may be mediated by <em>5HT</em>(2) receptors, but that serotonergic activation of <em>5HT</em>(1A) receptors specifically increases the production of high-frequency chirps. The enhancement of chirping by <em>5HT</em>(1A) receptors may result from interactions with cortisol and/or arginine vasotocin, which similarly enhance chirping and are influenced by <em>5HT</em>(1A) activity in other systems.

Serotonergic mechanisms play a central role in migraine pathology. However, the region-specific effects of serotonin (5-HT) mediated via multiple types of receptors in the nociceptive system are poorly understood. Using extracellular and patch-clamp recordings, we studied the action of 5-HT on the excitability of peripheral and central terminals of trigeminal afferents. 5-HT evoked long-lasting TTX-sensitive firing in the peripheral terminals of meningeal afferents, the origin site of migraine pain. Cluster analysis revealed that in majority of nociceptive fibers 5-HT induced either transient or persistent spiking activity with prevailing delta and theta rhythms. The 5-HT3-receptor antagonist MDL-72222 or 5-HT1B/D-receptor antagonist GR127935 largely reduced, but their combination completely prevented the excitatory pro-nociceptive action of 5-HT. The 5-HT3 agonist mCPBG activated spikes in MDL-72222-dependent manner but the <em>5HT</em>-1 receptor agonist sumatriptan did not affect the nociceptive firing. 5-HT also triggered peripheral CGRP release in meninges, which was blocked by MDL-72222.5-HT evoked fast membrane currents and Ca2+ transients in a fraction of trigeminal neurons. Immunohistochemistry showed expression of 5-HT3A receptors in fibers innervating meninges. Endogenous release of 5-HT from degranulated mast cells increased nociceptive firing. Low pH but not histamine strongly activated firing. 5-HT reduced monosynaptic inputs from trigeminal Aδ- and C-afferents to the upper cervical lamina I neurons and this effect was blocked by MDL-72222. Consistent with central inhibitory effect, 5-HT reduced CGRP release in the brainstem slices. In conclusion, 5-HT evokes powerful pro-nociceptive peripheral and anti-nociceptive central effects in trigeminal system transmitting migraine pain.

Long-term hyperserotoninemia induces heart valve disease in rats, and cases of cardiac valvulopathies have been reported in patients using ergolines, possibly through activation of the 5-hydroxytryptamine(2B) (<em>5HT</em>(2B)) receptor. The ergoline terguride (transdihydrolisuride) is a <em>5HT</em>(2B/2C) receptor antagonist. Using a rat model, we have investigated whether terguride could prevent serotonin-induced changes in general and heart disease specifically. During 4 months, twelve Sprague-Dawley rats were given daily subcutaneous serotonin injections; twelve rats received a combination of serotonin injections and terguride by gavage, whereas ten rats were untreated controls. Using echocardiography, rats with aortic insufficiency were found in all 3 groups, while pulmonary insufficiency was only found in two rats injected with serotonin alone. Animals given serotonin alone had significantly higher heart weights compared to the controls (p=0.029) and rats given terguride (p=0.034). Rats injected with serotonin alone developed macroscopic skin changes at the injection sites, histologically identified as orthokeratosis and acanthosis. Terguride completely prevented these changes (p=0.0001, p=0.0003). Liver weights were higher in the animals given serotonin alone compared to controls (p=0.014) and terguride treated animals (p=0.009). Stomach weights were higher in animals given serotonin alone compared to rats given terguride (p=0.012). In the mesenchymal cell-line MC3T3-E1, terguride almost completely inhibited serotonin-induced proliferation (p<0.01). Serotonin increases heart, liver and stomach weights, possibly through enhanced proliferation. Terguride inhibits these effects. We propose that terguride may have beneficial effects in the treatment of diseases such as carcinoid syndrome, where serotonin plays an important pathogenic role.

The age-related loss of locus coeruleus (LC) noradrenergic neurons, substantia nigra compacta (SNc) dopaminergic neurons, dopaminergic retinal amacrine (rAm) neurons and raphe serotonergic neurons, identified using antibodies against tyrosine hydroxylase (TH) and serotonin (<em>5HT</em>) was investigated in C57B1 mice aged 8 to 104 weeks. The neuronal somata were counted and their locations three-dimensionally reconstructed from serial sections alternately immunoreacted or Nissl stained. Nonlinear estimation analysis showed that decaying exponential equations best fitted the plots of neuronal numbers versus age and each subtype was lost according to different exponential constants of -0.015, -0.013, -0.004 and -0.001 for LC TH+, SNc TH+, rAm TH+ and raphe <em>5HT</em>+ neurons, respectively. Neurons were lost from all different subregions within the nuclei or the retinae. Counts of immediately adjacent TH-immunoreacted and Nissl-stained sections through the LC at different ages indicate that the neuronal loss was due to neuronal death rather than loss of TH immunoreactivity. The markedly different rates of age-related neuronal loss for the four monoaminergic subtypes offer a model to study the underlying molecular and cellular mechanisms.

The biogenic amine serotonin (5-hydroxytryptamine: <em>5HT</em>) is a widely distributed neuroactive substance of vertebrates and invertebrates. Among parasitic flatworms, in particularly the bloodfluke, Schistosoma mansoni, <em>5HT</em> is an important modulator of neuromuscular function and metabolism. Previous work has shown that schistosomes take up <em>5HT</em> from host blood via a carrier mediated mechanism. This transport is thought to contribute to the control of schistosome motility in the bloodstream and is essential for survival of the parasite. Here we provide the first molecular evidence for the existence of a <em>5HT</em> transporter in S. mansoni. A cDNA showing high homology with plasma membrane serotonin transporters (SERT) from other species was cloned and characterized by heterologous expression in cultured HEK293 cells. Functional studies showed that the recombinant schistosome transporter (SmSERT) mediates specific and saturable [(3)H]-<em>5HT</em> transport with a K(t)=1.30+/-0.05 microM. The heterologously expressed protein was inhibited by classic SERT blockers (clomipramine, fluoxetine, citalopram) and the same drugs also inhibited [(3)H]-<em>5HT</em> uptake by intact schistosomula in culture, suggesting that SmSERT may be responsible for this transport. Conventional (end-point) and real-time quantitative RT-PCR analyses determined that SmSERT is expressed both in the free-living stage (cercaria) and parasitic forms of S. mansoni but the expression level is significantly higher in the parasites. These results suggest that SmSERT is upregulated following cercarial transformation, possibly to mediate the recruitment of exogenous <em>5HT</em> from the host.

The inferior colliculus (IC) is involved in processing of auditory information, but also integrates acoustic information of aversive nature. In fact, chemical stimulation of the IC with semicarbazide (SMC) - an inhibitor of the GABA synthesizing enzyme glutamic acid decarboxylase - has been found to cause defensive behavior in an open-field test and functions as an unconditioned stimulus in the place conditioned aversion test (PCA). A question has arisen regarding whether the basolateral nucleus of the amygdala (BLA) is involved in the acquisition of the aversive information ascending from the IC and whether dopaminergic and serotoninergic mechanisms of the BLA regulate this process. Recent evidence has shown that inactivation of the BLA with muscimol inhibits the PCA and causes an increase in the aversiveness of the chemical stimulation of the IC. Based on this, we examined the effects of ketanserin and SCH-23390, antagonists of the <em>5HT</em>(2) and D(1) receptors, respectively, on the conditioned and unconditioned fear elicited by IC stimulation with SMC. The results obtained confirm the crucial role of 5-HT(2)- and D(1)-mechanisms of the BLA on conditioned fear in that ketanserin and SCH-23390 injections into the BLA caused a reduction in the PCA. On the other hand, ketanserin and SCH-23390 injections into the BLA enhanced the aversiveness of the IC injections of SMC. These findings suggest that while 5-HT(2) and DA(1) mechanisms in the BLA appear to facilitate the conditioned fear they inhibit the unconditioned fear triggered by IC activation.

The study was conducted on a human (Jurkat) T cell line, loaded with a Na+ fluorescent probe, SBFI/AM. Serotonin and an agonist of 5-HT3 receptor-channels, 2-methyl-<em>5HT</em>, evoked Na+ influx, whereas the agonists of other serotonergic receptor subtypes, i.e., 5-HT1A and 5-HT1B receptors, failed to induce Na+ influx in these cells. By using 3H-BRL43694, an agonist of 5-HT3 receptor-channels, we characterized 5-HT3 lymphocyte receptors which exhibited a density (Bmax) of 300 +/- 20 fmol/10(6) cells and a Kd of 30 nM in Jurkat T cells. The T-cell 5-HT3 receptor-channel is not regulated either by the protein kinase C or by the free intracellular calcium concentrations as the agents known to activate the PKC and to induce increases in intracellular free calcium concentrations failed to influence the free intracellular Na+ concentrations, [Na+]i, in these cells. Furthermore, an increase in [Na+]i, induced by 2-methyl-<em>5HT</em>, via 5-HT3 receptor-channels seems to stimulate T-cell activation by facilitating the progression of T cells from S to G2/M phase of the cell cycle.

There exists an abundance of barriers that hinder functional recovery following spinal cord injury, especially at chronic stages. Here, we examine the rescue of breathing up to 1.5 years following cervical hemisection in the rat. In spite of complete hemidiaphragm paralysis, a single injection of chondroitinase ABC in the phrenic motor pool restored robust and persistent diaphragm function while improving neuromuscular junction anatomy. This treatment strategy was more effective when applied chronically than when assessed acutely after injury. The addition of intermittent hypoxia conditioning further strengthened the ventilatory response. However, in a sub-population of animals, this combination treatment caused excess serotonergic (<em>5HT</em>) axon sprouting leading to aberrant tonic activity in the diaphragm that could be mitigated via <em>5HT</em>2 receptor blockade. Through unmasking of the continuing neuroplasticity that develops after injury, our treatment strategy ensured rapid and robust patterned respiratory recovery after a near lifetime of paralysis.

The differential distribution of serotonin (<em>5HT</em>) fibers in spinal laminae VII and X is described for the adult rat. The results indicate that descending <em>5HT</em> fibers preferentially innervate those regions of lamina VII that contain sympathetic and parasympathetic neurons. In lamina X, especially the dorsal commissural nucleus, large numbers of <em>5HT</em> fibers are observed throughout the spinal cord. Moreover, sympathetic nuclei are more richly innervated with <em>5HT</em> than the spinal parasympathetic nuclei. Spinal cord hemisections reveal that spinal autonomic nuclei are differentially innervated: ipsilateral serotoninergic projections to the intermediolateral cell column are preferentially interrupted. In addition, a large crossed <em>5HT</em> projection exists throughout the length of the spinal cord that decussates five to six spinal segments rostral to its termination. Both crossed and uncrossed <em>5HT</em> fibers span many spinal segments and have large numbers of collaterals. Spinal cord transections show that the vast majority of spinal <em>5HT</em> descends from the brainstem but that some <em>5HT</em> fibers are of intrinsic origin.

Olanzapine is an atypical antipsychotic agent of the thienobenzodiazepine class. Olanzapine blocks multiple neurotransmitter receptors, including dopaminergic (D(1), D(2), D(3), and D(4)), serotonergic (5-hydroxytryptamine 2A [5-HT(2A)], 5-HT(2C), 5-HT(3), and 5-HT(6)), adrenergic (α(1)), histaminic (H(1)), and muscarinic (M(1), M(2), M(3), and M(4)) receptors. Olanzapine has a high affinity for the <em>5HT</em>(2A) receptor, which is up to 5 times greater than the dopamine receptor, resulting in less propensity to the development of extrapyramidal side effects. The affinity of olanzapine for multiple receptors has lead to the identification of olanzapine as an important agent in the treatment of delirium, nausea, and vomiting. Olanzapine has been demonstrated to have opioid-sparing properties. Olanzapine is principally metabolized by glucuronidation, with a smaller metabolic contribution from the cytochrome oxidase system. Adverse effects of olanzapine include somnolence, postural hypotension, constipation, dizziness, restlessness, and weight gain. The purpose of this article is to outline the pharmacodynamics, pharmacology, and evidence for the use of olanzapine in palliative care.

This chapter covers antidepressants that fall into the class of serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors. That is, they bind to the 5-HT and NE transporters with varying levels of potency and binding affinity ratios. Unlike the selective serotonin (5-HT) reuptake inhibitors (SSRIs), most of these antidepressants have an ascending rather than a flat dose-response curve. The chapter provides a brief review of the chemistry, pharmacology, metabolism, safety and adverse effects, clinical use, and therapeutic indications of each antidepressant. Venlafaxine, a phenylethylamine, is a relatively weak 5-HT and weaker NE uptake inhibitor with a 30-fold difference in binding of the two transporters. Therefore, the drug has a clear dose progression, with low doses predominantly binding to the 5-HT transporter and more binding of the NE transporter as the dose ascends. Venlafaxine is metabolized to the active metabolite O-desmethylvenlafaxine (ODV; desvenlafaxine) by CYP2D6, and it therefore is subject to significant inter-individual variation in blood levels and response dependent on variations in CYP2D6 metabolism. The half-life of venlafaxine is short at about 5 h, with the ODV metabolite being 12 h. Both parent compound and metabolite have low protein binding and neither inhibit CYP enzymes. Therefore, both venlafaxine and desvenlafaxine are potential options if drug-drug interactions are a concern, although venlafaxine may be subject to drug-drug interactions with CYP2D6 inhibitors. At low doses, the adverse effect profile is similar to an SSRI with nausea, diarrhea, fatigue or somnolence, and sexual side effects, while venlafaxine at higher doses can produce mild increases in blood pressure, diaphoresis, tachycardia, tremors, and anxiety. A disadvantage of venlafaxine relative to the SSRIs is the potential for dose-dependent blood pressure elevation, most likely due to the NE reuptake inhibition caused by higher doses; however, this adverse effect is infrequently observed at doses below 225 mg per day. Venlafaxine also has a number of potential advantages over the SSRIs, including an ascending dose-antidepressant response curve, with possibly greater overall efficacy at higher doses. Venlafaxine is approved for MDD as well as generalized anxiety disorder, social anxiety disorder, and panic disorder. Desvenlafaxine is the primary metabolite of venlafaxine, and it is also a relatively low-potency 5-HT and NE uptake inhibitor. Like venlafaxine it has a favorable drug-drug interaction profile. It is subject to CYP3A4 metabolism, and it is therefore vulnerable to enzyme inhibition or induction. However, the primary metabolic pathway is direct conjugation. It is approved in the narrow dose range of 50-100 mg per day. Duloxetine is a more potent 5-HT and NE reuptake inhibitor with a more balanced profile of binding at about 10:1 for <em>5HT</em> and NE transporter binding. It is also a moderate inhibitor of CYP2D6, so that modest dose reductions and careful monitoring will be needed when prescribing duloxetine in combination with drugs that are preferentially metabolized by CYP2D6. The most common side effects identified in clinical trials are nausea, dry mouth, dizziness, constipation, insomnia, asthenia, and hypertension, consistent with its mechanisms of action. Clinical trials to date have demonstrated rates of response and remission in patients with major depression that are comparable to other marketed antidepressants reviewed in this book. In addition to approval for MDD, duloxetine is approved for diabetic peripheral neuropathic pain, fibromyalgia, and musculoskeletal pain. Milnacipran is marketed as an antidepressant in some countries, but not in the USA. It is approved in the USA and some other countries as a treatment for fibromyalgia. It has few pharmacokinetic and pharmacodynamic interactions with other drugs. Milnacipran has a half-life of about 10 h and therefore needs to be administered twice per day. It is metabolized by CYP3A4, but the major pathway for clearance is direct conjugation and renal elimination. As with other drugs in this class, dysuria is a common, troublesome, and dose-dependent adverse effect (occurring in up to 7% of patients). High-dose milnacipran has been reported to cause blood pressure and pulse elevations. Levomilnacipran is the levorotary enantiomer of milnacipran, and it is pharmacologically very similar to the racemic compound, although the side effects may be milder within the approved dosing range. As with other NE uptake inhibitors, it may increase blood pressure and pulse, although it appears to do so less than some other medications. All medications in the class can cause serotonin syndrome when combined with MAOIs.

Ceruloplasmin (Cp) is a ferroxidase involved in iron metabolism by converting Fe(2+) to Fe(3+), and by regulating cellular iron efflux. In the ceruloplasmin knockout (CpKO) mouse, the deregulation of iron metabolism results in moderate liver and spleen hemosiderosis, but the impact of Cp deficiency on brain neurochemistry and behavior in this animal model is unknown. We found that in contrast to peripheral tissues, iron levels in the hippocampus are significantly reduced in CpKO mice. Although it does not cause any discernable deficits in motor function or learning and memory, Cp deficiency results in heightened anxiety-like behavior in the open field and elevated plus maze tests. This anxiety phenotype is associated with elevated levels of plasma corticosterone. Previous studies provided evidence that anxiety disorders and long-standing stress are associated with reductions in levels of serotonin (<em>5HT</em>) and brain-derived neurotrophic factor (BDNF) in the hippocampus. We found that levels of <em>5HT</em> and norepinephrine (NE), and the expression of BDNF and its receptor trkB, are significantly reduced in the hippocampus of CpKO mice. Thus, Cp deficiency causes an anxiety phenotype by a mechanism that involves decreased levels of iron, <em>5HT</em>, NE, and BDNF in the hippocampus.

Objective: To conduct a systematic review of modern-era (post-millennium) clinical studies assessing the therapeutic effects of serotonergic psychedelics drugs for mental health conditions. Although the main focus was on efficacy and safety, study characteristics, duration of antidepressants effects across studies, and the role of the subjective drug experiences were also reviewed and presented.

Method: A systematic literature search (1^st Jan 2000 to 1^st May 2020) was conducted in Pubmed and Psychinfo for studies of patients undergoing treatment with a serotonergic psychedelic.

Results: Data from 16 papers, representing 10 independent psychedelic-assisted therapy trials (psilocybin=7, ayahuasca = 2, LSD=1) were extracted, presented in figures and tables, and narratively synthesized and discussed. Across these studies, a total of 188 patients suffering either anxiety and/or depressive symptoms associated with cancer (C-RPD), major depressive disorder (MDD), obsessive compulsive disorder (OCD) or substance use disorder (SUD) were included. The reviewed studies established feasibility and evidence of safety, alongside promising early data of efficacy in the treatment of depression, anxiety, OCD, and tobacco and alcohol use disorders. For a majority of patients, the therapeutic effects appeared to be long-lasting (weeks-months) after only 1 to 3 treatment session(s). All studies were conducted in line with guidelines for the safe conduct of psychedelic therapy and no severe adverse events were reported.

Conclusion: The resurrection of clinical psychedelic research provides early evidence for treatment efficacy and safety for a range of psychiatric conditions, and constitutes an exciting new treatment avenue in a health area with major unmet needs.

<strong class="sub-title"> Keywords: </strong> <em>5HT</em>; DMT; LSD; ayahuasca; psilocybin; psychedelic; serotonergic.

BACKGROUND

SSRIs suppress rapid eye movement (REM) sleep, probably by increasing serotonin in the brainstem, and also increase sleep fragmentation. Although in the UK, paroxetine (PAR) and citalopram (CIT) have recommended doses of 20 mg/day for the treatment of depression, the recommended dose of CIT in USA is higher (40 mg). If similar doses of PAR and CIT have similar effects on central serotonin then they should have similar effects on sleep measures in volunteers.

METHODS

This was a randomised, double blind placebo controlled crossover study in 12 healthy volunteers. Subjects took PAR 20 mg mane, CIT 20 mg mane or placebo mane for 3 days and sleep was recorded overnight at home on the third night. Standard measures of sleep were derived.

RESULTS

REM sleep was significantly suppressed and sleep fragmentation increased by both drugs. Measures of REM sleep and sleep continuity previously found to be altered by SSRIs were considered together and compared with placebo as a 'serotonin response'; this was significantly greater in the PAR group.

CONCLUSIONS

Sleep effects typical of SSRIs were greater with PAR 20 mg/day than CIT 20 mg/day, suggesting greater effects on <em>5HT</em> uptake blockade.

[3H]-Imipramine and [3H]-paroxetine label with high affinity a site which is associated with the serotonergic transporter in brain and platelets. The pharmacological profile of inhibition by drugs of [3H]-imipramine and [3H]-paroxetine binding is highly correlated with the potency of the drugs to inhibit the uptake of <em>5HT</em>. Denervation of serotonergic neurons by electrolytic lesions or with 5,7-dihydroxytryptamine produces marked decreases in the density of [3H]-imipramine as well as [3H]-paroxetine binding. Dissociation kinetic experiments support the view that the substrate recognition site for <em>5HT</em> is different from the modulatory site which is labelled by [3H]-imipramine or [3H]-paroxetine. The existence of an endogenous ligand acting on the [3H]-imipramine recognition site to modulate the <em>5HT</em> transporter was proposed by several laboratories. [3H]-Imipramine binding in platelets appears to be a biological marker in depression. Studies carried out in several laboratories report a significant decrease in the Bmax of platelet [3H]-imipramine binding without changes in Kd, when severely depressed untreated patients are compared with healthy volunteers matched for age and sex. The Bmax of platelet [3H]-imipramine binding appears to be a state-dependent biological marker in depression. It is tempting to speculate that the endocoid of the [3H]-imipramine recognition site may play a role in the pathogenesis of depression.

BACKGROUND

Rare diseases have been associated with more and more genetic and non genetic causes and risk factors. But this has not been systematically assessed in catatonia, one of the psychiatric syndromes, that is most frequently associated with medical condition.

OBJECTIVE

We sought to assess the medical and developmental risk factors of catatonia in children and adolescents.

METHODS

From 1993 to 2009, 58 youths aged 10 to 18 years were prospectively admitted for catatonia and were followed up after discharge. A multidisciplinary approach assessed patients' medical condition and developmental history. A causality assessment scored medical risk (maximum score=10; κ=0.91). We compared the prevalence of catatonia in these patients to that of 80 inpatients with bipolar I disorder admitted from 1993 to 2003 who were also followed up.

RESULTS

We found that 13 (22.4%) patients had medical conditions and 18 (31%) had a history of developmental disorder in the catatonia group, whereas 1 (1.3%) and 17 (22.6%) patients had the same conditions in the bipolar group (p<0.001; p=0.17, respectively). Medical conditions associated with catatonia included auto-immune encephalitis (systemic lupus erythematosus [N=3] and anti-NMDA-receptor encephalitis [N=1]), seizures (N=1), ciclosporin encephalitis (N=1), post hypoglycaemic coma encephalitis (N=1), and genetic or metabolic conditions (chorea [N=2], <em>5HT</em> cerebrospinal fluid deficit [N=1], storage disease [N=1], fatal familial insomnia [FFI; N=1], and PRODH mutations [N=1]). Six patients responded to a specific treatment approach related to their medical condition (e.g., plasma exchange in the case of auto-immune encephalitis).

CONCLUSIONS

Catatonia in children and adolescents is associated with a high prevalence of medical conditions. This needs to be acknowledged as it may greatly delay the treatment of catatonia and the diagnosis of medically related catatonia. Tragically, this may deny patients treatment opportunities.