Serotonin and Human Cognitive Performance

Schmitt, J.A.J.; Wingen, Marleen; Ramaekers, J. G.; Evers, Elisabeth A. T.; Riedel, Wim J.

doi:10.2174/138161206777698909

Cited by 225 publications

(159 citation statements)

References 126 publications

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“…Mood may be improved in depressed cognitively impaired older patients by treatment with antidepressants including selective serotonin reuptake inhibitors (SSRI) even in the absence of improvement in cognitive or motor domains (Schrag 2006;Ishihara and Brayne, 2006;Nebes et al, 2003). The actions of serotonin in the development and treatment of impairments seen in neurodegenerative diseases require further investigation (Gruden et al, 2007;Schmitt et al, 2006;Truchot et al, 2007).…”

Section: Possible Relevance Of 5-htt Axon Degeneration To Symptoms Ofmentioning

confidence: 99%

Dystrophic serotonergic axons in neurodegenerative diseases

Azmitia¹,

Nixon²

2008

Brain Research

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Neurodegenerative diseases such as Parkinson's disease (PD), frontal lobe dementia (FLD) and Diffuse Lewy-Body dementia (DLBD) have diverse neuropathologic features. Here we report that serotonin fibers are dystrophic in the brains of individuals with these three diseases. In neuropathologically normal (control) brains (n=3), serotonin axons immunoreactive (IR) with antibodies against the serotonin transporter (5-HTT) protein were widely distributed in cortex (entorhinal and dorsolateral prefrontal), hippocampus and rostral brainstem. 5-HTT-IR fibers of passage appeared thick, smooth, and un-branched in medial forebrain bundle, medial lemniscus and cortex white matter. The terminal branches were fine, highly branched and varicose in substantia nigra, hippocampus and cortical gray matter. In the diseased brains, however, 5-HTT-IR fibers in the forebrain were reduced in number and were frequently bulbous, splayed, tightly clustered and enlarged. Morphometric analysis revealed significant differences in the size distribution of the 5-HTT-IR profiles in dorsolateral prefrontal area between neurodegenerative diseases and controls. Our observations provide direct morphologic evidence for degeneration of human serotonergic axons in the brains of patients with neurodegenerative diseases despite the limited size (n=3 slices for each region (3) from each brain (4), total slices was n=36) and lack of extensive clinical characterization of the analyzed cohort. This is the first report of dystrophic 5-HTT-IR axons in postmortem human tissue

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Section: Possible Relevance Of 5-htt Axon Degeneration To Symptoms Ofmentioning

confidence: 99%

Dystrophic serotonergic axons in neurodegenerative diseases

Azmitia¹,

Nixon²

2008

Brain Research

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“…Whereas consolidation of new information into long-term memory appeared to be compromised by a reduction of central 5-HT activity; shortterm memory functions were intact. Several studies have subsequently confirmed that 5-HT is specifically involved in long-term memory functioning (for review, see Sambeth et al 2007;Schmitt et al 2006). Interestingly, ATD did not affect long-term memory retrieval or recognition when the depletion was induced after learning and consolidation of a word list (Schmitt et al 2000).…”

Section: Introductionmentioning

confidence: 98%

Acute tryptophan depletion dose dependently impairs object memory in serotonin transporter knockout rats

et al. 2008

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Rationale Acute tryptophan depletion (ATD) transiently lowers central serotonin levels and can induce depressive mood states and cognitive defects. Previous studies have shown that ATD impairs object recognition in rats. Objectives As individual differences exist in central serotonin neurotransmission, the impact of ATD may vary accordingly. In this experiment, we investigated the hypothesis that male serotonin transporter knockout (SERT −/− ), rats marked by a lower SERT function, are more vulnerable to the effects of ATD in an object recognition task than male wildtype (SERT +/+ ) and heterozygous (SERT +/− ) rats. Materials and methods Twelve male SERT +/+ , SERT +/− , and SERT −/− rats were treated with standard dose and lowdose ATD using a gelatine-based protein-carbohydrate mixture lacking tryptophan. In the control treatment, Ltryptophan was added to the mixture. Four hours after treatment, the rats were subjected to the object recognition task. In addition, the effects of ATD on plasma amino acid concentrations were measured, and concentrations of 5-HT and 5-HIAA were measured in the frontal cortex and hippocampus of these rats. Results Plasma TRP levels and central 5-HT and 5-HIAA levels were decreased in all genotypes after ATD, but effects were stronger in SERT −/− rats. The standard dose of ATD impaired object recognition in all genotypes. SERT −/− and SERT +/− rats were more vulnerable to low dose of ATD in the object recognition task compared to SERT +/+ rats. Conclusions These results indicate a greater sensitivity to ATD in SERT −/− and SERT +/− rats, which may be related to stronger central depletion effects in these rats.

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“…The introduction of fluoxetine (Prozac) and other selective serotonin reuptake inhibitors (SSRIs) has changed the treatment of depressive disorders (Wong et al, 1974;Wong et al, 1995) through acute and chronic effects (Lucki, 1998;Hoyer et al, 2002;Schmitt et al, 2006;Cools et al, 2008;Arnsten, 2009). The chemical hypothesis of depression emphasizes that the imbalance in the function of the serotonergic system is reinstated by SSRIs by elevating serotonin (5-HT) levels (Maes and Meltzer, 1995;Manji et al, 2001;Castrén, 2005), but alternative hypotheses have also been proposed (Lacasse and Leo, 2005;Nestler, 2008, 2010;Luscher et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Humans (Harmer et al, 2003;Schmitt et al, 2006) and animals (Clarke et al, 2004;Brigman et al, 2010) display altered cognitive performance after having their central 5-HT level experimentally manipulated. With limited studies performed on human pyramidal cells (McCormick and Williamson, 1989;Newberry et al, 1999), our current knowledge about synaptic mechanisms of 5-HT in the cortex is based on non-human in vitro experiments in which micromolar concentrations of 5-HT were applied (Andrade and Nicoll, 1987;Aghajanian and Marek, 1997;Schmitz et al, 1998b;Ciranna, 2006;Zhong et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Fluoxetine (Prozac) and Serotonin Act on Excitatory Synaptic Transmission to Suppress Single Layer 2/3 Pyramidal Neuron-Triggered Cell Assemblies in the Human Prefrontal Cortex

et al. 2012

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Selective serotonin reuptake inhibitors are the most widely prescribed drugs targeting the CNS with acute and chronic effects in cognitive, emotional and behavioral processes. This suggests that microcircuits of the human cerebral cortex are powerfully modulated by selective serotonin reuptake inhibitors, however, direct measurements of serotonergic regulation on human synaptic interactions are missing. Using multiple whole-cell patch-clamp recordings from neurons in acute cortical slices derived from nonpathological human samples of the prefrontal cortex, we show that neuronal assemblies triggered by single action potentials of individual neurons in the human cortex are suppressed by therapeutic doses of fluoxetine (Prozac). This effect is boosted and can be mimicked by physiological concentrations of serotonin through 5HT-2A and 5HT-1A receptors. Monosynaptic excitatory connections from pyramidal cells to interneurons were suppressed by application of serotonin leaving the monosynaptic output of GABAergic cells unaffected. Changes in failure rate, in paired-pulse ratio, and in the coefficient of variation of the amplitude of EPSPs suggest a presynaptic action of serotonin. In conclusion, activation of neuronal assemblies, which were suggested as building blocks of high order cognitive processes, are effectively downregulated by the acute action of selective serotonin reuptake inhibitors or serotonin at the site of pyramidal output in human microcircuits.

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Serotonin and Human Cognitive Performance

Cited by 225 publications

References 126 publications

Dystrophic serotonergic axons in neurodegenerative diseases

Dystrophic serotonergic axons in neurodegenerative diseases

Acute tryptophan depletion dose dependently impairs object memory in serotonin transporter knockout rats

Fluoxetine (Prozac) and Serotonin Act on Excitatory Synaptic Transmission to Suppress Single Layer 2/3 Pyramidal Neuron-Triggered Cell Assemblies in the Human Prefrontal Cortex

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