University of Leicester
Browse

Mechanisms Underlying Neurochemical Changes After Sub-Chronic Phencyclidine Treatment: Clues To The Neuropathology Of Schizophrenia

Download (9.44 MB)
thesis
posted on 2018-11-14, 10:51 authored by Ersin Yavas
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 non-pre-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 blood-oxygen-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 pre-treatment. 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.

History

Alternative title

Mechanisms Underlying Changes After Sub-Chronic PCP Treatment: Clues To Schizophrenia

Supervisor(s)

Young, Andrew

Date of award

2018-10-26

Author affiliation

Department of Neuroscience, Psychology and Behaviour

Awarding institution

University of Leicester

Qualification level

  • Doctoral

Qualification name

  • PhD

Language

en

Usage metrics

    University of Leicester Theses

    Categories

    No categories selected

    Keywords

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC