Smith, Jenny Claire Elizabeth; (2001) Effects of drugs which alter nmda receptor function on in vivo neurochemical changes following acute and repeated antidepressant drug treatment in the freely moving rat. Doctoral thesis (Ph.D.), University College London.

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Abstract

It has been suggested that the psychiatric disorder of depression is functionally associated with insufficient synaptic serotonin, noradrenaline and to a lesser extent dopamine. However, this alone does not seem to explain the mechanisms involved in depression, especially as all current antidepressants must be taken chronically for the clinical effects to be observed. The levels of the monoamines are seen to change earlier than this suggesting that some form of adaptation must be occurring before the antidepressant effect is observed. More recently it has been suggested that a dysfunction of N-methyl-D-aspartate (NMDA)-glutamatergic receptors may play an important role. Using in vivo microdialysis in freely moving male rats, the effects of drugs that alter NMDA receptor function were studied following acute and repeated dosing of antidepressant drugs. Clomipramine, a relatively selective serotonin reuptake inhibitor, was used as an example of a classical antidepressant in clinical use today. Reboxetine, a drug that is believed to exert its antidepressant activity through its selective noradrenaline reuptake inhibitory action, was used as an example of a novel antidepressant. Levels of serotonin (5-HT), dopamine (DA), noradrenaline (NA), and glutamate (GLU) were measured in the raphé nuclei and frontal cortex - these two regions are believed to be involved in depression and low levels of these monoamines in the frontal cortex are usually indicative of the disorder. Interestingly only one class of antagonist given in combination with either antidepressant was observed to increase frontal cortex monoamines after both acute and sub-chronic dosing. Amantadine is a weakly selective ion channel blocker that is used in the treatment of Parkinson's disease and has already been shown to exhibit antidepressant properties in these patients. The combination of reboxetine and amantadine results in frontal cortex levels of 5-HT and DA after 4 days of treatment equivalent to those observed after 14 days of reboxetine alone. It is therefore suggested that the combination of an antidepressant drug with this particular class of NMDA receptor antagonist may prove to be more effective than an antidepressant alone due to its ability to reduce the latent period seen with current antidepressant treatment.

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