Role for GDNF in biochemical and behavioral adaptations to drugs of abuse.
The present study examined a role for GDNF in adaptations to drugs of abuse. Infusion of GDNF into the ventral tegmental area (VTA), a dopaminergic brain region important for addiction, blocks certain biochemical adaptations to chronic cocaine or morphine as well as the rewarding effects of cocaine. Conversely, responses to cocaine are enhanced in rats by intra-VTA infusion of an anti-GDNF antibody and in mice heterozygous for a null mutation in the GDNF gene. Chronic morphine or cocaine exposure decreases levels of phosphoRet, the protein kinase that mediates GDNF signaling, in the VTA. Together, these results suggest a feedback loop, whereby drugs of abuse decrease signaling through endogenous GDNF pathways in the VTA, which then increases the behavioral sensitivity to subsequent drug exposure.
Messer
C J
CJ
Laboratory of Molecular Psychiatry and Yale Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center, New Haven 06508, USA.
Eisch
A J
AJ
Carlezon
W A
WA
Whisler
K
K
Shen
L
L
Wolf
D H
DH
Westphal
H
H
Collins
F
F
Russell
D S
DS
Nestler
E J
EJ
D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D013287:Illicit Drugs / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009294:Narcotics / Q000494:pharmacology; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism
D018765:Dopamine Uptake Inhibitors; C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D013287:Illicit Drugs; D009294:Narcotics; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009020:Morphine; D003042:Cocaine