Oxytocin reduces cocaine seeking and reverses chronic cocaine-induced changes in glutamate receptor function.
BACKGROUND
Oxytocin, a neurohypophyseal neuropeptide, is a potential mediator and regulator of drug addiction. However, the cellular mechanisms of oxytocin in drug seeking remain unknown.


METHODS
In the present study, we used a self-administration/reinstatement model to study the effects of oxytocin on cocaine seeking and its potential interaction with glutamate function at the receptor level.


RESULTS
Systemic oxytocin dose-dependently reduced cocaine self-administration during various schedules of reinforcement, including fixed ratio 1, fixed ratio 5, and progressive ratio. Oxytocin also attenuated reinstatement to cocaine seeking induced by cocaine prime or conditioned cues. Western-blot analysis indicated that oxytocin increased phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor GluA1 subunit at the Ser 845 site with or without accompanying increases in phosphorylation of extracellular signal-regulated kinase, in several brain regions, including the prefrontal cortex, bed nucleus of the stria terminalis, amygdala, and dorsal hippocampus. Immunoprecipitation of oxytocin receptor and GluA1 subunit receptors further demonstrated a physical interaction between these 2 receptors, although the interaction was not influenced by chronic cocaine or oxytocin treatment. Oxytocin also attenuated sucrose seeking in a GluA1- or extracellular-signal-regulated kinase-independent manner.


CONCLUSIONS
These findings suggest that oxytocin mediates cocaine seeking through interacting with glutamate receptor systems via second messenger cascades in mesocorticolimbic regions.
['Zhou|Luyi|L|', 'Sun|Wei-Lun|WL|', 'Young|Amy B|AB|', 'Lee|Kunhee|K|', 'McGinty|Jacqueline F|JF|', 'See|Ronald E|RE|']
D000818:Animals D001921:Brain D002491:Central Nervous System Agents D003042:Cocaine D019970:Cocaine-Related Disorders D019422:Dietary Sucrose D018765:Dopamine Uptake Inhibitors D004305:Dose-Response Relationship, Drug D058999:Drug-Seeking Behavior D005108:Extinction, Psychological D048049:Extracellular Signal-Regulated MAP Kinases D008297:Male D010121:Oxytocin D010766:Phosphorylation D017207:Rats, Sprague-Dawley D018091:Receptors, AMPA D012055:Reinforcement Schedule D012646:Self Administration
oxytocin cocaine glutamate receptor reinstatement self-administration.