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Likelihood of mechanistic roles for dopaminergic, serotonergic and glutamatergic receptors in tardive dyskinesia: A comparison of genetic variants in two independent patient populations.

Ivanova SA, Loonen AJ, Bakker PR, Freidin MB, Ter Woerds NJ, Al Hadithy AF, Semke AV, Fedorenko OY, Brouwers JR, Bokhan NA, van Os J, van Harten PN, Wilffert B - SAGE Open Med (2016)

Bottom Line: These patients were genotyped for 43 tag single nucleotide polymorphisms in five neurotransmitter receptor genes, and the results for the two populations were compared.Several significant associations with tardive dyskinesia were identified, but only GRIN2A (rs1345423) was found in both patient populations.This lack of agreement was probably due to the small effect size of the associations, the multiple testing and the small sample size of the Dutch patient population.

View Article: PubMed Central - PubMed

Affiliation: Mental Health Research Institute, Tomsk, Russian Federation; National Research Tomsk Polytechnic University, Tomsk, Russian Federation.

ABSTRACT

Objectives: An established theory for the pathogenesis of tardive dyskinesia is disturbed dopaminergic receptor sensitivity and/or dopaminergic intracellular signaling. We examined associations between genetic variants of neurotransmitter receptors and tardive dyskinesia.

Methods: We assessed tardive dyskinesia in Caucasian psychiatric inpatients from Siberia (N = 431) and a long-stay population from the Netherlands (N = 168). These patients were genotyped for 43 tag single nucleotide polymorphisms in five neurotransmitter receptor genes, and the results for the two populations were compared.

Results: Several significant associations with tardive dyskinesia were identified, but only GRIN2A (rs1345423) was found in both patient populations. This lack of agreement was probably due to the small effect size of the associations, the multiple testing and the small sample size of the Dutch patient population. After reviewing the literature, we propose that the constitutive stimulatory activity of serotonergic type 2 receptors may be relevant.

Conclusions: Inactivity of the serotonergic, type 2C receptor or blockade of these receptors by atypical antipsychotic drugs may decrease the vulnerability to develop tardive dyskinesia.

No MeSH data available.


Related in: MedlinePlus

Model for the distribution of 5-HT2A and 5-HT2C receptors in the midbrain, striatum, and prefrontal cortex.Note: Blue: GABAergic, MSNs or fast-spiking interneurons; grey: dopaminergic neuron; purple: serotonergic interneuron; red: glutamatergic cortico-striatal neuron; and tan: striatal cholinergic interneuron. The model explains the clinical differences when 5-HT2C receptors show far more constitutive activity than 5-HT2A receptors (colour figure in DOI: 10.1177/2050312116643673).
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fig2-2050312116643673: Model for the distribution of 5-HT2A and 5-HT2C receptors in the midbrain, striatum, and prefrontal cortex.Note: Blue: GABAergic, MSNs or fast-spiking interneurons; grey: dopaminergic neuron; purple: serotonergic interneuron; red: glutamatergic cortico-striatal neuron; and tan: striatal cholinergic interneuron. The model explains the clinical differences when 5-HT2C receptors show far more constitutive activity than 5-HT2A receptors (colour figure in DOI: 10.1177/2050312116643673).

Mentions: To understand how blockade of 5-HT2A/2C receptors results in less Parkinsonism and TD, the neuronal localization of these receptors should be considered (Figure 2).49 The 5-HT2A/2C receptors not only activate GABAergic interneurons within the midbrain, striatum, and prefrontal cortex, but also stimulate MSNs within the striatum.49 Blockade in the midbrain results in DA release, but blocking the striatum directly inhibit MSNs.49 This inhibition may protect these MSNs from neurotoxicity induced by oxidative stress caused by oxidative metabolism of the excess DA.2


Likelihood of mechanistic roles for dopaminergic, serotonergic and glutamatergic receptors in tardive dyskinesia: A comparison of genetic variants in two independent patient populations.

Ivanova SA, Loonen AJ, Bakker PR, Freidin MB, Ter Woerds NJ, Al Hadithy AF, Semke AV, Fedorenko OY, Brouwers JR, Bokhan NA, van Os J, van Harten PN, Wilffert B - SAGE Open Med (2016)

Model for the distribution of 5-HT2A and 5-HT2C receptors in the midbrain, striatum, and prefrontal cortex.Note: Blue: GABAergic, MSNs or fast-spiking interneurons; grey: dopaminergic neuron; purple: serotonergic interneuron; red: glutamatergic cortico-striatal neuron; and tan: striatal cholinergic interneuron. The model explains the clinical differences when 5-HT2C receptors show far more constitutive activity than 5-HT2A receptors (colour figure in DOI: 10.1177/2050312116643673).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2 - License 3
Show All Figures
getmorefigures.php?uid=PMC4834466&req=5

fig2-2050312116643673: Model for the distribution of 5-HT2A and 5-HT2C receptors in the midbrain, striatum, and prefrontal cortex.Note: Blue: GABAergic, MSNs or fast-spiking interneurons; grey: dopaminergic neuron; purple: serotonergic interneuron; red: glutamatergic cortico-striatal neuron; and tan: striatal cholinergic interneuron. The model explains the clinical differences when 5-HT2C receptors show far more constitutive activity than 5-HT2A receptors (colour figure in DOI: 10.1177/2050312116643673).
Mentions: To understand how blockade of 5-HT2A/2C receptors results in less Parkinsonism and TD, the neuronal localization of these receptors should be considered (Figure 2).49 The 5-HT2A/2C receptors not only activate GABAergic interneurons within the midbrain, striatum, and prefrontal cortex, but also stimulate MSNs within the striatum.49 Blockade in the midbrain results in DA release, but blocking the striatum directly inhibit MSNs.49 This inhibition may protect these MSNs from neurotoxicity induced by oxidative stress caused by oxidative metabolism of the excess DA.2

Bottom Line: These patients were genotyped for 43 tag single nucleotide polymorphisms in five neurotransmitter receptor genes, and the results for the two populations were compared.Several significant associations with tardive dyskinesia were identified, but only GRIN2A (rs1345423) was found in both patient populations.This lack of agreement was probably due to the small effect size of the associations, the multiple testing and the small sample size of the Dutch patient population.

View Article: PubMed Central - PubMed

Affiliation: Mental Health Research Institute, Tomsk, Russian Federation; National Research Tomsk Polytechnic University, Tomsk, Russian Federation.

ABSTRACT

Objectives: An established theory for the pathogenesis of tardive dyskinesia is disturbed dopaminergic receptor sensitivity and/or dopaminergic intracellular signaling. We examined associations between genetic variants of neurotransmitter receptors and tardive dyskinesia.

Methods: We assessed tardive dyskinesia in Caucasian psychiatric inpatients from Siberia (N = 431) and a long-stay population from the Netherlands (N = 168). These patients were genotyped for 43 tag single nucleotide polymorphisms in five neurotransmitter receptor genes, and the results for the two populations were compared.

Results: Several significant associations with tardive dyskinesia were identified, but only GRIN2A (rs1345423) was found in both patient populations. This lack of agreement was probably due to the small effect size of the associations, the multiple testing and the small sample size of the Dutch patient population. After reviewing the literature, we propose that the constitutive stimulatory activity of serotonergic type 2 receptors may be relevant.

Conclusions: Inactivity of the serotonergic, type 2C receptor or blockade of these receptors by atypical antipsychotic drugs may decrease the vulnerability to develop tardive dyskinesia.

No MeSH data available.


Related in: MedlinePlus