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PMID: 15385604 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Chronic haloperidol promotes corticostriatal long-term potentiation by targeting dopamine D2L receptors.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 24 ·No. 38 ·2004-09-22 ·Pages 8214-22

Centonze D, Usiello A, Costa C, Picconi B, Erbs E, Bernardi G, Borrelli E, Calabresi P

Abstract

Reduced glutamate-mediated synaptic transmission has been implicated in the pathophysiology of schizophrenia. Because antipsychotic agents might exert their beneficial effects against schizophrenic symptoms by strengthening excitatory transmission in critical dopaminoceptive brain areas, in the present study we have studied the effects of acute and chronic haloperidol treatment on striatal synaptic plasticity. Repetitive stimulation of corticostriatal terminals in slices induced either long-term depression or long-term potentiation (LTP) of excitatory transmission in control rats, whereas it invariably induced NMDA receptor-dependent LTP in animals treated chronically with haloperidol. Haloperidol effects were mimicked and occluded in mice lacking both D2L and D2S isoforms of dopamine D2 receptors (D2R-/-), in mice lacking D2L receptors and expressing normal levels of D2S receptors (D2R-/-;D2L-/-), and in mice lacking D2L receptors and overexpressing D2S receptors (D2L-/-). These data indicate that the blockade of D2L receptors was responsible for the LTP-favoring action of haloperidol in the striatum. In contrast, overexpression of D2S receptors uncovered a facilitatory role of this receptor isoform in LTP formation because LTP recorded from D2L-/- mice, but not those recorded from wild-type, D2R-/-, and D2R-/-;D2L-/- mice, was insensitive to the pharmacological blockade of D1 receptors. The identification of the cellular, molecular, and receptor mechanisms involved in the action of haloperidol in the brain is essential to understand how antipsychotic agents exert their beneficial and side effects.

MeSH Terms
Animals Antipsychotic Agents/pharmacology Binding Sites/drug effects Cerebral Cortex/drug effects,physiology Dopamine Antagonists/pharmacology Haloperidol/pharmacology Ligands Long-Term Potentiation/drug effects,physiology Long-Term Synaptic Depression/drug effects,physiology Male Mice Mice, Knockout Motor Activity/drug effects Neostriatum/drug effects,physiology Neuronal Plasticity/drug effects Organ Culture Techniques Patch-Clamp Techniques Protein Kinase C/drug effects,physiology Rats Rats, Wistar Receptors, Dopamine D1/antagonists & inhibitors Receptors, Dopamine D2/drug effects,genetics,metabolism Receptors, N-Methyl-D-Aspartate/drug effects,physiology Synaptic Transmission/drug effects,physiology Time Factors
Chemicals
Antipsychotic Agents Dopamine Antagonists Ligands Receptors, Dopamine D1 Receptors, Dopamine D2 Receptors, N-Methyl-D-Aspartate dopamine D2L receptor Protein Kinase C Haloperidol
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Centonze Diego
Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, 00133 Rome, Italy.
Usiello Alessandro
Costa Cinzia
Picconi Barbara
Erbs Eric
Bernardi Giorgio
Borrelli Emiliana
Calabresi Paolo
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.1274-04.2004
Published
2004-09-22
Pages
8214-22
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6729682
Subset
IM
Grants
Telethon · GGP02035 · Italy
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1523/JNEUROSCI.1274-04.2004 PMC Full Text View journal details
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