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The Journal of Neuroscience, January 15, 2001, 21(2):628-640

Adenosine Receptor Subtypes Modulate Two Major Functional Pathways for Hippocampal Serotonin Release

Motohiro Okada^{1, 2}, David J. Nutt², Takuya Murakami¹, Gang Zhu¹, Akihisa Kamata¹, Yuko Kawata¹, and Sunao Kaneko¹

¹ Department of Neuropsychiatry, Hirosaki University, Hirosaki 036-8216, Japan, and ² Psychopharmacology Unit, Bristol University, Bristol BS8 1TD, United Kingdom

To clarify the mechanisms of interaction between adenosine A₁ receptor (A1-R) and adenosine A₂ receptor (A2-R) on neurotransmitter release, this study determined the functional interactions among adenosine receptors (AD-Rs), voltage-sensitive Ca²⁺ channels (VSCCs), protein kinases (PKs), and synaptic proteins [N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors] on hippocampal serotonin release using in vivo microdialysis in freely moving rat. Basal serotonin release was regulated by two functional complexes: N-type VSCC (N-VSCC)/calcium-phospholipid-dependent protein kinase (PKC)/syntaxin (major pathway) and P-type VSCC (P-VSCC)/cyclic AMP-dependent protein kinase (PKA)/synaptobrevin (minor pathway). However, K⁺-evoked serotonin release was regulated by N-VSCC/PKC/syntaxin (minor pathway) and P-VSCC/PKA/synaptobrevin (major pathway). A1-R antagonists increased basal serotonin release, which was reduced by inhibitors of N-VSCC, PKC, and syntaxin predominantly and by inhibitors of PKA and synaptobrevin weakly, but was not affected by P-VSCC inhibitor. In the presence of A1-R antagonist, A2-R agonists increased basal serotonin release, which was inhibited by inhibitors of P-VSCC, PKA, and synaptobrevin predominantly and reduced by inhibitors of N-VSCC, PKC, and syntaxin weakly. Under the condition of activation of adenylate cyclase in the absence of A1-R antagonists, A2-R agonists increased basal serotonin release. A1-R antagonist and A2-R agonist enhanced K⁺-evoked serotonin release, which was inhibited by inhibitors of P-VSCC, PKA, and synaptobrevin predominantly. These results suggest that an activation of A1-R suppresses serotonin release via inhibition of both N-VSCC/PKC/syntaxin and P-VSCC/PKA/synaptobrevin pathways, and an activation of A2-R stimulates serotonin release via enhancement of the P-VSCC/PKA/synaptobrevin pathway. Therefore, PKA activity plays an important role in the interaction between A1-R and A2-R on hippocampal serotonin release.

Key words: adenosine; serotonin; microdialysis; voltage-sensitive Ca²⁺ channel; protein kinase; SNARE

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Copyright © 2001 Society for Neuroscience  0270-6474/01/212628-13$05.00/0

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