title: Region-specific activation of the AMPK system by cocaine: The role of D1 and D2 receptors.
abstract: The 5' adenosine monophosphate-activated protein kinase (AMPK) functions as an intracellular energy sensor that regulates and maintains energy balance. The psychostimulant drug cocaine has profound effects on behavior that are accentuated with repeated use, which is a process termed sensitization. Thus, the present study examined whether the sensitizing effects of cocaine could be observed in the AMPK system and aimed to determine whether these effects were mediated by dopamine (DA) D1 or D2 receptors. In the first set of experiments, rats were injected daily for 5days with either cocaine (15mg/kg, intraperitoneal [IP]) or saline. On the day 6, each group was divided into two subgroups and given either cocaine or saline. In the second set of experiments, rats were pretreated with SCH23390 (0.5mg/kg, IP), haloperidol (1mg/kg, IP), or both agents in combination, followed by cocaine or saline treatment. In the drug-naïve state, acute treatment with cocaine produced an increase in locomotor activity and increased AMPK phosphorylation in the frontal cortex but decreased it in the dorsal striatum. In the drug-sensitized state (following repeated treatment), the behavioral responsiveness to cocaine was augmented and accompanied by alterations in AMPK activity. The phosphorylation levels of the upstream kinases Ser-431-LKB1 and Thr-196-CaMK4 were congruent with the changes in AMPK activity. Thr-184/187-TAK1 was phosphorylated after chronic cocaine treatment in the dorsal striatum but not in the frontal cortex. The opposite effects induced by cocaine in the AMPK system in the dorsal striatum and frontal cortex may be explained by the differential activations of DA D1 and D2 receptors in these brain regions.
authors.affiliation: Clinical Research Institute, Seoul National University Hospital, 101 Daehak-Ro, Jongno-Gu, Seoul 110-744, Republic of Korea.
authors.forename: Shijie
authors.initials: S
authors.lastname: Xu
authors.affiliation: Institute of Human Behavioral Medicine, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul 110-744, Republic of Korea; Department of Psychiatry and Behavioral Science, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul 110-744, Republic of Korea. Electronic address: kangug@plaza.snu.ac.kr.
authors.forename: Ung Gu
authors.initials: UG
authors.lastname: Kang
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000378:metabolism; D059333:Central Nervous System Sensitization / Q000187:drug effects; D003042:Cocaine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D001552:Benzazepines; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D003042:Cocaine; D018765:Dopamine Uptake Inhibitors; D006220:Haloperidol; D020930:MAP Kinase Kinase Kinases; D017346:Protein Serine-Threonine Kinases; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D000099151:MAP Kinase Kinase Kinase 7; C534628:SCH 23390; C488755:Stk11 protein, rat; C517686:Camk4 protein, rat
keywords: AMP-activated protein kinase; Behavioral sensitization; Cocaine; Dopamine antagonist