The 5-HT2A serotonin receptor in executive function: Implications for neuropsychiatric and neurodegenerative diseases

Aznar, Susana; Hervig, Mona El-Sayed

doi:10.1016/j.neubiorev.2016.02.008

Cited by 72 publications

(51 citation statements)

References 276 publications

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“…We hypothesised that a reduction of 5-HT through a chronic TRP depletion by diet will increase the compulsive behaviour in vulnerable populations such as the HD Wistar rats compared to non-vulnerable populations such as LD Wistar rats and Lister Hooded rats and that could be accompanied by changes in the serotonin 5-HT 2A receptor, a serotonin receptor subtype proposed as a candidate for mediating compulsive behaviour (Aznar and Hervig 2016; Aznar and Klein 2013; Fineberg et al 2010, 2011; Navarro et al 2015). To test the previous hypothesis, we screened high and low drinking rates during SIP in both strains.…”

Section: Introductionmentioning

confidence: 99%

Tryptophan depletion affects compulsive behaviour in rats: strain dependent effects and associated neuromechanisms

et al. 2017

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RationaleCompulsive behaviour, present in different psychiatric disorders, such as obsessive-compulsive disorder, schizophrenia and drug abuse, is associated with altered levels of monoamines, particularly serotonin (5-hydroxytryptamine) and its receptor system.ObjectivesThe present study investigated whether 5-HT manipulation, through a tryptophan (TRP) depletion by diet in Wistar and Lister Hooded rats, modulates compulsive drinking in schedule-induced polydipsia (SIP) and locomotor activity in the open-field test. The levels of dopamine, noradrenaline, serotonin and its metabolite were evaluated, as well as the 5-HT2A and 5-HT1A receptor binding, in different brain regions.MethodsWistar rats were selected as high (HD) or low (LD) drinkers according to their SIP behaviour, while Lister hooded rats did not show SIP acquisition. Both strains were fed for 14 days with either a TRP-free diet (T−) or a TRP-supplemented diet (T+)ResultsThe TRP depletion diet effectively reduced 5-HT levels in the frontal cortex, amygdala and hippocampus in both strains of rats. The TRP-depleted HD Wistar rats were more sensitive to 5-HT manipulation, exhibiting more licks on SIP than did the non-depleted HD Wistar rats, while the LD Wistar and the Lister Hooded rats did not exhibit differences in SIP. In contrast, the TRP-depleted Lister Hooded rats increased locomotor activity compared to the non-depleted rats, while no differences were found in the Wistar rats. Serotonin 2A receptor binding in the striatum was significantly reduced in the TRP-depleted HD Wistar rats.ConclusionsThese results suggest that alterations of the serotonergic system could be involved in compulsive behaviour in vulnerable populations.

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Section: Introductionmentioning

confidence: 99%

Tryptophan depletion affects compulsive behaviour in rats: strain dependent effects and associated neuromechanisms

et al. 2017

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“…This is contradictory to our prior model in which pups had decreased weights during and at the end of the acute exposure [21, 39]. In the previous neonatal exposure model, our dosing regimen was 5 mg/kg/d of sertraline during the first 14 postnatal days which yielded sertraline levels consistent with maternal levels, exposing pups to a relatively high exposure which exceeded in utero exposure and led to a hypermetabolic state [37]. This new model accounted for placental passage of the medication and pups only received 1/3 rd of the maternal dose, which likely explains why no weight loss was observed.…”

Section: Discussionmentioning

confidence: 69%

“…Significant reductions were also observed in the 5-HT 1A and 5-HT 2A receptor binding density in the posterior cingulate cortex and fusiform gyrus in a study using post-mortem brain tissue from autistic and control individuals [33]. The 5-HT 2A receptor has been demonstrated to have an important role in executive function with both animal and human studies linking psychiatric diseases with disruptions in the 5-HT 2A receptor system [37]. Our study demonstrated increased mRNA levels of the 5-HT 1A receptor and 5-HT 2A receptor in the cortex which may contribute to why no behavioral phenotype was observed.…”

Section: Discussionmentioning

confidence: 99%

Perinatal SSRI exposure permanently alters cerebral serotonin receptor mRNA in mice but does not impact adult behaviors

Meyer

Dexter

et al. 2017

The Journal of Maternal-Fetal & Neonatal Medicine

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Purpose: Associations have been made between maternal selective serotonin reuptake inhibitor (SSRI) use during pregnancy and altered behavior in offspring, including an increased risk of autism. Given the important role serotonin plays in behavior, we hypothesized SSRI exposure in the perinatal period would alter central serotonin receptor expression and program adult behaviors in mice. Methods: Female mice were injected with sertraline or saline throughout pregnancy. Offspring continued to receive injections on postnatal days 1–14, a time period in mice similar to the third trimester in human pregnancy. Adult offspring underwent behavioral testing and serotonin receptor mRNA levels were quantified. Results: Compared to controls, SSRI exposed mice did not have a reduction in social interactions, spatial learning, or exploratory behavior. As adults, sertraline exposed mice had significantly increased mRNA levels of multiple 5-HT receptors, serotonin transporter (5-HTT), and tryptophan hydroxylase isoform 2 in the cerebral cortex. Conclusion: Although no behavioral phenotype was observed, SSRI exposure in the perinatal period permanently alters cerebral receptor mRNA levels. We speculate these shifts in mRNA expression provide important compensation during SSRI exposure. Further pre-clinical and clinical investigation into additional serotonin-regulated phenotypes is necessary to further assess the long-term implications of perinatal SSRI exposure.

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“…It has been suggested that reduced serotonin function could be linked to cognitive disturbances in ALZ [34]. Disorders in cognition have been linked to 5HT2A receptors, particularly in the prefrontal cortex [35]. Tryptophan depletion studies found impairments in declarative episodic memory using a verbal learning task paradigm, and the impairments were larger in women than men [36].…”

Section: Introductionmentioning

confidence: 99%

How Studies of the Serotonin System in Macaque Models of Menopause Relate to Alzheimer’s Disease1

Bethea

Reddy

Christian

2017

JAD

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Serotonin plays a key role in mood or affect, and dysfunction of the serotonin system has been linked to depression in humans and animal models. Depression appears prior to or coincident with overt symptoms of Alzheimer’s (ALZ) disease in about 50% of patients, and some experts consider it a risk factor for the development of ALZ. In addition, ALZ is more prevalent in women, who also show increased incidence of depression. Indeed, it has been proposed that mechanisms underlying depression overlap the mechanisms thought to hasten ALZ. Women undergo ovarian failure and cessation of ovarian steroid production in middle age and the postmenopausal period correlates with an increase in the onset of depression and ALZ. This laboratory has examined the many actions of ovarian steroids in the serotonin system of non-human primates using a rhesus macaque model of surgical menopause with short or long-term estradiol (E) or estradiol plus progesterone (E+P) replacement therapy. In this mini-review, we present a brief synopsis of the relevant literature concerning ALZ, depression and serotonin. We also present some of our data on serotonin neuron viability, the involvement of the caspase-independent pathway and AIF in serotonin-neuron viability, as well as gene expression related to neurodegeneration and neuron viability in serotonin neurons from adult and aged surgical menopausal macaques. We show that ovarian steroids, particularly E, are crucial for serotonin neuron function and health. In the absence of E, serotonin neurons are endangered and deteriorating toward apoptosis. The possibility that this scenario may proceed or accompany ALZ in postmenopausal women seems likely.

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The 5-HT2A serotonin receptor in executive function: Implications for neuropsychiatric and neurodegenerative diseases

Cited by 72 publications

References 276 publications

Tryptophan depletion affects compulsive behaviour in rats: strain dependent effects and associated neuromechanisms

Tryptophan depletion affects compulsive behaviour in rats: strain dependent effects and associated neuromechanisms

Perinatal SSRI exposure permanently alters cerebral serotonin receptor mRNA in mice but does not impact adult behaviors

How Studies of the Serotonin System in Macaque Models of Menopause Relate to Alzheimer’s Disease1

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