Pharmacological Blockade of Serotonin 5-HT7 Receptor Reverses Working Memory Deficits in Rats by Normalizing Cortical Glutamate Neurotransmission

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

Anatomy, Physiology, and Pathophysiology of Renal Circulation

This chapter covers functional anatomy, physiology, and pathophysiology of the renal circulation. While insights about the anatomy of the renal vasculature have evolved some, the understanding of the physiology has improved substantially. Regarding glomerular filtration rate and renal blood flow, this chapter discusses the three levels of organization that can be recognized in renal physiology: first, principle driving forces of renal blood flow and glomerular filtration (based on the Starling forces); second, autoregulation, the system that stabilizes renal blood flow and glomerular filtration rate upon changes in renal perfusion pressure; and last, the neuroendocrine systems that connect systemic hemodynamics to the regulation of renal blood and glomerular filtration. Regarding pathophysiology, the basic derangements happening in renovascular hypertension, in diabetic nephropathy, in hypertensive renal injury, and in cardiorenal syndrome are described