Depressive disorders are among the most frequent psychiatric diseases in the Western world
with prevalence between 9% and 18%. Poor compliance and inappropriate antidepressant
discontinuation invokes long-term morbidity, and appear linked to hippocampal shrinkage.
Despite major advances in pharmacological treatment of the illness over the past 3040 years,
currently available agents have distinct shortfalls both in clinical efficacy and in maintenance of
response. This implies a greater long-term morbidity with significant impact on the patient, the
patient's family as well as economic implications to health care managers and providers. The
major reason for this state of affairs is our poor understanding of the neurobiology of depression
and hence, of antidepressant (AD) action. AD drugs are thus not addressing the crucial
neurobiological target underlying the illness, and new strategies and treatments are urgently
needed. In recent years, depression has been associated with disturbances in excitotoxic
glutamatergic activity, yet this has not been systematically evaluated.
While the role of neurotransmitters such as serotonin, noradrenaline and dopamine has been
extensively studied, new evidence suggests a role for the unique neurotransmitter nitric oxide
(NO). Nitric oxide (NO), is activated by glutamatergic systems in various limbic and other
regions of the brain, and has recently also been implicated in anxiety and affective disorders. Of
special interest is the putative role of NO in cellular memory, synaptic plasticity and cell survival,
all-important processes in the neuropathology and neurodevelopment of depression.
Recent clinical studies have provided evidence of the role of the NO-pathway in depression,
while preclinical studies have demonstrated the anxiolytic and antidepressant actions of nitric
oxide synthase (NOS)-inhibitors. Moreover, NO interacts with other classical transmitters that
have a regulatory role on mood, particularly the monoamines, as well as glutamate and gammaaminobutyric
acid (GABA).
In the current study the role of the NO-cGMP pathway in AD action was investigated, after
chronic imipramine (IMI) and after IMI withdrawal, using a learned helplessness paradigm.
Behavioural changes, hippocampal NOS activity and cGMP accumulation was determined
together with pharmacological manipulation of the NO-cGMP pathway.
Chronic IMI, 15 mg/kg/day intraperitoneal (ip) administration induced a pronounced reduction in
swim immobility time in the forced swim test (FST), with no effect on horizontal or vertical
locomotor activity. These behavioural changes were accompanied by a significant reduction in
NOS enzyme activity and cGMP accumulation. In order to confirm the involvement of the NO-cGMP
pathway in the AD action of IMI, chronic (3 weeks) IMI treatment was followed by an
acute withdrawal of 7 days. Acute withdrawal, after chronic IMI treatment, resulted in a
significant increase in swim immobility time and an increase in NOS enzyme activity and cGMP
levels. In fact, NOS activity was raised above that of control, not just higher than the effect of
chronic IMI.
In order to assess the possible role of the NMDA-NO-cGMP pathway in AD withdrawal, the
NMDA receptor antagonist, memantine, and the NOS/guanylyl cyclase (GC) inhibitor,
methylene blue (MB), were administered during the 7 day IMI withdrawal period.
Memantine (5 mg/kg/d ip), during the 7 day IMI withdrawal period, significantly reversed the
increase in immobility time evoked after IMI withdrawal. This was accompanied by a significant
reduction in NOS enzyme activity and a tendency to decrease cGMP levels. This data confirms
that the antidepressant action of IMI, as well as IMI withdrawal, is associated with actions on the
NMDA-GIu-NO-cGMP pathway. Particularly. IMI withdrawal evokes an increase in glutamate
activity that is responsible for NOS activation.
During the 7 day IMI withdrawal period, MB (15 mg/kg/d ip) also significantly reversed the
increased immobility time after IMI withdrawal and was accompanied by a tendency to decrease
NOS enzyme activity and cGMP levels in the rat hippocampus, however statistical significance
was not reached. Although not emphatic, this data implies a possible role of the NO-cGMP
pathway in AD action and AD withdrawal.
In order to determine whether the observed IMI withdrawal effects on the NO-cGMP pathway
may occur through an initial destabilisation in the serotonergic system, the 5-HT2a/2c receptor
antagonist, ritanserin (4 mg/kg/d ip), was administered during the IMI withdrawal period.
These studies revealed that antidepressant withdrawal evokes an increase in 5-HT2-mediated
activity, and that antidepressant-induced NOS activation after withdrawal has its origin in
serotonergic hyperactivity. Clearly, this is supportive of a distinct relationship between the NO
and serotonergic system in antidepressant response. On its own, ritanserin was found to
increase NOS and cGMP levels, yet during IMI withdrawal this response was lost, suggesting
that IMI withdrawal alters the response to a 5-HT2a/2c receptor antagonist, which may have major
clinical implications.
In conclusion, the AD action of IMI, as well as chronic IMI withdrawal, involves actions on the
NO-cGMP pathway. Withdrawal of ADS is associated with a loss of AD efficacy together with an
increase in release of NO and cGMP. The NMDA antagonist, memantine, and the NOS/GC
inhibitor, MB, reversed these responses therefore suggesting that the NMDA-GIu-NO-cGMP
pathway may be a new putative target in understanding the neurobiology of AD action. Finally,
NOS activation following withdrawal suggest that inappropriate withdrawal during the treatment
of depression may mediate neurodegenerative pathology observed in recurrent depression,
possibly by severely increased hippocampal NOS activity which is toxic to neurons. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2005.
| Identifer | oai:union.ndltd.org:NWUBOLOKA1/oai:dspace.nwu.ac.za:10394/731 |
| Date | January 2004 |
| Creators | Retief, Renché |
| Publisher | North-West University |
| Source Sets | North-West University |
| Detected Language | English |
| Type | Thesis |
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