Selective inhibition of phosphodiesterase 5 enhances glutamatergic synaptic plasticity and memory in mice

Abstract

Phosphodiesterases (PDEs) belong to a family of proteins that control metabolism of cyclic nucleotides. Targeting PDE5, for enhancing cellular function, is one of the therapeutic strategies for male erectile dysfunction. We have investigated whether in vivo inhibition of PDE5, which is expressed in several brain regions, will enhance memory and synaptic transmission in the hippocampus of healthy mice. We have found that acute administration of sildenafil, a specific PDE5 inhibitor, enhanced hippocampus-dependent memory tasks. To elucidate the underlying mechanism in the memory enhancement, effects of sildenafil on long-term potentiation (LTP) were measured. The level of LTP was significantly elevated, with concomitant increases in basal synaptic transmission, in mice treated with sildenafil (1 mg/kg/day) for 15 days compared to control mice. These results suggest that moderate PDE5 inhibition enhances memory by increasing synaptic plasticity and transmission in the hippocampus.

Dysregulated nitric oxide signaling as a candidate mechanism of fragile X syndrome and other neuropsychiatric disorders

“…PDE type 5 inhibitors, which elevate cGMP levels by blocking their enzymatic degradation, are well known for their role in treating erectile dysfunction (Boolell et al, 1996; Sandner et al, 2008), but may have additional indications in the brain. Sildenafil has been shown to have antidepressant, anxiolytic, and cognitive effects, and to increase cGMP levels in the hippocampus (Rutten et al, 2005; Liebenberg et al, 2010, 2012; Uthayathas et al, 2013; Zhang et al, 2013). Tadalafil has similar antidepressant and anxiolytic effects, and has additionally been shown to reverse cognitive dysfunction by crossing the blood–brain barrier (Liebenberg et al, 2010, 2012; García-Barroso et al, 2013).…”

Rivastigmine but not vardenafil reverses cannabis-induced impairment of verbal memory in healthy humans

“…To circumvent this problem, glutamate concentrations could be indirectly increased with a non-toxic selective phosphodiesterase type 5 inhibitor (PDE5i). PDE5i's are presently marketed for erectile dysfunction, but there is substantial evidence that these drugs also promote memory acquisition and consolidation in animals (Devan et al 2007;Reneerkens et al 2012;Uthayathas et al 2013). PDE5 breaks down the cyclic nucleotide cGMP (Bender and Beavo 2006), which presynaptically stimulates the release of glutamate (Neitz et al 2011).…”

“…PDE5 breaks down the cyclic nucleotide cGMP (Bender and Beavo 2006), which presynaptically stimulates the release of glutamate (Neitz et al 2011). Thus, selective PDE5i's increase central levels of cGMP (Prickaerts et al 2002;Riazi et al 2006), and consequently glutamate (Uthayathas et al 2007(Uthayathas et al , 2013, and may thereby reverse the effects of THC on glutamate.…”

Differential changes in amygdala and frontal cortex Pde10a expression during acute and protracted withdrawal

“…PDE10A can hydrolyze both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP; Fujishige et al, 1999a; Loughney et al, 1999; Soderling et al, 1999) and is prominently expressed in the brain, particularly in the striatum (Fujishige et al, 1999b; Seeger et al, 2003). Like other PDEs, PDE10A may play an important role in neuronal plasticity by modulating the levels of active cAMP and cGMP available to participate in intracellular signaling cascades (Kroker et al, 2012; Wiescholleck and Manahan-Vaughan, 2012; Zhong et al, 2012; Uthayathas et al, 2013). Acute inhibition of PDE10A increased striatal neuronal activity following cortical stimulation (Threlfell et al, 2009), and chronic PDE10A inhibition or genetic deletion altered the expression of several genes encoding proteins involved in neurotransmission (Kleiman et al, 2011).…”