Despite their acknowledged efficacy, currently available antidepressants still demonstrate undesirable side effects, shortfalls in effectiveness and a delayed onset of action. All these agents act via monoaminergic mechanisms,
although recent studies have begun to note the potential role of the cholinergic system as well as the amino acid pathways in affective isorders.
It has been suggested that glutamate NMDA receptor activation may be involved in hippocampal degeneration seen in patients with depression, as well as contributing as a molecular target for the antidepressant action of
known antidepressant drugs. Glutamate either separately or via the release of nitric oxide, regulates the release of various transmitters in the brain critical for affective state, e.g. monoamines (noradrenaline, dopamine), indoleamines
(5HT), y-aminobutyric acid (GABA) and acetylcholine. The aim of this study
was to investigate N-methyl-D-aspartate (I\IMDA) and muscarinic M1 receptor characteristics and also GABA and acetylcholine levels in a genetic animal model of depression, the Flinders Sensitive Line (FSL) rat, with respect to its
control, viz. Flinders Resistant Line (FRL) rat, thereby establishing a possible role for the amino acid and cholinergic pathways in the hippocampus and frontal cortex, two brain areas implicated in depression. In addition, anxietylike
behaviours were assessed using the open field and social interaction
tests. A sensitive liquid chromatography tandem mass spectrometer
(LC/MS/MS) method was used in the quantification of acetylcholine as well as
high performance liquid chromatography with electrochemical detection
(HPLG-EGD) for the quantification of GABA in the above-mentioned brain
areas of FSL and FRL rats. NMDA and muscarinic M1 receptor
characteristics were expressed in terms of receptor denSity (Bmax) and affinity
(Kd) values and were performed using [3H]-MK801 (27.5 Gi/mmol) and
quinuclidinyl benzilate (52.0 Gilmmol) for NMDA and M1 receptors,
respectively. In addition, to provide evidence for face validity, behavioural assessments were routinely performed using the open field test and social
interaction test. Significantly elevated levels of acetylcholine were found in the frontal cortex but with significantly reduced levels in the hippocampus of FSL rats. Cortical
and hippocampal muscarinic receptor binding characteristics remained
unchanged, while no differences with regard to GABA levels and NMDA
receptor binding characteristics were noted in these brain areas. In
concordance with studies from the literature, aversive and locomotor
behaviour as measured in the open field test, provided evidence of anxiogenic
behaviour in the FSL rat, evinced by significantly less social interaction than
their FRL counterparts. In addition, evidence for a lack in general activity of
the FSL rat in the open field was also noted. Our data therefore suggest the
presence of a cholinergic dysfunction in both the frontal cortex and
hippocampus of the FSL rat, although this is not accompanied by
simultaneous changes in muscarinic M1 receptor binding in key limbic brain
regions. Although increased cholinergic drive is a recognised characteristic of FSL rats and is representative of the model's' construct validity, we suggest that the depressive phenotype of these animals is not related to altered cholinergic activity in a single brain region, but instead involves various limbic brain regions, possibly being more dependent on opposing cholinergic deficits in the cortex and hippocampus. / Thesis (M.Sc. (Pharmacology)--North-West University, Potchefstroom Campus, 2009.
| Identifer | oai:union.ndltd.org:NWUBOLOKA1/oai:dspace.nwu.ac.za:10394/4190 |
| Date | January 2008 |
| Creators | Van Zyl, Petrus Jurgens |
| Publisher | North-West University |
| Source Sets | North-West University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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