Glutamate is the principal excitatory neurotransmitter in the central nervous system and it is implicated in neural transmission, learning, memory processes and neuronal plasticity. In the glutamatergic synapse two main components are present; the glutamate receptors and the glutamate transporters. The receptors, the NMDA, AMPA, kainite and the metabotroptic receptors, are responsible for conveying neural transmission, including long term potentiation (LTP), synaptic strengthening and modification. The transporters, located to the neuronal membrane and to the membranes of surrounding astrocytes, regulates the extracellular concentration of glutamate and thereby the duration of the synaptic signal.
Alterations in both receptor and transporter systems have been suggested to be important in the pathogenesis of several acute and chronic nervous system diseases, such as psychosis, mood disorders, epilepsy, Parkinson's disease and Alzheimer's disease. The pathophysiology of these disorders is not yet completely understood and the involvement of glutamate is unclear. In this thesis we have sought to investigate the role of the glutamatergic system in the treatment of mood disorders and dementia. The antidepressant drug amitriptyline exerts its main effects on the serotonergic and noradrenergic systems and the antidementia drug rivastigmine acts mainly on the cholinergic system. However, given the close relationship between different neurotransmitter systems we have investigated the influence of amitriptyline and rivastigmine on the mRNA expression of the neuronal transporter, EAAC1, in rats. The results showed for the first time an involvement of EAAC1 in amitriptyline and rivastigmine treatment. Amitriptyline induced an acute increase in EAAC1 mRNA expression, which 24 hour after administration returned to baseline levels. Chronic treatment, on the other hand, induces a significant decrease in cortical areas, which we suggest results in enhanced neuronal transmission. Rivastigmine treatment, acute as well as chronic, induced increases in the mRNA expression in hippocampus. We hypothesize that this counteracts the excitotoxic glutamate levels seen in Alzheimer's disease.
Further, environmental enrichment has been shown to have beneficial effects on capillary supply, the number of glial cells and dendritic spines, the thickness and weight of cortex, the concentration of cholinesterase, LTP and synaptic strength in animals. It has also been reported that humans that lead an active life have a reduced risk of developing Alzheimer's disease. This suggests that an active and stimulated life may have a protective effect against dementia in man, by creating a cognitive reserve which provides a buffer against brain pathology or age-related changes. We investigated the influence of environmental enrichment on the mRNA expression of NMDA and AMPA receptors and on EAACl and showed for the first time that EAAC1 mRNA is decreased after environmental enrichment. This is probably followed by an increase of glutamate in the synapse, which in turn leads to enhanced neuronal transmission including enhanced memory formation and learning. Furthermore, we confirmed in greater detail previous findings on the upregulation of NMDA mRNA and show that the regulation is regionally and hemisphere specific. We also confirm that AMPA mRNA is not per se changed by environmental enrichment in adult animals.
This work provides further evidence about the involvement of the glutamatergic system in affective and cognitive disorders. Improved knowledge of the glutamatergic system will contribute to the development of strategies aimed at limiting pathological changes associated with glutamatergic dysfunctions.
Linköping: Linköpings universitet , 2006. , 66 p.