Cabergoline decreases alcohol drinking and seeking behaviors via glial cell line-derived neurotrophic factor.
BACKGROUND
Cabergoline is an ergotamine derivative that increases the expression of glial cell line-derived neurotrophic factor (GDNF) in vitro. We recently showed that GDNF in the ventral tegmental area (VTA) reduces the motivation to consume alcohol. We therefore set out to determine whether cabergoline administration decreases alcohol-drinking and -seeking behaviors via GDNF.


METHODS
Reverse transcription polymerase chain reaction (RT-PCR) and Enzyme-Linked ImmunoSorbent Assay (ELISA) were used to measure GDNF levels. Western blot analysis was used for phosphorylation experiments. Operant self-administration in rats and a two-bottle choice procedure in mice were used to assess alcohol-drinking behaviors. Instrumental performance tested during extinction was used to measure alcohol-seeking behavior. The [35S]GTPgammaS binding assay was used to assess the expression and function of the dopamine D2 receptor (D2R).


RESULTS
We found that treatment of the dopaminergic-like cell line SH-SY5Y with cabergoline and systemic administration of cabergoline in rats resulted in an increase in GDNF level and in the activation of the GDNF pathway. Cabergoline treatment decreased alcohol-drinking and -seeking behaviors including relapse, and its action to reduce alcohol consumption was localized to the VTA. Finally, the increase in GDNF expression and the decrease in alcohol consumption by cabergoline were abolished in GDNF heterozygous knockout mice.


CONCLUSIONS
Together, these findings suggest that cabergoline-mediated upregulation of the GDNF pathway attenuates alcohol-drinking behaviors and relapse. Alcohol abuse and addiction are devastating and costly problems worldwide. This study puts forward the possibility that cabergoline might be an effective treatment for these disorders.
Carnicella
Sebastien
S
The Gallo Research Center, University of California, San Francisco, Emeryville, California, USA.
Ahmadiantehrani
Somayeh
S
He
Dao-Yao
DY
Nielsen
Carsten K
CK
Bartlett
Selena E
SE
Janak
Patricia H
PH
Ron
Dorit
D
D000427:Alcohol Deterrents; D000428:Alcohol Drinking / Q000188:drug therapy* / Q000523:psychology*; D000818:Animals; D000077465:Cabergoline; D003216:Conditioning, Operant / Q000187:drug effects; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D004873:Ergolines / Q000008:administration & dosage / Q000494:pharmacology*; D005108:Extinction, Psychological / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007274:Injections, Intraperitoneal; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008845:Microinjections; D051381:Rats; D012646:Self Administration; D013378:Substantia Nigra / Q000502:physiology
D000427:Alcohol Deterrents; D018491:Dopamine Agonists; D004873:Ergolines; D051100:Glial Cell Line-Derived Neurotrophic Factor; D000077465:Cabergoline