Phosphodiesterase 10A inhibition modulates the sensitivity of the mesolimbic dopaminergic system to D-amphetamine: involvement of the D1-regulated feedback control of midbrain dopamine neurons.

Full Abstract

Phosphodiesterase (PDE) 10A is highly expressed in medium spiny neurons of the striatum, at the confluence of the corticostriatal glutamatergic and the midbrain dopaminergic pathways, both believed to be involved in the physiopathology of schizophrenia. There is a growing body of evidence suggesting that targeting PDE10A may be beneficial for the treatment of positive symptoms in schizophrenia. The aim of the present study was to investigate how PDE10A inhibition modulates mesolimbic dopaminergic neurotransmission. We found that the selective PDE10A inhibitor, MP-10, blocked D-amphetamine-induced hyperactivity as well as D-amphetamine-induced dopamine efflux in the nucleus accumbens in a dose-dependent manner. We further investigated the mechanism by which PDE10A inhibition affects dopaminergic neurotransmission. We report that MP-10 potentiated the effect of a high but not a low dose of D-amphetamine on the mean firing rate of dopaminergic neurons recorded from the ventral tegmental area. Similarly, the effect of a high, but not a low dose of D-amphetamine, was completely reversed by the selective D(1) antagonist, SCH23390. These data suggest that the D(1)-regulated feedback control of midbrain dopamine neurons is a critical pathway involved in the modulation of the response of mesolimbic dopamine neurons to D-amphetamine by PDE10A inhibition.

Author information

Author/s: Sotty, Florence (F); Montezinho, Liliana P (LP); Steiniger-Brach, Björn (B); Nielsen, Jacob (J);

Affiliation: Department of Neurophysiology, H. Lundbeck A/S, Copenhagen-Valby, Denmark. fsot(-atsign-)lundbeck.com

Journal and publication information

Publication Type: Journal Article

Journal: Journal of neurochemistry (J Neurochem), published in England. (Language: eng)

Reference: 2009-May; vol 109 (issue 3) : pp 766-75

Dates: Created 2009/05/05; Completed 2009/06/09;

PMID: 19236563, status: MEDLINE (last retrieval date: 6/9/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Action Potentials - drug effects; physiology
Animals
Benzazepines - pharmacology
Dextroamphetamine - pharmacology
Dopamine - metabolism
Dose-Response Relationship, Drug
Drug Administration Routes
Drug Interactions
Male
Mesencephalon - cytology

Mesencephalon - cytology
Microdialysis - methods
Motor Activity - drug effects
Neurons - drug effects; physiology
Nucleus Accumbens - drug effects; metabolism
Phosphodiesterase Inhibitors - administration & dosage
Phosphoric Diester Hydrolases - metabolism
Rats
Rats, Wistar
Receptors, Dopamine D1 - antagonists & inhibitors; physiology

Associated Chemicals: Benzazepines (0) ; Phosphodiesterase Inhibitors (0) ; Receptors, Dopamine D1 (0) ; SCH 23390 (0) ; Dextroamphetamine (51-64-9) ; PDE10A protein, rat (EC 3.1.4.-) ; Phosphoric Diester Hydrolases (EC 3.1.4.-)

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