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

  title={Inhibition of the striatum-enriched phosphodiesterase PDE10A: A novel approach to the treatment of psychosis},
  author={Judith A. Siuciak and Douglas S. Chapin and John F. Harms and Lorraine A. Lebel and Sheryl A. McCarthy and Leslie K. Chambers and Alka Shrikhande and Stephen K.-F. Wong and Frank S. Menniti and Christopher J. Schmidt},

Effects of phosphodiesterase 10 inhibition on striatal cyclic AMP and peripheral physiology in rats.

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.

Inhibition of Phosphodiesterase 10A Increases the Responsiveness of Striatal Projection Neurons to Cortical Stimulation

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.

Chronic Suppression of Phosphodiesterase 10A Alters Striatal Expression of Genes Responsible for Neurotransmitter Synthesis, Neurotransmission, and Signaling Pathways Implicated in Huntington's Disease

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.

Selective Effects of PDE10A Inhibitors on Striatopallidal Neurons Require Phosphatase Inhibition by DARPP-321,2,3

PDE10A inhibitors share with antipsychotic medications the property of activating preferentially PKA-dependent signaling in D2 MSNs, demonstrating that PDE10A regulates basal cAMP levels.

Antipsychotic-like effects of a novel phosphodiesterase 10A inhibitor T-251 in rodents

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 the

Increased social interaction in mice deficient of the striatal medium spiny neuron‐specific phosphodiesterase 10A2

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.



Striatum- and testis-specific phosphodiesterase PDE10A isolation and characterization of a rat PDE10A.

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.

Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum.

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.

Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction.

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.

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.

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.

Loss of haloperidol induced gene expression and catalepsy in protein kinase A-deficient mice.

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.

Dopamine Induces a PI3-Kinase-Independent Activation of Akt in Striatal Neurons: A New Route to cAMP Response Element-Binding Protein Phosphorylation

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.