Potentiation and prolongation of long-term odor memory in neonate rats using a phosphodiesterase inhibitor

Chemically induced long-term potentiation (cLTP) could potentially work by directly stimulating the biochemical machinery that underlies synaptic plasticity, bypassing the need for synaptic activation. Previous reports suggested that agents that raise cAMP concentration might have this capability. We examined the cLTP induced in acute slices by application of Sp-cAMPS or a combination of the adenylyl cyclase activator, forskolin, and the phosphodiesterase inhibitor, rolipram. Under our conditions, cLTP was induced but only if inhibition was reduced. We found that this form of cLTP was blocked by a N-methyl-d-aspartate receptor (NMDAR) antagonist and required the low-frequency test stimulation typically used to monitor the strength of synapses. Interestingly, similar LTP could be induced by lowering the Mg2+ concentration of the ACSF during forskolin/rolipram or Sp-cAMPS application or even by just lowering Mg2+ concentration alone. This LTP was also NMDAR dependent and required only a few (∼5) low-frequency stimuli for its induction. The finding that even low-frequency synaptic stimulation was sufficient for LTP induction indicates that a highly sensitized plasticity state was generated. The fact that some stimulation was required means that potentiation is probably restricted to the stimulated axons, limiting the usefulness of this form of cLTP. However, when similar experiments were conducted using slice cultures, potentiation occurred without test stimuli, probably because the CA3–CA1 connections are extensive and because presynaptic spontaneous activity is sufficient to fulfill the activity requirement. As in acute slices, the potentiation was blocked by an NMDAR antagonist. Our general conclusion is that the induction of LTP caused by elevating cAMP requires presynaptic activity and NMDA channel opening. The method of inducing cLTP in slice cultures will be useful when it is desirable to produce NMDAR-dependent LTP in a large fraction of synapses.

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Abstract 387: Prolactin-Releasing Peptide, the Novel Endogenous Ligand of the Orphan Receptor GPR10, Regulates Cardiac Contractility

Circulation ◽

10.1161/circ.116.suppl_16.ii_61-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Attila Kónyi ◽

Réka Skoumal ◽

Anna-Maria Kubin ◽

Iván G Horváth ◽

Miklós Tóth ◽

...

Keyword(s):

Positive Inotropic Effect ◽

Phosphodiesterase Inhibitor ◽

Orphan Receptor ◽

Inotropic Effect ◽

Inotropic Response ◽

Endogenous Ligand ◽

Pkc Alpha ◽

Prolactin Releasing Peptide ◽

Pp2a Inhibitor

The hypothalamic prolactin-releasing peptide (PrRP), which is the endogenous ligand of the orphan receptor GPR10, plays an important role in the regulation of the central stress response, sleep regulation and feeding behavior. Although specific binding sites have been found in the rat myocardium, the functional importance of PrRP in the regulation of cardiovascular system is still unknown. The objective of the present study was to characterize the direct cardiac effects of PrRP as well as the underlying signaling mechanisms. In the isolated perfused, paced rat heart preparation (male 7-week-old, Sprague-Dawley rats, n=138), intracoronary infusion of PrRP-31 (1–30 nmol/L) for 15 min induced a dose-dependent, slowly developing positive inotropic effect, with a maximal increase in developed tension at the dose of 10 nmol/L (13.6%±3.1, P< 0.001). Next we tested if various counter-regulatory mechanisms could modify the effect of PrRP. The phosphodiesterase inhibitor IBMX (10 μmol/L) failed to alter the inotropic response to PrRP (10.7±1.9%, P=N.S.) excluding the involvement of cAMP-dependent mechanisms. In contrast, the specific protein kinase C-alfa (PKC-alpha) inhibitor Ro32– 0432 (100 nmol/L) significantly increased the inotropic response to PrRP (21.6±3.4%, P<0.05) as well as the phosphorylation of phospholamban at Ser-16 (1.5±0.09 vs. 1.0±0.18; P<0.001) as measured by Western blotting. Moreover, the protein phosphatase (PP1/PP2A) inhibitor calyculin A (CyA) augmented the effect of PrRP on contractility (20.7 ±1.7%, P<0.001) similarly to PKC-alpha inhibition, whereas the PP2A inhibitor okadaic acid (10 nmol/L) had no effect (7.8±1.0 %, P=N.S.). Furthermore, long-term (120 min) administration of PrRP resulted in a greater increase in contractility (20.3±3.1 %) as compared to short-term infusion (15 min; P<0.05). Our results provide the first evidence for the functional significance of PrRP in the heart. The positive inotropic effect of PrRP is mediated via cAMP-independent mechanisms, which are suppressed by enhanced activity of PKC-alpha and PP1. We suggest that PrRP may play an important role in the long-term regulation of myocardial contractility.

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The pharmacodynamic action of the cyclic AMP phosphodiesterase inhibitor rolipram on prolactin producing rat pituitary adenoma (GH4C1) cells

Bioscience Reports ◽

10.1007/bf01117237 ◽

1990 ◽

Vol 10 (4) ◽

pp. 375-388 ◽

Cited By ~ 4

Author(s):

Jan O. Gordeladze

Keyword(s):

Pituitary Adenoma ◽

Phosphodiesterase Inhibitor ◽

Protein S ◽

Selective Inhibition ◽

Phosphoinositide Metabolism ◽

Camp Accumulation ◽

Camp Phosphodiesterase ◽

Cells In Culture ◽

Rat Pituitary

Rolipram (4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone) represents a new class of specific low Km cAMP phosphodiesterase (PDE) inhibitors. This compound enhances basal, hormone- and forskolin-elicited cAMP accumulation in prolactin (PRL) producing rat pituitary adenoma (GH4C1) cells in culture (ED50=5·10−8 M). This effect is due to a selective inhibition of the low Km cAMP PDE (type III), since neither basal nor hormone-stimulated adenylate cyclase (AC) nor the Ca2+/calmodulin-dependent PDE were affected by rolipram. The drug enhanced vasoactive intestinal polypeptide (VIP)-stimulated PRL-secretion, while thyroliberin (TRH)- and 12-0-tetradecanoyl phorbol-13-acetate (TPA)-elicited PRL egress were slightly reduced indicating a cAMP-mediated reduction of protein kinase C (PK-C) mediated PRL release. Interestingly, inhibition of PRL secretion by somatostatin (SRIH) was completely suppressed suggesting cAMP-mediated inactivation of some GTP-binding protein(s) of the αi family (Gαi2 or Gk). Rolipram did not affect phosphoinositide metabolism (i.e. IP3 accumulation), neither acutely nor after long term administration. Rolipram, like the cAMP PDE inhibitor Ro 20–1724, did not influence AC and PDE I, but dose-dependently inhibited PDE III activity. Long term incubation of GH4C1 cells with rolipram in the presence of noradrenaline (NA) exerted a marginal decrease of β-receptor number, AC activation and cAMP accumulation, while Ro 20–1724 brought about a marked down-regulation and desensitization of the AC complex. In summary, rolipram selectively interacts with PDE III in rat pituitary adenoma cells in culture and does not result in β-adrenoceptor AC downregulation. These features are not shared by the other drugs tested.

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Protein Phosphatases Mediate Depotentiation Induced by High-Intensity Theta-Burst Stimulation

Journal of Neurophysiology ◽

10.1152/jn.01041.2001 ◽

2003 ◽

Vol 89 (2) ◽

pp. 684-690 ◽

Cited By ~ 29

Author(s):

Maeng-Hee Kang-Park ◽

Meredith A. Sarda ◽

Katherine H. Jones ◽

Scott D. Moore ◽

Shirish Shenolikar ◽

...

Keyword(s):

Synaptic Plasticity ◽

Stimulus Intensity ◽

Protein Phosphatase ◽

High Intensity ◽

Protein Phosphatases ◽

Hippocampal Slices ◽

Phosphodiesterase Inhibitor ◽

Long Term Potentiation ◽

Theta Burst

We have previously reported that varying stimulus intensity produces qualitatively different types of synaptic plasticity in area CA1 of hippocampal slices: brief low-intensity (LI) theta-burst (TB) stimuli induce long-term potentiation (LTP), but if the stimulus intensity is increased (to mimic conditions that may exist during seizures), LTP is not induced; instead, high-intensity (HI) TB stimuli erase previously induced LTP (“TB depotentiation”). We now have explored the mechanisms underlying TB depotentiation using extracellular field recordings with pharmacological manipulations. We found that TB depotentiation was blocked by okadaic acid and calyculin A (inhibitors of serine/threonine protein phosphatases PP1 and PP2A), FK506 (a specific blocker of calcineurin, a Ca2+/calmodulin (CaM) protein phosphatase), and 8-Br-cAMP (an activator of protein kinase A) with 3-isobutyl-1-methylxanthine (IBMX, a phosphodiesterase inhibitor). These results suggest that protein phosphatase pathways are involved in the TB depotentiation similar to other type of down-regulating synaptic plasticity such as low-frequency stimulation (LFS)-induced long-term depression (LTD) and depotentiation in the rat hippocampus. However, TB depotentiation and LFS depotentiation could have differential functional significance.

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