An investigation into the interaction of dopamine and glutamate in behaviours relevant to schizophrenia
<p>Aberrant dopaminergic activity is widely believed to underlie at least some of the symptoms seen in schizophrenia. This belief is partly based on all currently used antipsychotics antagonising the dopaminergic D2 receptor. However, there is less agreement on what causes this aberrant dopami...
| Main Author: | |
|---|---|
| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2016
|
| Subjects: |
| _version_ | 1797107729231249408 |
|---|---|
| author | Boerner, T |
| author2 | Bannerman, D |
| author_facet | Bannerman, D Boerner, T |
| author_sort | Boerner, T |
| collection | OXFORD |
| description | <p>Aberrant dopaminergic activity is widely believed to underlie at least some of the symptoms seen in schizophrenia. This belief is partly based on all currently used antipsychotics antagonising the dopaminergic D2 receptor. However, there is less agreement on what causes this aberrant dopamine activity. One candidate is a glutamatergic change upstream of the dopamine system. I investigated this glutamate theory of schizophrenia by examining the effect of glutamatergic manipulations on the dopamine system during behaviours relevant to schizophrenia in rodents.</p>
<p>One of these manipulations consisted of systemic injections of the putative antipsychotic LY354740, a group II metabotropic glutamate receptor agonist. This revealed that the effect of LY354740 on the dopamine system was apparently dependent on the internal state of the animal. Even though it is proposed as a putative antipsychotic, LY354740 could actually enhance phasic dopamine responses to reward in the nucleus accumbens core as measured by fast-scan cyclic voltammetry (FCV). Furthermore, at least under some circumstances, LY354740 appeared to exacerbate behavioural effects of amphetamine. </p>
<p>The second manipulation of the glutamate system consisted of a knockout of the GluA1 glutamatergic AMPA-receptor subunit in mice. These GluA1 KO mice displayed deficits in short-term memory and hyperactivity which may reflect an aberrant salience phenotype which could be relevant to schizophrenia. The group II metabotropic glutamate receptor agonist, LY354740, could ameliorate the hyperactivity but failed to rescue the cognitive, short-term memory deficits in a test of spatial working memory. </p>
<p>The phenotype of GluA1 KO mice was further investigated using FCV in tasks relevant to schizophrenia. These experiments showed that GluA1 KO mice exhibited a hyperdopaminergic phenotype. They had increased phasic dopamine responses to neutral stimuli which were slower to habituate. They also exhibited increased dopamine signals to reward delivery in an instrumental conditioning task. In a simple Pavlovian conditioning task, however, they did not show increased phasic dopamine responses.</p>
<p>In summary, two very different glutamatergic interventions relevant to schizophrenia could, under certain circumstances, increase phasic dopamine responses in tasks relevant to schizophrenia. This gives additional evidence for a role of glutamate in schizophrenia.</p> |
| first_indexed | 2024-03-07T07:18:44Z |
| format | Thesis |
| id | oxford-uuid:aaa49032-7f15-4bac-b779-b3970e9ba455 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:18:44Z |
| publishDate | 2016 |
| record_format | dspace |
| spelling | oxford-uuid:aaa49032-7f15-4bac-b779-b3970e9ba4552022-09-14T11:38:47ZAn investigation into the interaction of dopamine and glutamate in behaviours relevant to schizophreniaThesishttp://purl.org/coar/resource_type/c_db06uuid:aaa49032-7f15-4bac-b779-b3970e9ba455Behavioural NeuroscienceNeuropsychopharmacologyEnglishHyrax Deposit2016Boerner, TBannerman, DWalton, MHarrison, P<p>Aberrant dopaminergic activity is widely believed to underlie at least some of the symptoms seen in schizophrenia. This belief is partly based on all currently used antipsychotics antagonising the dopaminergic D2 receptor. However, there is less agreement on what causes this aberrant dopamine activity. One candidate is a glutamatergic change upstream of the dopamine system. I investigated this glutamate theory of schizophrenia by examining the effect of glutamatergic manipulations on the dopamine system during behaviours relevant to schizophrenia in rodents.</p> <p>One of these manipulations consisted of systemic injections of the putative antipsychotic LY354740, a group II metabotropic glutamate receptor agonist. This revealed that the effect of LY354740 on the dopamine system was apparently dependent on the internal state of the animal. Even though it is proposed as a putative antipsychotic, LY354740 could actually enhance phasic dopamine responses to reward in the nucleus accumbens core as measured by fast-scan cyclic voltammetry (FCV). Furthermore, at least under some circumstances, LY354740 appeared to exacerbate behavioural effects of amphetamine. </p> <p>The second manipulation of the glutamate system consisted of a knockout of the GluA1 glutamatergic AMPA-receptor subunit in mice. These GluA1 KO mice displayed deficits in short-term memory and hyperactivity which may reflect an aberrant salience phenotype which could be relevant to schizophrenia. The group II metabotropic glutamate receptor agonist, LY354740, could ameliorate the hyperactivity but failed to rescue the cognitive, short-term memory deficits in a test of spatial working memory. </p> <p>The phenotype of GluA1 KO mice was further investigated using FCV in tasks relevant to schizophrenia. These experiments showed that GluA1 KO mice exhibited a hyperdopaminergic phenotype. They had increased phasic dopamine responses to neutral stimuli which were slower to habituate. They also exhibited increased dopamine signals to reward delivery in an instrumental conditioning task. In a simple Pavlovian conditioning task, however, they did not show increased phasic dopamine responses.</p> <p>In summary, two very different glutamatergic interventions relevant to schizophrenia could, under certain circumstances, increase phasic dopamine responses in tasks relevant to schizophrenia. This gives additional evidence for a role of glutamate in schizophrenia.</p> |
| spellingShingle | Behavioural Neuroscience Neuropsychopharmacology Boerner, T An investigation into the interaction of dopamine and glutamate in behaviours relevant to schizophrenia |
| title | An investigation into the interaction of dopamine and glutamate in behaviours relevant to schizophrenia |
| title_full | An investigation into the interaction of dopamine and glutamate in behaviours relevant to schizophrenia |
| title_fullStr | An investigation into the interaction of dopamine and glutamate in behaviours relevant to schizophrenia |
| title_full_unstemmed | An investigation into the interaction of dopamine and glutamate in behaviours relevant to schizophrenia |
| title_short | An investigation into the interaction of dopamine and glutamate in behaviours relevant to schizophrenia |
| title_sort | investigation into the interaction of dopamine and glutamate in behaviours relevant to schizophrenia |
| topic | Behavioural Neuroscience Neuropsychopharmacology |
| work_keys_str_mv | AT boernert aninvestigationintotheinteractionofdopamineandglutamateinbehavioursrelevanttoschizophrenia AT boernert investigationintotheinteractionofdopamineandglutamateinbehavioursrelevanttoschizophrenia |