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More Cocaine—More Glutamate—More Addiction

      Over the last 15 years, animal models of cocaine reinforcement and reinstated drug seeking have pointed to the involvement of nucleus accumbens dopamine and glutamate neurotransmission in regulating drug intake and drug seeking, respectively (
      • Pierce R.C.
      • Kumaresan V.
      The mesolimbic dopamine system: The final common pathway for the reinforcing effect of drugs of abuse?.
      ,
      • Kalivas P.W.
      • Volkow N.D.
      New medications for drug addiction hiding in glutamatergic neuroplasticity.
      ). For reinstated drug seeking, evidence supporting glutamate transmission in the core subcompartment of the accumbens (NAcore) is conclusive, including: 1) α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonists prevent reinstatement of cocaine seeking; and 2) there exist enduring neuroadaptations in glutamate transmission, such as downregulated glutamate transport or upregulated calcium-permeable AMPA receptors, that if normalized prevent reinstated cocaine seeking. In contrast with the clear involvement of glutamate in reinstated drug seeking, self-administration paradigms have been used to show that dopamine transmission in the accumbens is a necessary factor for reinforcing cocaine use. Thus, there is a generally assumed axiom among addiction researchers and clinicians that while dopamine transmission supports the learning and subsequent repeated use of cocaine, glutamate release in the accumbens drives relapse to drug seeking, especially in the NAcore and after periods of drug withdrawal. However, the study by Doyle et al. (
      • Doyle S.E.
      • Ramôa C.
      • Garber G.
      • Newman J.
      • Toor Z.
      • Lynch W.J.
      A shift in the role of glutamatergic signaling in the nucleus accumbens core with the development of an addicted phenotype.
      ) in this issue of Biological Psychiatry provides important insights into how glutamatergic transmission in the NAcore can also be recruited to contribute to the reinforcing properties of cocaine when animals are allowed access to larger quantities of cocaine.
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