Mechanisms underlying changes aftersub-chronic pcp treatment: Clues toschizophrenia
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- Tez No: 716856
- Danışmanlar: Belirtilmemiş.
- Tez Türü: Doktora
- Konular: Psikoloji, Psychology
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2018
- Dil: İngilizce
- Üniversite: University of Leicester
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Belirtilmemiş.
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 331
Özet
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Özet (Çeviri)
Dopamine is one of the major neurotransmitters in the mammalian brain and changes in its concentration have been associated with schizophrenia. However, dopamine dysfunction alone cannot account for the genesis of schizophrenia. One unifying theory suggests that there is a disruption of the glutamate-dopamine balance such that glutamate has an effect of increasing dopamine release. Conversely, several studies have reported that the excitatory actions of ionotropic glutamate receptor neurotransmission play an important role in regulating extracellular dopamine levels in the striatum. To understand the potential role of glutamatergic mechanisms in schizophrenia, phencyclidine (PCP), a non-competitive N-methyl-D-aspartic acid receptor (NMDAR) antagonist which models aspects of schizophrenia, was used in the current study. In addition to glutamate, acetyl choline neurotransmission, which is known to modulate dopamine release, also changes after PCP pre-treatment. However, the extent to which PCP modulates cholinergic systems and how such modulation contributes to PCP's psychotomimetic effects are not fully understood. The current study showed that the mechanism of action of PCP involves NMDAR and nicotinic acetyl choline receptor (nAChR) modulation of dopamine function, specifically in the nucleus accumbens shell. The effects of NMDAR and nAChR activation on dopamine release in the nucleus accumbens were assessed using fast scan cyclic voltammetry (FSCV) in brain slices from rats sub-chronically pre-treated with PCP, an animal model of schizophrenia. NMDA increased basal dopamine release in both pre-treated and nonpre-treated striatal slices, but there was no consistent change in potassium-evoked dopamine release. Moreover, NMDA attenuated electrically stimulated dopamine release, a change which was reversed by metabotropic glutamate receptors 2 and 3 (mGluR2/3) antagonism. This suggests that NMDA augments glutamate release via activation of NMDAR on dopaminergic axon terminals, an effect which is dependent on mGluR 2/3 receptors, and that activation of NMDARs, in turn, increases electrically stimulated dopamine release. The nAChR agonist nicotine and the antagonist dihydro-β-erythroidine hydrobromide (DHβE) both modulated dopamine release in brain slices as well. In addition to studies in brain slice preparations, the effects of PCP on cholinergic and dopaminergic mechanisms were assessed through bloodoxygen-level dependent (BOLD) contrast using pharmacological magnetic resonance imaging (phMRI). Specifically, changes in brain-wide BOLD responses to nicotine and amphetamine administration were assessed before and after either saline or PCP pre-treatment. The results indicated that cholinergic and dopaminergic mechanisms were disrupted by PCP treatment. However, resting state MRI showed that brain resting-state functional connectivity was not altered by PCP pre-treatment. Thus, both in vitro and in vivo experiments suggest that cholinergic systems in nucleus accumbens were partially interrupted by subchronic PCP pretreatment. Therefore, future studies of the role of dopamine and glutamate in schizophrenia should consider the modulatory role of cholinergic systems. Together, these studies suggest that the cholinergic system in nucleus accumbens may serve as an important therapeutic target for treatment of schizophrenia.
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