Modulation of adenosine responses in Ca1 area of rat hippocampus

Shahraki, Ali (2003) Modulation of adenosine responses in Ca1 area of rat hippocampus. PhD thesis, University of Glasgow.

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In various conditions like hypoxia, ischemia and brain injury, the extracellular levels of the important neuromodulator, adenosine are increased. This study has considered the effects of adenosine in the CA1 area of hippocampus and its interactions with metabotropic glutamate receptors, nitric oxide and free radicals. Single and paired-pulse stimuli have been applied to the Schaffer collateral fibers in stratum radiatum and extracellular recordings were made from the CA1 pyramidal cell layer of hippocampal slices. We have examined excitatory postsynaptic potentials and paired-pulse interactions to obtain more information about the site and mechanism of these interactions. The results show suppression of adenosine sensitivity by metabotropic glutamate receptors, explained by a selectively reduced responsiveness to Ai receptor stimulation, which does not involve any facilitation of A2A adenosine receptors, since it can be obtained in the absence of endogenous adenosine and is not prevented by the A2A receptor blocker ZM241385. The glutamate receptors involved are of the group I class since the suppression of adenosine sensitivity is produced by ACPD and the group I selective compound DHPG. Furthermore, the effects of DHPG could be prevented by LY367385, a selective antagonist at the mGlu1n subtype of group I receptors. The selective antagonist at mGlu5 receptors, SIB 1893, did not prevent the suppression of adenosine sensitivity by DHPG. Blockade of the DHPG/adenosine interaction was also obtained by superfusion with the protein kinase C inhibitor chelerythrine. Since the suppression of adenosine responses by metabotropic receptor agonists was seen in the paired-pulse paradigm, we conclude that the observed interactions occur at the level of the presynaptic terminals. The interaction with adenosine receptors is not specific, but applies also to a suppression of responses mediated by the GABAB receptor agonist baclofen. In conclusion, activation of the mGlu1a subtype of receptor can suppress responses mediated via adenosine A1 receptors, probably by activating protein kinase C. Since the changes induced by metabotropic glutamate receptor agonists last for at least 60 minutes, the data also imply that these interactions could play an important role in changes of synaptic function long after even transient increases of glutamate release in the CNS. The second part of this study investigated the interaction between adenosine and nitric oxide. Activation of NMDA receptors has been shown to suppress neuronal responses to adenosine in hippocampal slices. Since NMDA receptor activation is known to lead to the generation of nitric oxide (NO), we have now examined whether NO is able to modify neuronal responses to adenosine and mediate the actions of NMDA. The superfusion of the NO donor, S-nitroso-N-acetylpenicillamine (SNAP) induced a long-lasting potentiation of fEPSP slope and reduced responses to adenosine. The guanylate cyclase inhibitor ODQ prevented the inhibitory effects of SNAP on adenosine responses and also prevented the SNAP-induced LTP, suggesting that the action of NO is mediated through cyclic GMP. The third part of this study was to examine the effects of another free radical species, superoxide on adenosine responses and fEPSPs to determine whether the suppression effects on adenosine were specific for NO. Superfusion of a xanthine / xanthine oxidase mixture (X/XO) induced LTP and significantly suppressed responses to adenosine. ODQ and superoxide dismutase (SOD) prevented the inhibitory effects of X/XO on adenosine responses and their induction of LTP, suggesting that oxygen free radicals are involved, probably due to formation of peroxynitrite. The effects of ODQ and SOD on the interaction between adenosine and NMDA indicate that cGMP does not mediate this interaction but oxygen free radicals might contribute. Paired-pulse interactions showed that the suppression of inhibitory effects of adenosine by NO and X/XO are happening presynaptically. Overall we have demonstrated several factors which can modify adenosine sensitivity in the hippocampus. These interactions may contribute to the physiological and pathological regulation of neuronal excitability and plasticity.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Neurosciences.
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: Stone, Prof. Trevor W.
Date of Award: 2003
Depositing User: Enlighten Team
Unique ID: glathesis:2003-71031
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 09 May 2019 14:28
Last Modified: 02 Jun 2021 14:07
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