Galanin protects against behavioral and neurochemical correlates of opiate reward.
The mechanisms underlying responses to drugs of abuse have been widely investigated; however, less is known about pathways normally protective against the development of drug reinforcement. These pathways are also important since they may regulate individual differences in vulnerability to addiction. The neuropeptide galanin and its binding sites are expressed in brain areas important for drug reward. Previous studies have shown that centrally infused galanin attenuates morphine place preference and peripheral injection of galnon, a galanin agonist, decreases opiate withdrawal signs. The current studies in galanin knockout (GKO) mice examined the hypothesis that galanin is an endogenous negative regulator of opiate reward and identified downstream signaling pathways regulated by galanin. We show that GKO mice demonstrate increased locomotor activation following morphine administration, which is inhibited by acute administration of galnon. GKO mice also show enhanced morphine place preference, supporting the idea that galanin normally antagonizes opiate reward. In addition, morphine-induced ERK1/2 phosphorylation was increased in the VTA of both wild-type and GKO mice, but only the GKO mice showed increases in ERK1/2 and CREB phosphorylation in the amygdala or nucleus accumbens. Furthermore, a single systemic injection of galnon in GKO mice was sufficient to reverse some of the biochemical changes brought about by morphine administration. These data suggest that galanin normally attenuates behavioral and neurochemical effects of opiates; thus, galanin agonists may represent a new class of therapeutic targets for opiate addiction.
Hawes
Jessica J
JJ
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508, USA.
Brunzell
Darlene H
DH
Narasimhaiah
Roopashree
R
Langel
Ulo
U
Wynick
David
D
Picciotto
Marina R
MR
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects*; D003216:Conditioning, Operant / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019004:Galanin / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009021:Morphine Dependence / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology*; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009294:Narcotics / Q000494:pharmacology; D012201:Reward; D015398:Signal Transduction / Q000187:drug effects
D017362:Cyclic AMP Response Element-Binding Protein; D009294:Narcotics; D009020:Morphine; D019004:Galanin; D048049:Extracellular Signal-Regulated MAP Kinases