Rolipram, a Selective Inhibitor of Phosphodiesterase Type 4, Pronouncedly Enhanced the Forskolin-Induced Promotion of Dopamine Biosynthesis in Primary Cultured Rat Mesencephalic Neurons.

Abstract

ABSTRACT-A selective inhibitor of cyclic nucleotide phosphodiesterase (PDE) 4, rolipram, markedly enhanced the forskolin-induced increase of intracellular dopamine and dihydroxyphenylacetate (DOPAC, a metabolite of dopamine) levels in primary cultured rat mesencephalic neurons and the forskolin-induced increase of dopamine and DOPAC in extracellular medium. Selective inhibitors of PDE2, PDE3, PDE5 and PDE6 did not have such a promoting effect, and the PDE1 inhibitor vinpocetine and W-7 caused dopa mine depletion in the neurons. These findings suggested that PDE4 plays a major role in regulating the intracellular cAMP level to control the dopamine biosynthesis in mesencephalic neurons, whereas PDE 1 regulates dopamine release instead.

Distinct Roles of PDE4 and PDE10A in the Regulation of cAMP/PKA Signaling in the Striatum

“…Rolipram treatment did not affect the HVA/dopamine ratio, indicating that the primary effect of the inhibitor is an increase in the metabolism of newly synthesized dopamine by MAO at dopaminergic terminals, without an accompanying increase in dopamine release. Together, these data are consistent with results from previous studies in which rolipram was found to increase dopamine synthesis without altering dopamine release (Schoffelmeer et al, 1985; Yamashita et al, 1997a,b). The data extend those observations by demonstrating that phosphorylation of TH at Ser40 is a likely mechanism for mediating the action of rolipram on dopamine synthesis.…”

“…Inhibition of PDE10A by papaverine increases phosphorylation of cAMP-dependent substrates, including the cAMP-response element-binding protein (CREB) and extracellular receptor kinase (ERK), by activating cAMP/PKA signaling (Siuciak et al, 2006b). PDE4B, another striatal-enriched PDE, likely plays a regulatory role in dopaminergic neurotransmission because inhibition of PDE4 by rolipram stimulates dopamine synthesis (Kehr et al, 1985; Schoffelmeer et al, 1985; Yamashita et al, 1997a). However, the precise role of PDE4 in dopaminergic neurotransmission is currently unknown.…”

Advanced Research on Dopamine Signaling to Develop Drugs for the Treatment of Mental Disorders: Biochemical and Behavioral Profiles of Phosphodiesterase Inhibition in Dopaminergic Neurotransmission

“…The PKA-dependent phosphorylation of TH at Ser40 increases the catalytic activity of TH (3, 4), the rate-limiting step in dopamine biosynthesis (46). It has been reported that rolipram increases dopamine synthesis without altering dopamine release (47,48). In our study, the inhibition of PDE4 by rolipram in the presence of haloperidol resulted in the increase in DOPAC/dopamine ratio, but not HVA/dopamine ratio, in the striatum in vivo, suggesting the increase in metabolism of dopamine by monoamine oxidase (MAO) at dopaminergic terminals (21).…”

Inhibition of phosphodiesterase-4 decreases ethanol intake in mice

“…Rolipram, perfused into the jugular vein, decreases the firing of dopaminergic neurons in the ventral tegmental area (Scuvee-Moreau et al 1987). It also enhances dopamine release and/or biosynthesis in the cultured mesencephalic neurons (Yamashita et al 1997) and in the striatum in vivo (Nishi et al 2008). At high doses such as 3 mg/kg, rolipram has been shown to reduce the binding of dopamine D1 and D2 receptors as well as muscarinic cholinergic receptors to their ligands in the brain, probably by changing cAMP-PKA signaling and protein phosphorylation (Hosoi et al 2002, 2003).…”