Extending the previously mentioned behavioral pharmacologic and neuropharmacologic studies are the results of a very comprehensive study by Meinhardt and coworkers,200 demonstrating that: (1) in ethanol-dependent rats, glutamate-related gene changes were primarily seen in the mPFC, rather than the Acb or amygdala; (2) within the mPFC of ethanol-dependent rats, downregulation of the NMDA-receptor subunits Glun2a and Glun2b, as well as mGlu2, but not mGlu3, and egr1 (early growth response protein 1: Zif268, a transcription factor involved in neuroplasticity and vesicular exo-cytosis at excitatory synapses) were significant in the infralimbic mPFC only, with mGlu2 displaying the greatest reduction; (3) the AcbSh receives its glutamatergic projections primarily from the infralimbic mPFC, according to retrograde tracing, and these projection neurons displayed significant ethanol-dependence-associated downregulation of mGlu2, Egr2, and Egr4; (4) while basal glutamate in the AcbSh did not differ between ethanol-dependent and control rats, peripheral administration of the mGlu2/3 agonist LY379268 significantly reduced extracellular glutamate in the AcbSh of control but not ethanol-dependent rats, suggesting a downregulation of mGlu2/3 function; (5) ethanol-dependent rats displayed greater relapse (almost twice as many responses) and progressive
