Changes In Serotonin Neurotransmission Research Articles

Changes in serotonin neurotransmission as assayed by microdialysis after acute, intermittent or chronic ethanol administration and withdrawal.

The serotonergic neurotransmitter system is involved in many ethanol-induced changes, including many behavioural alterations, as well as contributing to alcohol dependence and its withdrawal. This review has evaluated microdialysis studies where alterations in the serotonin system, that is, serotonin, 5-HT, or its metabolite 5-hydroxyindoleacetic acid, 5-HIAA, have been reported during different ethanol intoxication states, as well as in animals showing alcohol preference or not. Changes in 5-HT receptors and the 5-HT transporter are briefly reviewed to comprehend the significance of changes in microdialysate 5-HT concentrations. Changes in 5-HT content following acute, chronic and during ethanol withdrawal states are evaluated. In addition, the serotoninergic system was assessed in animals that have been genetically selected for alcohol preference to ascertain whether changes in this monoamine microdialysate content may contribute to alcohol preference. Changes occurred in 5-HT signalling in the limbic brain regions, increasing after acute ethanol administration in specific brain regions, particularly at higher doses, while chronic alcohol exposure essentially decreased serotonergic transmission. Such changes may play a pivotal role in emotion-driven craving and relapse. Depending on the dosage, mode of administration and consumption rate, ethanol affects specific brain regions in different ways, enhancing or reducing 5-HT microdialysate content, thereby inducing behavioural and cognitive functions and enhancing ethanol consumption. Microdialysis studies demonstrated that ethanol induces several alterations in 5-HT content as well as its metabolites, 5-HIAA and 5-HTOL, not only in its release from a specific brain region but also in the modifications of its different receptor subtypes and its transporter.

Association between the loudness dependence of auditory evoked potentials and age in patients with schizophrenia and depression.

ObjectiveAlthough serotonergic dysfunction is significantly associated with major depressive disorder (MDD) and schizophrenia (SCZ), comparison of serotonergic dysfunction in both diseases has received little attention. Serotonin hypotheses have suggested diminished and elevated serotonin activity in MDD and SCZ, respectively. However, the foundations underlying these hypotheses are unclear regarding changes in serotonin neurotransmission in the aging brain. The loudness dependence of auditory evoked potentials (LDAEP) reflects serotonin neurotransmission. The present study compared the LDAEP between patients with SCZ or MDD and healthy controls (HCs). We further examined whether age was correlated with the LDAEP and clinical symptoms.MethodsThis prospective clinical study included 105 patients with SCZ (n = 54) or MDD (n = 51). Additionally, 35 HCs were recruited for this study. The LDAEP was measured on the midline channels via 62 electroencephalography channels.ResultsPatients with SCZ or MDD showed a significantly smaller mean LDAEP than those in HCs. The LDAEP was positively correlated with age in patients with SCZ or MDD.ConclusionsChanges in central serotonergic activity could be indicated by evaluating the LDAEP in patients with SCZ or MDD. Age-related reductions in serotonergic activity may be screened using the LDAEP in patients with SCZ or MDD.

Unraveling the architecture of the dorsal raphe synaptic neuropil using high-resolution neuroanatomy.

The dorsal raphe nucleus (DRN), representing the main source of brain’s serotonin, is implicated in the pathophysiology and therapeutics of several mental disorders that can be debilitating and life-long including depression, anxiety and autism. The activity of DRN neurons is precisely regulated, both phasically and tonically, by excitatory glutamate and inhibitory GABAergic axons arising from extra-raphe areas as well as from local sources within the nucleus. Changes in serotonin neurotransmission associated with pathophysiology may be encoded by alterations within this network of regulatory afferents. However, the complex organization of the DRN circuitry remains still poorly understood. Using a recently developed high-resolution immunofluorescence technique called array tomography (AT) we quantitatively analyzed the relative contribution of different populations of glutamate axons originating from different brain regions to the excitatory drive of the DRN. Additionally, we examined the presence of GABA axons within the DRN and their possible association with glutamate axons. In this review, we summarize our findings on the architecture of the rodent DRN synaptic neuropil using high-resolution neuroanatomy, and discuss possible functional implications for the nucleus. Understanding of the synaptic architecture of neural circuits at high resolution will pave the way to understand how neural structure and function may be perturbed in pathological states.

Possible Precipitation of Migraine Attacks with Prophylactic Treatment

The initiation of a prophylactic treatment in a migraine sufferer depends upon the stratification of the patient’s frequency of attacks and the disability they cause, as well as the patient’s acute consumption and comorbid diseases. We report on 14 patients who were among a group of 618 migraine sufferers who received a new preventative treatment. These 14 patients developed an increase in the frequency of their migraine attacks that was possibly induced by this new prophylactic treatment. The clinical description of the migraine attacks remained the same but the frequency of the attacks of migraine without aura was dramatically increased. This is, to our knowledge, the first description of a possible precipitation of attacks of migraine without aura with a prophylactic treatment. There is no link with a specific class of prophylactic treatment. We hypothesize that the migraine sufferers who experienced aggravation after the new prophylactic drug had been introduced had a paradoxical decrease in the induction threshold for cortical spreading depression (CSD). Mechanisms of such a decrease are unknown and are probably multifactorial, but changes in serotonin neurotransmission have been experimentally demonstrated to modify cortical excitability and favour CSD. The aggravation was described only for attacks without aura. However, with only 14 patients, it is not possible to predict whether suffering from that the type of migraine is a factor that predisposes a patient to aggravation. While additional cases are necessary, physicians should be aware of the possibility that prophylactic treatment may exacerbate migraine attacks.

An examination of acute changes in serotonergic neurotransmission using the loudness dependence measure of auditory cortex evoked activity: effects of citalopram, escitalopram and sertraline

The underlying effect of serotonergic neurotransmission has been implicated in several psychiatric disorders. The inability to routinely and non-invasively determine the integrity of the serotonergic system in vivo has limited our understanding of disorders with a putative serotonergic abnormality. The loudness dependence of the auditory evoked potential (LDAEP) has been proposed as a reliable measure of central serotonin function in humans. While animal studies suggest that the LDAEP is sensitive to changes in central serotonin neurotransmission, evidence in humans has been indirect and inconsistent. The aim of this study was to assess the sensitivity of the LDAEP to acute augmentation in central serotonergic neurotransmission in humans. The study used a double-blind, placebo-controlled cross-over design, in which healthy subjects were tested under four acute treatment conditions, with pharmacologically equivalent single doses of placebo, escitalopram (10 mg), citalopram (20 mg) and sertraline (50 mg) to examine the direct effect of acute enhancement of synaptic serotonin on the LDAEP. Furthermore, the outcome of the serotonergic modulatory effects on the LDAEP was also examined using two methods (dipole source analysis (DSA) vs. scalp analysis). Escitalopram, citalopram and sertraline had no effects on the LDAEP and were independent of the analysis method used. These findings question the sensitivity of the LDAEP to acute changes in serotonin neurotransmission and its validity as a reliable measure of central serotonin function in humans.

The Effect of Citalopram Pretreatment on Neuronal Responses to Neuropsychological Tasks in Normal Volunteers: An fMRI Study

Changes in serotonin neurotransmission have also been implicated in the etiology and treatment of impulse control disorders, depression, and anxiety. We have investigated the effect of enhancing serotonin function on fundamental brain processes that we have proposed are abnormal in these disorders. In all, 12 male volunteers received citalopram (7.5 mg intravenously) and placebo pretreatment in a single-blind crossover design before undertaking Go/No-go, Loss/No-loss, and covert (aversive) face emotion recognition tasks during functional magnetic resonance imaging (fMRI). Blood oxygenation level dependent responses were analyzed using Statistical Parametric Mapping (SPM2). The tasks activated prefrontal and subcortical regions generally consistent with literature with lateral orbitofrontal cortex (BA47) common to the three tasks. Citalopram pretreatment enhanced the right BA47 responses to the No-go condition, but attenuated this response to aversive faces. Attenuations were seen following citalopram in the medial orbitofrontal (BA11) responses to the No-go and No-loss (ie relative reward compared with Loss) conditions. The right amygdala response to aversive faces was attenuated by citalopram. These results support the involvement of serotonin in modulating basic processes involved in psychiatric disorders but argue for a process-specific, rather than general effect. The technique of combining drug challenge with fMRI (pharmacoMRI) has promise for investigating human psychiatric disorders.

Up-regulation of tryptophan hydroxylase expression and serotonin synthesis by sertraline.

The neurotransmitter serotonin is involved in a variety of brain functions, and abnormal changes in serotonin neurotransmission are associated with an array of psychiatric disorders, including depression. Sertraline is a selective serotonin reuptake inhibitor (SSRI) and an effective antidepressant. Sertraline increases the serotonin concentration in the synaptic cleft by a short-term action; however, clinical improvement is observed only after several weeks, suggesting that the therapeutic effect may be caused by long-term alterations in serotonin transmission. We determined the effects of sertraline on serotonin synthesis in vivo and in vitro. Long-term treatment of rats with sertraline up-regulated mRNA and protein levels of the serotonin-synthesizing enzyme tryptophan hydroxylase (TPH), as determined by in situ hybridization and immunocytochemistry, respectively. In vitro studies using RBL-2H3 cells also showed an increase in mRNA and protein levels of TPH by sertraline, as determined by Northern blot and immunoblot analyses, respectively. This was accompanied by increases in the levels of TPH enzymatic activity and total serotonin. These data demonstrate that in addition to the known short-term action as an uptake blocker, sertraline also exerts a long-term effect on the serotonin neurotransmission by enhancing serotonin synthesis. A similar effect was observed with another SSRI, fluoxetine, but not with the non-SSRI chlorpromazine. The up-regulation of TPH gene expression by sertraline was attenuated by the protein kinase A (PKA) inhibitor N-[2-(p-bromocinnamylamine)-ethyl]-5-isoquinolinesulfonamine, suggesting that a mechanism involving the PKA signaling pathway might at least in part mediate the long-term therapeutic action.