Sustained Administration of Trazodone Enhances Serotonergic Neurotransmission: In Vivo Electrophysiological Study in the Rat Brain

Despite its clinical use for more than two decades, the mechanisms by which trazodone acts as an antidepressant are not clear, because it has affinity for a variety of 5-hy-droxytryptamine (5-HT; serotonin) receptors and the 5-HT transporter. This study examined the effects of sustained trazodone administration on 5-HT neurotransmission. Elec-trophysiological recordings were conducted in anesthetized rats. Subcutaneously implanted minipumps delivered vehicle or trazodone (10 mg/kg/day) for 2 and 14 days. A 2-day trazodone administration suppressed the firing rate of raphe 5-HT neurons, which recovered to baseline after 14 days. This was attributable to 5-HT1A autoreceptor desensitization because the suppressant effect of the 5-HT autoreceptor agonist lysergic acid diethylamide was dampened in 14-day trazodone-treated rats. Prolonged trazodone administration did not change the sensitivity of postsynaptic 5-HT1A and 2-adrenergic receptors in hippocampus, but enhanced syn-aptic 5-HT levels because the 5-HT1A antagonist N-{2-[4 (2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclo-hexanecarboxamide trihydrochloride (WAY-100635) en-hanced hippocampal firing in treated rats, but not in controls. Trazodone administration for 14 days increased the 50% recovery time value, an index of 5-HT transporter blockade in vivo, and decreased the inhibitory function of terminal 5-HT1B autoreceptors on the electrically evoked release of 5-HT. The agonistic action of trazodone at 5-HT1A receptors was characterized as being full because it did not attenuate the inhibitory action of 5-HT when coapplied locally. The enhanced 5-HT neurotransmission by trazodone is caused in part by reuptake blockade and activation of postsynaptic 5-HT1A receptors, which may account for its effectiveness in major depression

How do legislative changes affect religious education?

RESUMEN: La evolución histórica de la enseñanza religiosa en el marco legislativo en base a los cambios producidos en las distintas leyes educativas en el sistema educativo español. ABSTRACT: The historical evolution of religious education in the legislative framework based on the changes produced in the different educational laws in the Spanish educational system

Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease

Polyglutamine diseases are a class of dominantly inherited neurodegenerative disorders for which there is no effective treatment. Here we provide evidence that activation of serotonergic signalling is beneficial in animal models of Machado-Joseph disease. We identified citalopram, a selective serotonin reuptake inhibitor, in a small molecule screen of FDA-approved drugs that rescued neuronal dysfunction and reduced aggregation using a Caenorhabditis elegans model of mutant ataxin 3-induced neurotoxicity. MOD-5, the C. elegans orthologue of the serotonin transporter and cellular target of citalopram, and the serotonin receptors SER-1 and SER-4 were strong genetic modifiers of ataxin 3 neurotoxicity and necessary for therapeutic efficacy. Moreover, chronic treatment of CMVMJD135 mice with citalopram significantly reduced ataxin 3 neuronal inclusions and astrogliosis, rescued diminished body weight and strikingly ameliorated motor symptoms. These results suggest that small molecule modulation of serotonergic signalling represents a promising therapeutic target for Machado-Joseph disease.This work was supported by Fundação para a Ciência e Tecnologia (FCT) and COMPETE through the projects ‘[PTDC/SAU-GMG/112617/2009] (to P.M.) and [EXPL/ BIM-MEC/0239/2012] (to A.T.C.)’, by National Ataxia foundation (to P.M.), by Ataxia UK (to P.M.), by National Institutes of Health (NIH) ‘[GM038109, GM081192, AG026647, and NS047331] (to R.I.M.)’, by The Chicago Biomedical Consortium (to R.I.M.) and by the Ellison Medical Foundation (to R.I.M.). A.T.C., A.J., S.E., L.S.S., C.B., S.D.S., A.S.F. and A.N.C. were supported by the FCT individual fellowships SFRH/BPD/79469/2011, SFRH/BD/76613/2011, SFRH/BD/78554/2011, SFRH/BD/ 84650/2012, SFRH/BPD/74452/2010, SFRH/BD/78388/ 2011, SFRH/BPD/91562/2012 and SFRH/BD/51059/2010, respectively. FCT fellowships are co-financed by POPH, QREN, Governo da República Portuguesa and EU/FSE.info:eu-repo/semantics/publishedVersio

Responsiveness of 5-HT1A and 5-HT2 receptors in the rat orbitofrontal cortex after long-term serotonin reuptake inhibition

Background: The only antidepressant drugs that are effective in the treatment of obsessive-compulsive disorder (OCD) are those that effectively block the reuptake of serotonin (5-hydroxytryptamine; 5-HT). In humans, positron emission tomography studies have implicated the orbitofrontal cortex (OFC) in the mediation of OCD symptoms. In animals, administration of selective serotonin reuptake inhibitors (SSRIs) for 8 weeks (but not 3 weeks) led to increased release of 5-HT in the OFC, because of desensitization of the terminal 5-HT autoreceptors. However, the increase in synaptic levels of 5-HT in the OFC after long-term administration of SSRIs might be cancelled out by desensitization of postsynaptic 5-HT receptors. This study was undertaken to investigate if these OFC receptors adapt under such conditions. Methods: In vivo electrophysiologic techniques were used in this animal study. Male Sprague-Dawley rats received the SSRI paroxetine or vehicle control, delivered by implanted osmotic minipumps, for 3 or 8 weeks. With the rats under anesthesia, neuronal responsiveness to the microiontophoretic application of various drugs was assessed by determining the number of spikes suppressed per nanoampere of ejection current. Results: After administration of paroxetine for either 3 weeks or 8 weeks, there was no modification in the inhibitory effect of 5-HT, the preferential 5-HT 2A receptor agonist (+)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI) or the preferential 5-HT 2C receptor agonist 3-chlorophenyl piperazine dihydrochloride (mCPP). In contrast, the inhibitory effect of the 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propilamino)-tetralin (8-OH-DPAT) was attenuated in the OFC after both 3 and 8 weeks of paroxetine administration. Conclusion: These results indicate a desensitization of postsynaptic 5-HT 1A receptors in the OFC but a lack of compensatory adaptation of the 5-HT receptor(s) mediating the main effect of 5-HT in this brain region. These observations imply that the activation of normosensitive postsynaptic 5-HT 2 -like receptors may mediate the effect of enhanced 5-HT release in the OFC. Contexte : Seuls les antidépresseurs qui parviennent à bloquer le recaptage de la sérotonine (5-HT) sont efficaces dans le traitement du trouble obsessionnel compulsif (TOC). Chez l'humain, les études fondées sur la tomographie par émission de positrons ont lié le cortex orbitofrontal (COF) avec la médiation des symptômes du TOC. Chez l'animal, l'administration d'inhibiteurs sélectifs du recaptage de la sérotonine (ISRS) pendant huit semaines (plutôt que trois semaines) a conduit à une libération accrue de 5-HT dans le COF, en raison de l'hyposensibilisation des autorécepteurs terminaux de la 5-HT. L'hyposensibilisation des récepteurs post-synaptiques de la 5-HT pourrait toutefois neutraliser l'accroissement des taux synaptiques de 5-HT dans le COF suite à un traitement de longue durée faisant appel aux ISRS. Cette étude visait à étudier la question de savoir si ces récepteurs du COF s'adaptent dans ces conditions. Méthodes : Des techniques in vivo en électrophysiologie ont été appliqués dans cette étude chez l'animal. Pendant trois ou huit semaines, on a administré à des rats mâles de Sprague-Dawley soit de la paroxétine, un ISRS, soit un véhicule de contrôle, au moyen de minipompes osmotiques implantées. Chez les rats sous anesthésie, la réponse neuronale à l'application microiontophorétique de diverses substances a été évaluée par la détermination du nombre de potentiels d'action supprimés par nanoampère de courant éjecté. Résultats : Suite à l'administration de paroxétine pendant trois ou huit semaines, il n'y a pas eu de modification de l'effet d'inhibition de la 5-HT, du chlorhy

Serotonin excites fast-spiking interneurons in the striatum

Fast-spiking interneurons (FSIs) control the output of the striatum by mediating feed-forward GABAergic inhibition of projection neurons. Their neuromodulation can therefore critically affect the operation of the basal ganglia. We studied the effects of 5-hydroxytryptamine (5-HT, serotonin), a neurotransmitter released in the striatum by fibres originating in the raphe nuclei, on FSIs recorded with whole-cell techniques in rat brain slices. Bath application of serotonin (30 μm) elicited slow, reversible depolarizations (9 ± 3 mV) in 37/46 FSIs. Similar effects were observed using conventional whole-cell and gramicidin perforated-patch techniques. The serotonin effects persisted in the presence of tetrodotoxin and were mediated by 5-HT2C receptors, as they were reversed by the 5-HT2 receptor antagonist ketanserin and by the selective 5-HT2C receptor antagonist RS 102221. Serotonin-induced depolarizations were not accompanied by a significant change in FSI input resistance. Serotonin caused the appearance of spontaneous firing in a minority (5/35) of responsive FSIs, whereas it strongly increased FSI excitability in each of the remaining responsive FSIs, significantly decreasing the latency of the first spike evoked by a current step and increasing spike frequency. Voltage-clamp experiments revealed that serotonin suppressed a current that reversed around −100 mV and displayed a marked inward rectification, a finding that explains the lack of effects of serotonin on input resistance. Consistently, the effects of serotonin were completely occluded by low concentrations of extracellular barium, which selectively blocks Kir2 channels. We concluded that the excitatory effects of serotonin on FSIs were mediated by 5-HT2C receptors and involved suppression of an inwardly rectifying K+ current

Acute escitalopram treatment inhibits REM sleep rebound and activation of MCH-expressing neurons in the lateral hypothalamus after long term selective REM sleep deprivation.

RATIONALE: Selective rapid eye movement sleep (REMS) deprivation using the platform-on-water ("flower pot") method causes sleep rebound with increased REMS, decreased REMS latency, and activation of the melanin-concentrating hormone (MCH) expressing neurons in the hypothalamus. MCH is implicated in the pathomechanism of depression regarding its influence on mood, feeding behavior, and REMS. OBJECTIVES: We investigated the effects of the most selective serotonin reuptake inhibitor escitalopram on sleep rebound following REMS deprivation and, in parallel, on the activation of MCH-containing neurons. METHODS: Escitalopram or vehicle (10 mg/kg, intraperitoneally) was administered to REMS-deprived (72 h) or home cage male Wistar rats. During the 3-h-long "rebound sleep", electroencephalography was recorded, followed by an MCH/Fos double immunohistochemistry. RESULTS: During REMS rebound, the time spent in REMS and the number of MCH/Fos double-labeled neurons in the lateral hypothalamus increased markedly, and REMS latency showed a significant decrease. All these effects of REMS deprivation were significantly attenuated by escitalopram treatment. Besides the REMS-suppressing effects, escitalopram caused an increase in amount of and decrease in latency of slow wave sleep during the rebound. CONCLUSIONS: These results show that despite the high REMS pressure caused by REMS deprivation procedure, escitalopram has the ability to suppress REMS rebound, as well as to diminish the activation of MCH-containing neurons, in parallel. Escitalopram caused a shift from REMS to slow wave sleep during the rebound. Furthermore, these data point to the potential connection between the serotonergic system and MCH in sleep regulation, which can be relevant in depression and in other mood disorders

Relevance of Norepinephrine–Dopamine Interactions in the Treatment of Major Depressive Disorder

Central dopaminergic and noradrenergic systems play essential roles in controlling several forebrain functions. Consequently, perturbations of these neurotransmissions may contribute to the pathophysiology of neuropsychiatric disorders. For many years, there was a focus on the serotonin (5-HT) system because of the efficacy of selective serotonin reuptake inhibitors (SSRIs), the most prescribed antidepressants in the treatment of major depressive disorder (MDD). Given the interconnectivity within the monoaminergic network, any action on one system may reverberate in the other systems. Analysis of this network and its dysfunctions suggests that drugs with selective or multiple modes of action on dopamine (DA) and norepinephrine (NE) may have robust therapeutic effects. This review focuses on NE-DA interactions as demonstrated in electrophysiological and neurochemical studies, as well as on the mechanisms of action of agents with either selective or dual actions on DA and NE. Understanding the mode of action of drugs targeting these catecholaminergic neurotransmitters can improve their utilization in monotherapy and in combination with other compounds particularly the SSRIs. The elucidation of such relationships can help design new treatment strategies for MDD, especially treatment-resistant depression