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.
Highlights
The 5-HT7 receptor, a postsynaptic G protein coupled receptor was identified in 1993 through a homology cloning strategy and found to modulate positive cAMP formation via Gs[1]
These results suggest that blockade of 5HT7 receptors may have anxiolytic and antidepressant activity in humans. 5-HT7 receptor antagonists have been evaluated in animal models predictive of antipsychotic-like activity
The results of the present work indicated that the selective 5-HT7 receptor antagonist SB-269970 reversed MK-801 but not scopolamine -induced cognitive deficit in the delayed non-matching to position (DNMTP) task
Summary
The 5-HT7 receptor, a postsynaptic G protein coupled receptor was identified in 1993 through a homology cloning strategy and found to modulate positive cAMP formation via Gs[1]. Mice treated with 5-HT7 receptor antagonists as well as mice lacking the 5-HT7 receptors display decreased immobility time in the tail suspension test [7,8,9,10]. These results suggest that blockade of 5HT7 receptors may have anxiolytic and antidepressant activity in humans. NMDA antagonists such as ketamine and phencyclidine (PCP) induce hyperactivity, stereotypy and sensorimotor gating deficits in multiple species including humans and they can exacerbate positive symptoms of schizophrenia. Current antipsychotics do not show strong efficacy in cognitive deficit associated with psychiatric disorders including depression and schizophrenia
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