Neuroimmunophilin GPI-1046 reduces ethanol consumption in part through activation of GLT1 in alcohol-preferring rats

Neuroscience. 2012 Dec 27;227:327-35. doi: 10.1016/j.neuroscience.2012.10.007. Epub 2012 Oct 8.

Abstract

We have previously shown that ceftriaxone, β-lactam antibiotic known to upregulate glutamate transporter 1 (GLT1), reduced ethanol intake in alcohol-preferring (P) rats. GLT1 is a glial glutamate transporter that regulates the majority of extracellular glutamate uptake. We tested in this study the effects of neuroimmunophilin GPI-1046 (3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate), known also to upregulate GLT1 expression, in ethanol intake in P rats. Male P rats had concurrent access to free choice of 15% and 30% ethanol, water, and food for five weeks. On Week 6, P rats continued in this drinking and food regimen and they were administered either 10 or 20mg/kg GPI-1046 (i.p.), or a vehicle for five consecutive days. Body weight, ethanol intake, and water consumption were measured daily for 8 days starting on Day 1 of GPI-1046 or vehicle i.p. injections. We have also tested the effect of GPI-1046 (20mg/kg) on daily sucrose (10%) intake. The data revealed significant dose-dependent effects in the reduction of ethanol intake starting 48 h after the first treatment with GPI-1046 throughout treatment and post-treatment periods. There were also dose-dependent increases in water intake. However, GPI-1046 treatment did not affect the body weight of all animals nor sucrose intake. Importantly, GPI-1046 (20mg/kg) increased GLT1 level compared to all groups in nucleus accumbens core (NAc-core). Alternatively, GPI-1046 (10mg/kg) upregulated GLT1 level in NAc-core compared to vehicle (ethanol naïve) group. Moreover, both doses of GPI-1046 increased significantly GLT1 level in the prefrontal cortex (PFC) compared to ethanol naïve vehicle group. GPI-1046 (20mg/kg) increased GLT1 level in PFC compared to naïve control group that was exposed to water and food only. These findings demonstrated that neuroimmunophilin GPI-1046 attenuates ethanol intake in part through the upregulation of GLT1 in PFC and NAc-core.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alcohol Drinking / drug therapy*
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Body Weight / drug effects
  • Central Nervous System Depressants / administration & dosage*
  • Dose-Response Relationship, Drug
  • Drinking / drug effects
  • Ethanol / administration & dosage*
  • Food Preferences / drug effects
  • Gene Expression Regulation / drug effects
  • Glutamate Plasma Membrane Transport Proteins / metabolism*
  • Male
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism*
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism*
  • Pyrrolidines / therapeutic use*
  • Rats
  • Sucrose / administration & dosage
  • Sweetening Agents / administration & dosage
  • Time Factors

Substances

  • Central Nervous System Depressants
  • GPI 1046
  • Glutamate Plasma Membrane Transport Proteins
  • Pyrrolidines
  • Sweetening Agents
  • Ethanol
  • Sucrose