Relevance of 5-HT2A Receptor Modulation of Pyramidal Cell Excitability for Dementia-Related Psychosis: Implications for Pharmacotherapy

Burstein, Ethan S.

doi:10.1007/s40263-021-00836-7

Cited by 9 publications

(3 citation statements)

References 144 publications

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“…For example, previous evidence have shown that female sex hormones modulate 5-HT1A receptors, which have been suggested as one of the explanations for higher prevalence of major depressive disorder in females [42]. In addition, previous studies have proposed that genetic variation in the serotonin receptor gene 5-HT2A is associated with the occurrence of hallucinations and delusions in patients with AD [43,44]. Also, loss of neuroprotective effects of estrogen, such as modulation of neurotransmitter synthesis, synaptic plasticity and mitochondrial activity, related to menopausal changes in women might play a role in differential manifestations of MBI symptoms [45].…”

Section: Discussionmentioning

confidence: 99%

Gender/Sex Differences in the Association of Mild Behavioral Impairment with Cognitive Aging

Wolfová

Creese

Aarsland

et al. 2022

JAD

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Background: While the gender/sex differences in neuropsychiatric symptoms in dementia population are well described, gender/sex differences in mild behavioral impairment (MBI) in dementia-free populations and the relationship to cognitive performance and to subsequent cognitive decline have not been studied. Objective: We aimed to explore gender/sex differences in the association of MBI with the level of cognitive performance and its rate of decline in a dementia-free cohort. Methods: We studied 8,181 older adults enrolled in the online PROTECT UK Study. MBI was assessed using the MBI Checklist and cognition was measured by digit span, paired associate learning, spatial working memory, and verbal reasoning. Statistical analysis was conducted using linear regression models and linear mixed-effects models. Results: Out of 8,181 individuals (median age 63 years, 73% females), 11% of females and 14% of males had MBI syndrome. Females exhibited less often symptoms of decreased motivation (45% versus 36% in males), impulse dyscontrol (40% versus 44% in males; p = 0.001) and social inappropriateness (12% versus 15% ; p < 0.001), while they showed more often symptoms of emotional dysregulation (45% versus 36% ; p < 0.001). The associations of MBI domains with some measures of cognitive performance and decline were stronger in males than females, with the exception of the association of emotional dysregulation with the rate of cognitive decline in verbal reasoning, which was present exclusively in females. Conclusion: MBI may influence cognition to a greater extent in males than in females. We propose that predictors and biomarkers of dementia should consider gender/sex as an effect modifier.

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Section: Discussionmentioning

confidence: 99%

Gender/Sex Differences in the Association of Mild Behavioral Impairment with Cognitive Aging

Wolfová

Creese

Aarsland

et al. 2022

JAD

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“…The results of present study demonstrate that NMDAR hypofunction in cortical PV-positive interneurons confers two contrasting altered 5-HT2AR responses to 5-HT, lack of response in Grin1 -deleted PV interneuron terminals and greater intrinsic excitability in the pyramidal neurons. Since up-regulation of 5-HT2ARs in pyramidal neurons has been proposed as a common neural mechanism that could predispose to psychosis [ 77 , 78 ], the Grin1 mutant mouse can be a suitable model for research into the pathophysiology of psychosis in schizophrenia and other types of psychotic disorders.…”

Section: Discussionmentioning

confidence: 99%

5-HT2A receptor dysregulation in a schizophrenia relevant mouse model of NMDA receptor hypofunction

et al. 2022

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Blockade of N-methyl-D-aspartate receptors (NMDAR) is known to augment cortical serotonin 2A receptors (5-HT2ARs), which is implicated in psychosis. However, the pathways from NMDAR hypofunction to 5-HT2AR up-regulation are unclear. Here we addressed in mice whether genetic deletion of the indispensable NMDAR-subunit Grin1 principally in corticolimbic parvalbumin-positive fast-spiking interneurons, could up-regulate 5-HT2ARs leading to cortical hyper-excitability. First, in vivo local-field potential recording revealed that auditory cortex in Grin1 mutant mice became hyper-excitable upon exposure to acoustic click-train stimuli that release 5-HT in the cortex. This excitability increase was reproduced ex vivo where it consisted of an increased frequency of action potential (AP) firing in layer 2/3 pyramidal neurons of mutant auditory cortex. Application of the 5-HT2AR agonist TCB-2 produced similar results. The effect of click-trains was reversed by the 5-HT2AR antagonist M100907 both in vivo and ex vivo. Increase in AP frequency of pyramidal neurons was also reversed by application of Gαq protein inhibitor BIM-46187 and G protein-gated inwardly-rectifying K+ (GIRK) channel activator ML297. In fast-spiking interneurons, 5-HT2AR activation normally promotes GABA release, contributing to decreased excitability of postsynaptic pyramidal neurons, which was missing in the mutants. Moreover, unlike the controls, the GABAA receptor antagonist (+)-bicuculline had little effect on AP frequency of mutant pyramidal neurons, indicating a disinhibition state. These results suggest that the auditory-induced hyper-excitable state is conferred via GABA release deficits from Grin1-lacking interneurons leading to 5-HT2AR dysregulation and GIRK channel suppression in cortical pyramidal neurons, which could be involved in auditory psychosis.

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“…It has been described several times how the function of serotonin system is important in the development of VH in different pathologies, such as schizophrenia [39], dementia [40], and PB [41]. Importantly, pimavanserin, a 5-HT 2A inverse agonist, was approved for treatment of psychosis including VH in PD patients [42,43], indicating the important role of the serotonergic system in the development of VH.…”

Section: Discussionmentioning

confidence: 99%

Serotonin-Related Functional Genetic Variants Affect the Occurrence of Psychiatric and Motor Adverse Events of Dopaminergic Treatment in Parkinson’s Disease: A Retrospective Cohort Study

Redenšek

Blagus

Trošt

et al. 2022

JPM

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The serotonergic system is important in Parkinson’s disease (PD) pathogenesis as it can take over dopamine production after a large portion of dopaminergic neurons is lost through neurodegeneration. The aim of this study was to evaluate the effect of genetic variability of serotonergic genes on the occurrence of motor complications and psychiatric adverse events (AE) due to dopaminergic treatment. We enrolled 231 patients and their clinical data were collected. Genotyping was performed for eight genetic variants. Logistic regression was used for analysis. Carriers of the HTR1A rs6295 GC genotype (OR = 2.58; 95% CI = 1.15–5.78; p = 0.021), TPH2 rs4290270 AA genotype (OR = 2.78; 95% CI = 1.08–7.03; p = 0.034), and at least one TPH2 rs4570625 T allele (OR = 1.86; 95% CI = 1.00–3.44; p = 0.047) had increased risk for visual hallucinations (VH). Additionally, carriers of at least one SLC6A4 5-HTTPLR rs25531 S (OR = 0.52; 95% CI = 0.28–0.96; p = 0.037) or at least one LG allele (OR = 0.37; 95% CI = 0.14–0.97; p = 0.044) had a decreased chance for VH. Constructed haplotypes of the TPH2 showed increased risk for VH (OR = 1.94; 95% CI = 1.06–3.55; p = 0.032) and impulse control disorders (OR = 5.20; 95% CI = 1.86–14.50; p = 0.002). Finally, individual gene–gene interactions showed decreased odds for the development of motor AE. Our findings suggest that the serotonergic pathway may play an important role in the development of AE resulting from dopaminergic treatment.

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Relevance of 5-HT2A Receptor Modulation of Pyramidal Cell Excitability for Dementia-Related Psychosis: Implications for Pharmacotherapy

Cited by 9 publications

References 144 publications

Gender/Sex Differences in the Association of Mild Behavioral Impairment with Cognitive Aging

Gender/Sex Differences in the Association of Mild Behavioral Impairment with Cognitive Aging

5-HT2A receptor dysregulation in a schizophrenia relevant mouse model of NMDA receptor hypofunction

Serotonin-Related Functional Genetic Variants Affect the Occurrence of Psychiatric and Motor Adverse Events of Dopaminergic Treatment in Parkinson’s Disease: A Retrospective Cohort Study

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