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PMID: 9323127 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine.

Cell ·Vol. 90 ·No. 6 ·1997-09-19 ·Pages 991-1001

Rubinstein M, Phillips TJ, Bunzow JR, Falzone TL, Dziewczapolski G, Zhang G, Fang Y, Larson JL, McDougall JA, Chester JA, Saez C, Pugsley TA, Gershanik O, Low MJ, Grandy DK

Abstract

The human dopamine D4 receptor (D4R) has received considerable attention because of its high affinity for the atypical antipsychotic clozapine and the unusually polymorphic nature of its gene. To clarify the in vivo role of the D4R, we produced and analyzed mutant mice (D4R-/-) lacking this protein. Although less active in open field tests, D4R-/- mice outperformed wild-type mice on the rotarod and displayed locomotor supersensitivity to ethanol, cocaine, and methamphetamine. Biochemical analyses revealed that dopamine synthesis and its conversion to DOPAC were elevated in the dorsal striatum from D4R-/- mice. Based on these findings, we propose that the D4R modulates normal, coordinated and drug-stimulated motor behaviors as well as the activity of nigrostriatal dopamine neurons.

MeSH Terms

3,4-Dihydroxyphenylacetic Acid/metabolism Amino Acid Sequence Animals Antipsychotic Agents/pharmacology Behavior, Animal/drug effects Central Nervous System Depressants/pharmacology Clozapine/pharmacology Cocaine/pharmacology Corpus Striatum/anatomy & histology,chemistry,metabolism Dopamine/metabolism Dopamine Agents/pharmacology Ethanol/pharmacology Genotype Humans Levodopa/analysis,pharmacokinetics Locomotion/drug effects Maternal Behavior/drug effects Methamphetamine/pharmacology Mice Mice, Knockout Molecular Sequence Data Motor Activity/drug effects Mutagenesis, Site-Directed/physiology Narcotics/pharmacology Nucleus Accumbens/chemistry,metabolism Receptors, Dopamine D2/deficiency,genetics Receptors, Dopamine D4 Sensitivity and Specificity Substantia Nigra/anatomy & histology,chemistry,metabolism Transcription, Genetic/genetics

Chemicals

Antipsychotic Agents Central Nervous System Depressants DRD4 protein, human Dopamine Agents Drd4 protein, mouse Narcotics Receptors, Dopamine D2 3,4-Dihydroxyphenylacetic Acid Receptors, Dopamine D4 Ethanol Methamphetamine Levodopa Cocaine Clozapine Dopamine

Authors & Affiliations

15 authors, click to expand affiliations / ORCID

Rubinstein M

Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, CONICET, and Depto. Química Biologica, FCEyN, Universidad de Buenos Aires, Argentina.

Phillips T J

Bunzow J R

Falzone T L

Dziewczapolski G

Zhang G

Fang Y

Larson J L

McDougall J A

Chester J A

Saez C

Pugsley T A

Gershanik O

Low M J

Grandy D K

Article Info

Journal

Cell

Abbr.

Cell

ISSN

0092-8674

DOI

10.1016/s0092-8674(00)80365-7

Published

1997-09-19

Pages

991-1001

Language

English

Region

United States

NLM ID

0413066

Subset

Grants

NIAAA NIH HHS · P60 AA010760 · United States

External Links

PubMed source DOI: 10.1016/s0092-8674(00)80365-7 View journal details

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Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine.

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