Effect of Modulation of the Astrocytic Glutamate Transporters' Expression on Cocaine-Induced Reinstatement in Male P Rats Exposed to Ethanol

Alcohol Alcohol. 2021 Feb 24;56(2):210-219. doi: 10.1093/alcalc/agaa104.


Aim: Reinforcing properties of ethanol and cocaine are mediated in part through the glutamatergic system. Extracellular glutamate concentration is strictly maintained through several glutamate transporters, such as glutamate transporter 1 (GLT-1), cystine/glutamate transporter (xCT) and glutamate aspartate transporter (GLAST). Previous findings revealed that cocaine and ethanol exposure downregulated GLT-1 and xCT, and that β-lactam antibiotics restored their expression.

Methods: In this study, we investigated the effect of ampicillin/sulbactam (AMP/SUL) (200 mg/kg, i.p.), a β-lactam antibiotic, on cocaine-induced reinstatement and locomotor activity in male alcohol preferring (P) rats using free choice ethanol (15 and 30%, v/v) and water. We also investigated the effect of co-exposure to ethanol and cocaine (20 mg/kg, i.p.) on GLT-1, xCT and GLAST expression in the nucleus accumbens (NAc) core, NAc shell and dorsomedial prefrontal cortex (dmPFC).

Results: Cocaine exposure decreased ethanol intake and preference. Cocaine and ethanol co-exposure acquired place preference and increased locomotor activity compared to ethanol-exposed rats. GLT-1 and xCT expression were downregulated after cocaine and ethanol co-exposure in the NAc core and shell, but not in dmPFC. AMP/SUL attenuated reinstatement to cocaine as well attenuated the decrease in locomotor activity and ethanol intake and preference. These effects were associated with upregulation of GLT-1 and xCT expression in the NAc core/shell and dmPFC. GLAST expression was not affected after ethanol and cocaine co-exposure or AMP/SUL treatment.

Conclusion: Our findings demonstrate that astrocytic glutamate transporters within the mesocorticolimbic area are critical targets in modulating cocaine-seeking behavior while being consuming ethanol.

MeSH terms

  • Alcohol Drinking / psychology*
  • Amino Acid Transport System X-AG / metabolism*
  • Amino Acid Transport Systems, Acidic / metabolism
  • Animals
  • Astrocytes / metabolism*
  • Cocaine / administration & dosage*
  • Cocaine-Related Disorders / psychology*
  • Drug-Seeking Behavior*
  • Ethanol / administration & dosage*
  • Excitatory Amino Acid Transporter 1 / metabolism
  • Excitatory Amino Acid Transporter 2 / metabolism
  • Male
  • Rats
  • beta-Lactams / pharmacology


  • Amino Acid Transport System X-AG
  • Amino Acid Transport Systems, Acidic
  • Excitatory Amino Acid Transporter 1
  • Excitatory Amino Acid Transporter 2
  • Slc1a2 protein, rat
  • Slc1a3 protein, rat
  • beta-Lactams
  • xCT protein, rat
  • Ethanol
  • Cocaine