Seite - (000187) - in Biomedical Chemistry: Current Trends and Developments

glutamatergic signaling, promoting presynaptic glutamate and altering postsynaptic response to glutamate release. Increased release is involved in decreased presynaptic inhibitory regulation by mGluR2/3 autoreceptors (Baker, 2003). After withdrawal there is a reduction in extracellular glutamate due to loss of cystine-glutamate exchanger, which is responsible for the majority of glutamate in the synaptic cleft and maintains the tone for mGluR2/3 (Baker, 2003). Postsynaptic responses are associated with changes in intracellular signaling and trafficking of glutamate receptors to the membrane, such as the reduction of scaffolding proteins like PSD-95 and Homer (Ghasemzadeh, 2003; Yao, 2004). As an example, chronic methamphetamine (METH) involves excitotoxicity following increased glutamate release, which is thought to create oxidative stress and DA terminal degeneration, particularly in the striatum (Nash, 1992). The striatum receives glutamatergic input mainly from cortical terminals, and the corticostriatal pathway is regulated by basal ganglia circuits, particularly the GABAergic nigrothalamic and glutamatergic thalamocortical pathways (Gerfen, 1989). The striatal GABAergic projections terminate in the SN, which contains high density of DA neurons that project to the striatum (Trevitt, 2002). DA regulates GABAergic signaling in the SN and to the thalamus (Aceves, 1995; Timmerman, 1997). METH increases glutamate in the striatum through a polysynaptic pathway, characterized by an increase in striatonigral GABA transmission, which will decrease nigrothalamic GABAergic signaling, disinhibiting thalamocortical glutamatergic transmission, ultimately causing an increase in glutamatergic release in striatum via the corticostriatal pathway. The increase of glutamate in the striatum will contribute to the degeneration of DA terminals, leading to a long- term depletion of DA in this brain region (Mark, 2004). It was also shown that regulation of VGLUT1 expression and function via this polysynaptic pathway facilitates vesicular accumulation and glutamate release in the striatum after METH administration, contributing to a sustained increase in glutamatergic transmission in the corticostriatal pathway (Mark, 2007). The increase in glutamate release might lead to an overstimulation of NMDARs and consequent oxidative stress contributing to neuronal damage (Gunasekar, 1995).