Inhibition of the striatum-enriched phosphodiesterase PDE10A: A novel approach to the treatment of psychosis

@article{Siuciak2006InhibitionOT,
  title={Inhibition of the striatum-enriched phosphodiesterase PDE10A: A novel approach to the treatment of psychosis},
  author={J. Siuciak and D. Chapin and J. Harms and L. Lebel and S. McCarthy and L. Chambers and A. Shrikhande and S. Wong and F. Menniti and C. J. Schmidt},
  journal={Neuropharmacology},
  year={2006},
  volume={51},
  pages={386-396}
}
Phosphodiesterase 10A (PDE10A) is a recently identified cyclic nucleotide phosphodiesterase expressed primarily in dopaminoreceptive medium spiny neurons of the striatum. We report that papaverine is a potent, specific inhibitor of PDE10A and use this compound to explore the role of PDE10A in regulating striatal function. Papaverine administration produces an increase in striatal tissue levels of cGMP and an increase in extracellular cAMP measured by microdialysis. These cyclic nucleotide… Expand
Alterations in gene regulation following inhibition of the striatum-enriched phosphodiesterase, PDE10A
TLDR
Findings support the hypothesis that PDE10A modulates signal transduction in both striatal output pathways and suggest that Pde10A inhibitors may offer a unique approach to the treatment of schizophrenia. Expand
The PDE10A inhibitor, papaverine, differentially activates ERK in male and female rat striatal slices
TLDR
Results indicate that circulating levels of female hormones, and in particular estrogen, regulate the effects of PDE10A inhibition on ERK1/2 phosphorylation in medium spiny neurons, an effect possibly linked to estrogen's regulation of D2 receptors. Expand
Effects of phosphodiesterase 10 inhibition on striatal cyclic AMP and peripheral physiology in rats.
TLDR
The more selective MP10 had significantly less effects on body temperature and cardiovascular functions, but reduced locomotor activity to a similar extend as papaverine, compared to a more specific PDE10A inhibitor MP10. Expand
Inhibition of Phosphodiesterase 10A Increases the Responsiveness of Striatal Projection Neurons to Cortical Stimulation
TLDR
Findings indicate that inhibition of striatal PDE10A activity increases the responsiveness of MSNs to depolarizing stimuli, and support further investigation of selective targeting of PDE signaling pathways in MSN subpopulations. Expand
Chronic Suppression of Phosphodiesterase 10A Alters Striatal Expression of Genes Responsible for Neurotransmitter Synthesis, Neurotransmission, and Signaling Pathways Implicated in Huntington's Disease
TLDR
Chronic inhibition of PDE10A produced up-regulation of mRNAs encoding genes that included prodynorphin, synaptotagmin10, phosphodiesterase 1C, glutamate decarboxylase 1, and diacylglycerol O-acyltransferase and a down- regulation of m RNAs encoding choline acetyl transferase and Kv1, suggesting potential neuroprotective cascades capable of neuroprotection. Expand
Selective Effects of PDE10A Inhibitors on Striatopallidal Neurons Require Phosphatase Inhibition by DARPP-321,2,3
TLDR
PDE10A inhibitors share with antipsychotic medications the property of activating preferentially PKA-dependent signaling in D2 MSNs, demonstrating that PDE10A regulates basal cAMP levels. Expand
Inhibition of phosphodiesterase 10A has differential effects on dopamine D1 and D2 receptor modulation of sensorimotor gating
TLDR
These findings indicate that TP-10 cannot block dopamine agonist-induced deficits in PPI in the presence of D1 activation and suggest that the effect of PDE10A inhibition on D1 signaling may be counterproductive in some models of antipsychotic activity. Expand
Antipsychotic-like effects of a novel phosphodiesterase 10A inhibitor T-251 in rodents
TLDR
T-251 showed a potent inhibitory activity against human PDE10A (IC50 = 0.050 nmol/L) and showed high selectivity over other PDE families which have over 10,000-fold IC50 values and suggests that T-251 would be a novel antipsychotic with an improved side-effect profile. Expand
Facilitation of Corticostriatal Transmission following Pharmacological Inhibition of Striatal Phosphodiesterase 10A: Role of Nitric Oxide-Soluble Guanylyl Cyclase-cGMP Signaling Pathways
The striatum contains a rich variety of cyclic nucleotide phosphodiesterases (PDEs), which play a critical role in the regulation of cAMP and cGMP signaling. The dual-substrate enzyme PDE10A is theExpand
Increased social interaction in mice deficient of the striatal medium spiny neuron‐specific phosphodiesterase 10A2
TLDR
A physiological role is established for PDE10A2 in regulating cAMP pathway and social interaction, and cAMP signaling cascade in striatal medium spiny neurons might be involved in regulating social interaction behavior in mice. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 47 REFERENCES
Genetic deletion of the striatum-enriched phosphodiesterase PDE10A: Evidence for altered striatal function
TLDR
The findings suggest that PDE10A is involved in regulating striatal output, possibly by reducing the sensitivity of medium spiny neurons to glutamatergic excitation, and presents a novel treatment for psychosis. Expand
Striatum- and testis-specific phosphodiesterase PDE10A isolation and characterization of a rat PDE10A.
TLDR
Findings indicate that PDE10A functions in these tissues, and its presence in the neurons of the striatum and the olfactory tubercle regions of the brain is indicated. Expand
Immunohistochemical localization of PDE10A in the rat brain
TLDR
Data suggest a role for PDE10A in regulating activity within both the striatonigral and striatopallidal pathways, and a second, distinct function for the enzyme in these regions. Expand
Differential effects of selective and non-selective neuroleptics on intracellular and extracellular cyclic AMP accumulation in rat striatal slices
TLDR
The increase in dopamine-stimulated cyclic AMP efflux caused by D2 antagonists reflects increased intracellular cyclicAMP accumulation rather than an effect on the efflux mechanism, and dopamine enhances cyclIC AMP accumulation via a D1 receptor, and simultaneously inhibits it through a D2 receptor. Expand
Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum.
TLDR
Activation of ERK, by a multilevel protein phosphatase-controlled mechanism, functions as a detector of coincidence of dopamine and glutamate signals converging on medium-size striatal neurons and is critical for long-lasting effects of drugs of abuse. Expand
Discriminatory roles for D1 and D2 dopamine receptor subtypes in the in vivo control of neostriatal cyclic GMP.
The D1 and D2 subtypes of the dopamine receptor have been distinguished by their opposing effects on levels of neostriatal cyclic adenosine monophosphate (cAMP). The studies reported here show thatExpand
Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction.
TLDR
Sildenafil is shown to enhance the erectile response (duration and rigidity of erection) to visual sexual stimulation, thus highlighting the important role of PDE5 in human penile erection. Expand
Modulation of neuroleptic activity of 9,10-didehydro-N-methyl-(2-propynyl)-6-methyl-8-aminomethylergoline bimaleinate (LEK-8829) by D1 intrinsic activity in hemi-parkinsonian rats.
TLDR
D1 agonistic activity of LEK-8829 confers its anti-parkinsonian drug-like properties and modulates its neuroleptic drug- like properties, which are dependent on the blockade of dopamine D2 receptors, which imply that atypical antipsychotics with D1 intrinsic activity might have a reduced propensity for the induction of extrapyramidal syndrome. Expand
Loss of haloperidol induced gene expression and catalepsy in protein kinase A-deficient mice.
TLDR
A direct role is established for protein kinase A as a mediator of haloperidol induced gene induction and cataleptic behavior in mice harboring a targeted disruption of the RIIbeta subunit of protein kinases A. Expand
Dopamine Induces a PI3-Kinase-Independent Activation of Akt in Striatal Neurons: A New Route to cAMP Response Element-Binding Protein Phosphorylation
TLDR
It is proposed that this signaling pathway plays a pivotal role in DA-induced regulation of gene expression and long-term neuronal adaptation in the striatum and is implicating in the Ras/ERK signaling cascade in this process. Expand
...
1
2
3
4
5
...