scholarly journals Putative role of pharmacogenetics to elucidate the mechanism of tardive dyskinesia in schizophrenia

2019 ◽  
Vol 20 (17) ◽  
pp. 1199-1223 ◽  
Author(s):  
Anton JM Loonen ◽  
Bob Wilffert ◽  
Svetlana A Ivanova
Keyword(s):  
Oxidative Stress ◽  
Tardive Dyskinesia ◽  
Genetic Variants ◽  
Long Term Potentiation ◽  
Specific Gene ◽  
Medium Spiny Neurons ◽  
Spiny Neurons ◽  
Long Term Treatment

Identifying biomarkers which can be used as a diagnostic tool is a major objective of pharmacogenetic studies. Most mental and many neurological disorders have a compiled multifaceted nature, which may be the reason why this endeavor has hitherto not been very successful. This is also true for tardive dyskinesia (TD), an involuntary movement complication of long-term treatment with antipsychotic drugs. The observed associations of specific gene variants with the prevalence and severity of a disorder can also be applied to try to elucidate the pathogenesis of the condition. In this paper, this strategy is used by combining pharmacogenetic knowledge with theories on the possible role of a dysfunction of specific cellular elements of neostriatal parts of the (dorsal) extrapyramidal circuits: various glutamatergic terminals, medium spiny neurons, striatal interneurons and ascending monoaminergic fibers. A peculiar finding is that genetic variants which would be expected to increase the neostriatal dopamine concentration are not associated with the prevalence and severity of TD. Moreover, modifying the sensitivity to glutamatergic long-term potentiation (and excitotoxicity) shows a relationship with levodopa-induced dyskinesia, but not with TD. Contrasting this, TD is associated with genetic variants that modify vulnerability to oxidative stress. Reducing the oxidative stress burden of medium spiny neurons may also be the mechanism behind the protective influence of 5-HT2 receptor antagonists. It is probably worthwhile to discriminate between neostriatal matrix and striosomal compartments when studying the mechanism of TD and between orofacial and limb-truncal components in epidemiological studies.

New insights into the mechanism of drug-induced dyskinesia

CNS Spectrums ◽  
2012 ◽  
Vol 18 (1) ◽  
pp. 15-20 ◽  
Author(s):  
Anton J. M. Loonen ◽  
Svetlana A. Ivanova
Keyword(s):  
Antipsychotic Drugs ◽  
Term Treatment ◽  
Medium Spiny Neurons ◽  
Indirect Pathway ◽  
Drug Induced ◽  
Disease Research ◽  
Spiny Neurons ◽  
Long Term Treatment ◽  
Cortical Circuit

Dyskinesia is an extrapyramidal movement disorder characterized by involuntary, repetitive, irregular motions that affect the mouth and face and/or the limbs and trunk. Tardive dyskinesia (TD) is a well-known complication of long-term treatment with antipsychotic drugs. Dyskinesia is also induced with levodopa, a treatment for Parkinson's disease, and it occurs spontaneously as a symptom of Huntington's disease. Research on the pathogenesis of TD has focused on a dysfunction of either the dopaminergic or serotonergic system. However, recent evidence has suggested that we should focus on the possible damage of GABAergic medium spiny neurons (MSNs). MSNs are the first station in the cortico-striato-thalamo-cortical circuit that regulates the amplitude and velocity of movements. Two pathways can be distinguished in this circuit: a direct pathway, which increases movements (hyperkinesia), and an indirect pathway, which decreases movements (hypokinesia). Both pathways are activated by glutamatergic corticostriatal neurons. Here, we discuss some evidence that supports the hypothesis that indirect pathway MSNs are damaged in dyskinesia.

scholarly journals Internal sensation of pleasure can be explained as a specific conformation of semblance: Inference from electrophysiological findings

2019 ◽  
Author(s):  
Kunjumon Vadakkan
Keyword(s):  
Long Term Potentiation ◽  
Medium Spiny Neurons ◽  
Functional Link ◽  
Spiny Neurons ◽  
Term Potentiation ◽  
Reduced Ring ◽  
Electrophysiological Findings ◽  
Motor Actions ◽  
Internal Sensation

Semblance hypothesis was able to find a solution for the generation of first- person internal sensation of memory along with provisions for behavioral motor actions. The derived inter-postsynaptic functional LINK (IPL) mechanism was able to explain a large number of findings from different levels of the system ranging from perception to sleep. It was possible to explain long-term potentiation (LTP) as the effect of experimental scaling-up of the changes occurring during natural learning. By keeping the latter relationship as a baseline, it was possible to explain long-term depression (LTD) observed in the nucleus accumbens (NAc), a scaled-up change of a mechanism responsible for inducing internal sensation of pleasure. This mechanism provides inter-connectable explanations for the attenuation of postsynaptic potentials, reduced ring of medium spiny neurons and the finding that LTD induced by stimulation of one pathway to NAc occludes the LTD induction by another pathway.

Neuronal degeneration and oxidative stress in the SNc of 6-OHDA intoxicated rats; improving role of silymarin long-term treatment

2020 ◽  
Vol 393 (12) ◽  
pp. 2427-2437 ◽  
Author(s):  
Rasool Haddadi ◽  
Shahla Eyvari-Brooshghalan ◽  
Alireza Mohajjel Nayebi ◽  
Mohammadmahdi Sabahi ◽  
Sara Ami Ahmadi
Keyword(s):  
Oxidative Stress ◽  
Neuronal Degeneration ◽  
Term Treatment ◽  
Long Term Treatment ◽  
And Oxidative Stress

scholarly journals Accumbens D2-MSN hyperactivity drives behavioral supersensitivity

2020 ◽  
Author(s):  
Anna Kruyer ◽  
Jeffrey Parilla-Carerro ◽  
Courtney Powell ◽  
Lasse Brandt ◽  
Stefan Gutwinski ◽  
...  
Keyword(s):  
D2 Receptor ◽  
Treatment Resistance ◽  
Term Treatment ◽  
Antipsychotic Treatment ◽  
Medium Spiny Neurons ◽  
Therapeutic Approaches ◽  
Spiny Neurons ◽  
Long Term Treatment ◽  
Underlying Mechanisms

ABSTRACTAntipsychotic-induced behavioral supersensitivity is a problematic consequence of long-term treatment with antipsychotic drugs and is characterized by emergence of refractory symptoms and dyskinesias. The underlying mechanisms are unknown, and no rational approaches exist to prevent or reverse antipsychotic-induced supersensitivity. Here we describe major adaptations impacting populations of striatal medium spiny neurons (MSNs) during the development of behavioral supersensitivity and reveal a prominent role played by D2 receptor expressing MSNs. We show that enhanced D2-MSN activity underlies several symptoms spanning from psychostimulant sensitization, to antipsychotic treatment resistance and drug addiction. Our data warn against severe adverse events following antipsychotic treatment discontinuation and offer insight that may inform therapeutic approaches to overcome antipsychotic-induced supersensitivity.

scholarly journals Internal sensation of pleasure can be explained as a specific conformation of semblance: Inference from electrophysiological findings

2019 ◽  
Author(s):  
Kunjumon Vadakkan
Keyword(s):  
Long Term Potentiation ◽  
Medium Spiny Neurons ◽  
Functional Link ◽  
Spiny Neurons ◽  
Term Potentiation ◽  
Reduced Ring ◽  
Electrophysiological Findings ◽  
Motor Actions ◽  
Internal Sensation

Semblance hypothesis was able to find a solution for the generation of first- person internal sensation of memory along with provisions for behavioral motor actions. The derived inter-postsynaptic functional LINK (IPL) mechanism was able to explain a large number of findings from different levels of the system ranging from perception to sleep. It was possible to explain long-term potentiation (LTP) as the effect of experimental scaling-up of the changes occurring during natural learning. By keeping the latter relationship as a baseline, it was possible to explain long-term depression (LTD) observed in the nucleus accumbens (NAc), a scaled-up change of a mechanism responsible for inducing internal sensation of pleasure. This mechanism provides inter-connectable explanations for the attenuation of postsynaptic potentials, reduced ring of medium spiny neurons and the finding that LTD induced by stimulation of one pathway to NAc occludes the LTD induction by another pathway.

Cognitive Treatment for OCD

2012 ◽  
Author(s):  
Maureen L. Whittal ◽  
Melisa Robichaud
Keyword(s):  
Term Treatment ◽  
Future Directions ◽  
Cognitive Treatment ◽  
Long Term Treatment ◽  
Inflated Responsibility ◽  
And Control ◽  
The Relationship ◽  
Control Of Thoughts

The cornerstone of cognitive treatment (CT) for OCD is based upon the knowledge that unwanted intrusions are essentially a universal experience. As such, it is not the presence of the intrusion that is problematic but rather the associated meaning or interpretation. Treatment is flexible, depending upon the nature of the appraisals and beliefs, but can include strategies focused on inflated responsibility and overestimation of threat, importance and control of thoughts, and the need for perfectionism and certainty. The role of concealment and the relationship to personal values are important maintaining and etiological factors. The short-term and long-term treatment outcome is reviewed, along with predictors of treatment response and mechanisms of action, and the chapter concludes with future directions regarding CT for OCD.

The role of PKMζ in the maintenance of long-term memory: a review

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Hamish Patel ◽  
Reza Zamani
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Long Term Potentiation ◽  
Global Memory ◽  
Long Term Memory ◽  
Compensatory Mechanism ◽  
Term Memory ◽  
Kinase C

Abstract Long-term memories are thought to be stored in neurones and synapses that undergo physical changes, such as long-term potentiation (LTP), and these changes can be maintained for long periods of time. A candidate enzyme for the maintenance of LTP is protein kinase M zeta (PKMζ), a constitutively active protein kinase C isoform that is elevated during LTP and long-term memory maintenance. This paper reviews the evidence and controversies surrounding the role of PKMζ in the maintenance of long-term memory. PKMζ maintains synaptic potentiation by preventing AMPA receptor endocytosis and promoting stabilisation of dendritic spine growth. Inhibition of PKMζ, with zeta-inhibitory peptide (ZIP), can reverse LTP and impair established long-term memories. However, a deficit of memory retrieval cannot be ruled out. Furthermore, ZIP, and in high enough doses the control peptide scrambled ZIP, was recently shown to be neurotoxic, which may explain some of the effects of ZIP on memory impairment. PKMζ knockout mice show normal learning and memory. However, this is likely due to compensation by protein-kinase C iota/lambda (PKCι/λ), which is normally responsible for induction of LTP. It is not clear how, or if, this compensatory mechanism is activated under normal conditions. Future research should utilise inducible PKMζ knockdown in adult rodents to investigate whether PKMζ maintains memory in specific parts of the brain, or if it represents a global memory maintenance molecule. These insights may inform future therapeutic targets for disorders of memory loss.

scholarly journals Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing

2021 ◽  
Author(s):  
Sujeong Yang ◽  
Sylvain Gigout ◽  
Angelo Molinaro ◽  
Yuko Naito-Matsui ◽  
Sam Hilton ◽  
...  
Keyword(s):  
Chondroitin Sulphate ◽  
Memory Loss ◽  
Memory Deficits ◽  
Long Term Potentiation ◽  
Aged Mice ◽  
Age Related ◽  
Term Potentiation ◽  
Early Memory

AbstractPerineuronal nets (PNNs) are chondroitin sulphate proteoglycan-containing structures on the neuronal surface that have been implicated in the control of neuroplasticity and memory. Age-related reduction of chondroitin 6-sulphates (C6S) leads to PNNs becoming more inhibitory. Here, we investigated whether manipulation of the chondroitin sulphate (CS) composition of the PNNs could restore neuroplasticity and alleviate memory deficits in aged mice. We first confirmed that aged mice (20-months) showed memory and plasticity deficits. They were able to retain or regain their cognitive ability when CSs were digested or PNNs were attenuated. We then explored the role of C6S in memory and neuroplasticity. Transgenic deletion of chondroitin 6-sulfotransferase (chst3) led to a reduction of permissive C6S, simulating aged brains. These animals showed very early memory loss at 11 weeks old. Importantly, restoring C6S levels in aged animals rescued the memory deficits and restored cortical long-term potentiation, suggesting a strategy to improve age-related memory impairment.

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