Dopamine D3 receptor knock-out mice exhibit increased behavioral sensitivity to the anxiolytic drug diazepam.
Dopamine D(3) receptors (DRsD3) seem to have a pivotal role in mood disorders. Using the elevated plus maze (EPM) and the novelty-induced grooming test (NGT), we assessed the responses of DRD3-deficient (D(3)(-/-)) mice to the acute treatment (different testing time) with the anxiolytic drug, diazepam. D(3)(-/-) mice treated with diazepam (0.1 or 0.5mg/kg) exhibited a better behavioral response in the EPM than their wild type (WT). Furthermore, in D(3)(-/-) mice, but not in WT, 1mg/kg diazepam induced anxiolytic effects at all testing times. The contribution of DRsD3 in the anxiolytic effects of diazepam was confirmed by similar results obtained in EPM by using the selective DRD3 antagonist U99194A (10mg/kg) in combination with diazepam, in WT animals. D(3)(-/-) mice treated with diazepam (all doses), also showed a decrease in grooming behavior. However, the [(3)H]flunitrazepam autoradiographic analysis revealed no significant changes in D(3)(-/-) mice compared to WT, suggesting that if γ-aminobutyric acid receptor GABA(A) changes are involved, they do not occur at the level of binding to benzodiazepine site. These data suggest that D(3)(-/-) mice exhibit low baseline anxiety levels and provide the evidence that the DRD3 is involved in the modulation of benzodiazepine anxiolytic effects.
Leggio
Gian Marco
GM
Department of Experimental and Clinical Pharmacology, University of Catania, V.le A. Doria 6, 95125 Catania, Italy.
Micale
Vincenzo
V
Le Foll
Bernard
B
Mazzola
Carmen
C
Nobrega
José N
JN
Drago
Filippo
F
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy* / Q000235:genetics; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000378:metabolism; D003975:Diazepam / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D006120:Grooming / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019964:Mood Disorders / Q000188:drug therapy / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D009928:Organ Specificity; D011897:Random Allocation; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011963:Receptors, GABA-A / Q000378:metabolism; D013997:Time Factors
D014151:Anti-Anxiety Agents; C493594:Drd3 protein, mouse; D009419:Nerve Tissue Proteins; D050637:Receptors, Dopamine D3; D011963:Receptors, GABA-A; D003975:Diazepam