Susceptibility of dopamine D5 receptor targeted mice to cysteamine.
BACKGROUND
Recently we demonstrated that gastric mucosa of rats can synthesize, store and release dopamine. Out of five different subtypes, mRNA of D5 (=D1b) dopamine receptor is very abundant in the gastric epithelium. D1 receptor selective dopamine agonists have been shown to protect against experimental gastro-duodenal lesions.


OBJECTIVE
To test the hypothesis that protective effects of dopamine involve D5 receptors, mucosal lesions were induced in D5 receptor deficient (KO) and wild-type (WT) mice using cysteamine. Morphology and gastric acid secretion of D5 KO mice were also studied.


METHODS
Single doses of 600 mg/kg, 300 mg/kg cysteamine or vehicle were administered subcutaneously to fasted animals. After 24 h, number and severity of gastro-duodenal lesions were analyzed. Basal and histamine-induced maximal gastric acid output were measured by a stomach-sac wash-through method.


RESULTS
All the KOs in the 600 mg/kg cysteamine group died within 4 h showing symptoms of toxicity while three out of four WTs survived (P<0.05). Mortality after 300 mg/kg cysteamine was significantly higher in KOs versus the WTs: 6/14 versus 2/11, P<0.05. Gastric lesion-index was also significantly higher in KOs (median, middle quartile): four (3-9) versus 0 (0-0), P<0.05. Duodenal lesions did not develop from this single dose of cysteamine in either genotype. Basal and histamine-induced maximal gastric acid output were comparable in the two genotypes.


CONCLUSIONS
This study demonstrates that loss of D5 receptor causes mucosal vulnerability and increased toxicity of cysteamine in genetically manipulated mice. Thus, D5 receptor subtype is indeed likely to be involved in protective effects of dopamine in the stomach.
Hunyady
B
B
First Department of Internal Medicine, Medical Faculty, University of Pécs, Hungary. hunyady@clinics.pote.hu
Palkovits
M
M
Mózsik
G
G
Molnár
J
J
Fehér
K
K
Tóth
Z
Z
Zólyomi
A
A
Szalayova
I
I
Key
S
S
Sibley
D R
DR
Mezey E
D000818:Animals; D003543:Cysteamine / Q000494:pharmacology*; D019610:Cytoprotection / Q000502:physiology*; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050641:Receptors, Dopamine D5; D012016:Reference Values
C493606:Drd5 protein, mouse; D017447:Receptors, Dopamine D1; D050641:Receptors, Dopamine D5; D003543:Cysteamine