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Title: An investigation of changes in NMDA-receptor evoked monoamine efflux following administration of antidepressant drugs : a microdialysis study in vivo
Author: Sadideen, Faddy
ISNI:       0000 0001 3544 5534
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2003
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It is widely accepted that the symptoms of depression are due, in part, to abnormal monoaminergic tone in the brain, primarily serotonin, noradrenaline and to a lesser extent dopamine. This constitutes the monoamine theory of depression. Antidepressants (ADs) work by increasing the extracellular concentration of monoamines at the synapse. Though, their mechanism is not fully understood, it has been suggested that chronic AD treatments can affect NMDA receptor function in the brain. Using in vivo microdialysis in freely moving rats, the effects of acute, 7-day subchronic and chronic doses of the ADs paroxetine and clomipramine treatment on the NMDA- evoked efflux of extracellular DA, 5-HT and their metabolites, DOPAC and 5-HIAA respectively in the frontal cortex were investigated. The duration of these effects after 48 hours and 14 days of drug cessation, and the effect of the co-administration of NMDA antagonists with paroxetine on monoamine levels and their metabolites was also investigated. Acute injection of paroxetine (10 and 20 mg/kg i.p.) did not affect dialysate DA or 5-HT content in the frontal cortex. Clomipramine at 10 and 20 mg/kg caused a decrease in extracellular DA without exerting any influence on dialysate 5-HT levels. Local infusion of 100μM NMDA into the frontal cortex decreased both extracellular DA and 5-HT levels in this region. 21 day treatment of rats with paroxetine and clomipramine increased 5-HT levels to 150% and 147% above basal levels respectively. The same treatment increased DA levels to 200% and 186% above basal levels. When NMDA infusion was preceded by a single injection of paroxetine/clomipramine no marked differences between NMDA and NMDA+paroxetine/clomipramine treated groups were observed. Subchronic (7-days) and chronic (21-days) treatment with paroxetine/clomipramine were able to abolish the NMDA-evoked decrease in dialysate DA and 5-HT levels. This effect lasted for a period of 48 hours but was abolished following a 14-day 'drug holiday'. This suggests that adaptive functional changes occur in NMDA receptor function during treatment with AD drugs. These results suggest that the NMDA receptor is subject to adaptive changes following chronic AD treatment. Interestingly, the co-administration of acute paroxetine with NMDA antagonists (amantadine, budipine, CGP 40116 and ifenprodil) causes an increase in extracellular 5-HT which may prove to have clinical implications.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available