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- Title
Pharmacological Blockade of Serotonin 5-HT<sub>7</sub> Receptor Reverses Working Memory Deficits in Rats by Normalizing Cortical Glutamate Neurotransmission.
- Authors
Bonaventure, Pascal; Aluisio, Leah; Shoblock, James; Boggs, Jamin D.; Fraser, Ian C.; Lord, Brian; Lovenberg, Timothy W.; Galici, Ruggero
- Abstract
The role of 5-HT7 receptor has been demonstrated in various animal models of mood disorders; however its function in cognition remains largely speculative. This study evaluates the effects of SB-269970, a selective 5-HT7 antagonist, in a translational model of working memory deficit and investigates whether it modulates cortical glutamate and/or dopamine neurotransmission in rats. The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist. SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/ kg) but augmented the deficit induced by scopolamine (0.06 mg/kg). The ability of SB-269970 to modulate MK-801-induced glutamate and dopamine extracellular levels was separately evaluated using biosensor technology and microdialysis in the prefrontal cortex of freely moving rats. SB-269970 normalized MK-801 -induced glutamate but not dopamine extracellular levels in the prefrontal cortex. Rat plasma and brain concentrations of MK-801 were not affected by co-administration of SB- 269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. These results indicate that 5-HT7 receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission.
- Subjects
EXPERIMENTAL pharmacology; SEROTONIN antagonists; SEROTONIN receptors; ANIMAL memory; LABORATORY rats; AFFECTIVE disorders; GLUTAMIC acid; NEURAL transmission; DOPAMINERGIC neurons
- Publication
PLoS ONE, 2011, Vol 6, Issue 6, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0020210