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Our earlier studies showed that inhibition of VMAT2 caused depletion of dopamine in rat striatum accompanied with outflow of glutamate and production of hydroxyl radical. Inhibition of VMAT2 is observed in an early phase of Parkinson’s Disease (PD) as evidenced by PET studies in PD patients and in non-human primates. Recently it is observed that many neurons also release a classical transmitter other than the one with which they are usually associated. It is shown that neurons releasing monoamines can also release the excitatory transmitter glutamate. All neurons contain glutamate for its role in protein synthesis and metabolism, but they also express VGLUTs required for excitotoxic glutamate release. Moreover, it is also shown that several catecholamine cells such as VTA dopamine neurons are able corelease glutamate. Disturbed function of both, VMAT 2 and VGLUT may start catecholamine neurons degeneration that occurs at the early pre-clinical stage of PD. Accumulation of cytosolic dopamine may be neurotoxic for neurons through the generation of free radicals. Similarly, glutamate released from neurons or glial cells via GLT-1 transporter or cystine-glutamate exchanger or purinergic P2X7 receptor may stimulate glutamate receptors on various cells, induce increase in intracellular calcium which leads to excitotoxicity and generation of free radicals. ATP is required for packing of dopamine or glutamate in neuronal and glial vesicles and disturbed vesicular function results in ATP metabolism to adenosine in the presence of 5’-nucleotidase. In our study we tried to understand the early changes in dopamine synapses and glial cell responses which may provide insights on PD pathology. We injected animals with reserpine to inhibit vesicular transport and measured veratridine-evoked (100 µM) dopamine, glutamate and adenosine release using microdialysis in frontal cortex of freely moving rats. Extracellular dopamine, adenosine and glutamate were assayed by HPLC with electrochemical, fluorescenece and VIS detection. Reserpine at a single dose of 2.5 mg/kg increased veratridine-evoked glutamate release to 200% and adenosine release to 5 000% of baseline 20 h after administration. Reserpine at a dose of 0.25 mg/kg given repeatedly for 14 days increased evoked-glutamate release to maximum 210% and adenosine to 1 400% of baseline. At the same time veratridine-induced DA release was also markedly increased as compared to control animals. Veratridine-evoked glutamate and adenosine release were increased by 150 and 600% of baseline, respectively in intact rats. Obtained results indicate that under conditions of damaged vesicular transport there is significant overflow of glutamate and adenosine as well as increase in dopamine release in the rat frontal cortex. Marked increase in extracellular adenosine release may lead to activation of adenosine A2A receptors located in glutamate terminals or glial cells causing damage through induction of oxidative stress by glutamate or dopamine. Corelease of neurotransmitters and neuromodulators from neuronal or glial cells with disturbed vesicular transport may underline cortical pathology observed in PD.
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Muscarinic receptor subtypes in the alimentary tract

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Acetylcholine is a transmitter in preganglionic autonomic and postganglionic parasympathetic nerves and a non-neuronal paracrine mediator in the alimentary tract. Acetylcholine is involved in the control of almost any function within these organ systems, and almost every cell type expresses multiple muscarinic receptor subtypes. Although muscarinic receptors at non-neuronal effector cells commonly are of the M3 subtype, the population usually consists of a mixture of muscarinic receptor subtypes often co-acting postsynaptically. However, the pattern of heterogeneity of varies between different tissues. The population in gland parenchymal tissue often consists of a mixture of M1 and M3 receptors, smooth muscle tissue of the gut of M2 and M3, blood vessels of M1, M3, M4 and M5 and neuronal cells of M1 and M4. Nitric oxide production, effects on inflammation and proliferation may involve M1, M3 and M5 receptors. Muscarinic receptors expressed on nerve terminals may indirectly modulate the responses by inhibition or facilitation of neuronal transmission in the autonomic nervous system. The present review describes signalling mechanisms, expression and functional effects of muscarinic receptors in salivary glands and in the gastrointestinal tract.
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