title: Effects of ampicillin, cefazolin and cefoperazone treatments on GLT-1 expressions in the mesocorticolimbic system and ethanol intake in alcohol-preferring rats.
abstract: Chronic ethanol consumption is known to downregulate expression of the major glutamate transporter 1 (GLT-1), which increases extracellular glutamate concentrations in subregions of the mesocorticolimbic reward pathway. While β-lactam antibiotics were initially identified as potent upregulators of GLT-1 expression, only ceftriaxone has been extensively studied in various drug addiction models. Therefore, in this study, adult male alcohol-preferring (P) rats exposed chronically to ethanol were treated with other β-lactam antibiotics, ampicillin, cefazolin or cefoperazone (100mg/kg) once daily for five consecutive days to assess their effects on ethanol consumption. The results demonstrated that each compound significantly reduced ethanol intake compared to the saline-treated control group. Importantly, each compound significantly upregulated both GLT-1 and pAKT expressions in the nucleus accumbens and prefrontal cortex compared to saline-treated control group. In addition, only cefoperazone significantly inhibited hepatic aldehyde dehydrogenase-2 enzyme activity. Moreover, these β-lactams exerted only a transient effect on sucrose drinking, suggesting specificity for chronically inhibiting ethanol reward in adult male P rats. Cerebrospinal fluid concentrations of ampicillin, cefazolin or cefoperazone have been confirmed using high-performance liquid chromatography. These findings demonstrate that multiple β-lactam antibiotics demonstrate efficacy in reducing alcohol consumption and appear to be potential therapeutic compounds for treating alcohol abuse and/or dependence. In addition, these results suggest that pAKT may be an important player in this effect, possibly through increased transcription of GLT-1.
authors: University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology, Toledo, OH, USA.
authors: P S S
authors: PS
authors: Rao
authors: University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology, Toledo, OH, USA.
authors: S
authors: S
authors: Goodwani
authors: Indiana University School of Medicine, Department of Psychiatry, Indianapolis, IN, USA.
authors: R L
authors: RL
authors: Bell
authors: University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacy Practice, Toledo, OH, USA.
authors: Y
authors: Y
authors: Wei
authors: University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacy Practice, Toledo, OH, USA.
authors: S H S
authors: SH
authors: Boddu
authors: University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology, Toledo, OH, USA. Electronic address: youssef.sari@utoledo.edu.
authors: Y
authors: Y
authors: Sari
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy*; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000667:Ampicillin / Q000134:cerebrospinal fluid / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D002437:Cefazolin / Q000134:cerebrospinal fluid / Q000627:therapeutic use; D002438:Cefoperazone / Q000134:cerebrospinal fluid / Q000627:therapeutic use; D002492:Central Nervous System Depressants / Q000009:adverse effects*; D003216:Conditioning, Operant / Q000187:drug effects; D004326:Drinking / Q000187:drug effects; D000431:Ethanol / Q000009:adverse effects*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D005518:Food Preferences / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D002492:Central Nervous System Depressants; D027342:Excitatory Amino Acid Transporter 2; D024101:Mitochondrial Proteins; C493395:Slc1a2 protein, rat; D013549:Sweetening Agents; D000431:Ethanol; D013395:Sucrose; D000667:Ampicillin; D002438:Cefoperazone; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D051058:Oncogene Protein v-akt; D002437:Cefazolin
keywords: EAAT2; alcohol intake; ampicillin; cefazolin; cefoperazone; glutamate