PMID- 23995381
OWN - NLM
STAT- MEDLINE
DCOM- 20140324
LR  - 20230620
IS  - 1432-2072 (Electronic)
IS  - 0033-3158 (Print)
IS  - 0033-3158 (Linking)
VI  - 229
IP  - 3
DP  - 2013 Oct
TI  - Glutamatergic targets for new alcohol medications.
PG  - 539-54
LID - 10.1007/s00213-013-3226-2 [doi]
AB  - RATIONALE: An increasingly compelling literature points to a major role for the 
      glutamate system in mediating the effects of alcohol on behavior and the 
      pathophysiology of alcoholism. Preclinical studies indicate that glutamate 
      signaling mediates certain aspects of ethanol's intoxicating and rewarding 
      effects, and undergoes adaptations following chronic alcohol exposure that may 
      contribute to the withdrawal, craving and compulsive drug-seeking that drive 
      alcohol abuse and alcoholism. OBJECTIVES: We discuss the potential for targeting 
      the glutamate system as a novel pharmacotherapeutic approach to treating alcohol 
      use disorders, focusing on five major components of the glutamate system: the 
      N-methyl-D-aspartate (NMDA) receptor and specific NMDA subunits, the glycineB 
      site on the NMDA receptors (NMDAR), 
      L-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid ionotropic (AMPA) and 
      kainate (KAR) receptors, metabotropic receptors (mGluR), and glutamate 
      transporters. RESULTS: Chronic alcohol abuse produces a hyperglutamatergic state, 
      characterized by elevated extracellular glutamate and altered glutamate receptors 
      and transporters. Pharmacologically manipulating glutamatergic neurotransmission 
      alters alcohol-related behaviors including intoxication, withdrawal, and 
      alcohol-seeking, in rodents and human subjects. Blocking NMDA and AMPA receptors 
      reduces alcohol consumption in rodents, but side-effects may limit this as a 
      therapeutic approach. Selectively targeting NMDA and AMPA receptor subunits 
      (e.g., GluN2B, GluA3), or the NMDAR glycineB site offers an alternative approach. 
      Blocking mGluR5 potently affects various alcohol-related behaviors in rodents, 
      and mGluR2/3 agonism also suppresses alcohol consumption. Finally, glutamate 
      transporter upregulation may mitigate behavioral and neurotoxic sequelae of 
      excess glutamate caused by alcohol. CONCLUSIONS: Despite the many challenges that 
      remain, targeting the glutamate system offers genuine promise for developing new 
      treatments for alcoholism.
FAU - Holmes, Andrew
AU  - Holmes A
AD  - Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol 
      Abuse and Alcoholism, NIH, Bethesda, MD, USA, holmesan@mail.nih.gov.
FAU - Spanagel, Rainer
AU  - Spanagel R
FAU - Krystal, John H
AU  - Krystal JH
LA  - eng
GR  - UL1 RR024139/RR/NCRR NIH HHS/United States
GR  - 2P50AA012870/AA/NIAAA NIH HHS/United States
GR  - ZIA AA000411-09/ImNIH/Intramural NIH HHS/United States
GR  - ZIA AA000411/ImNIH/Intramural NIH HHS/United States
GR  - UL1RR024139/RR/NCRR NIH HHS/United States
GR  - P50 AA012870/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Review
DEP - 20130901
PL  - Germany
TA  - Psychopharmacology (Berl)
JT  - Psychopharmacology
JID - 7608025
RN  - 0 (Protein Subunits)
RN  - 0 (Receptors, AMPA)
RN  - 0 (Receptors, Kainic Acid)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 3KX376GY7L (Glutamic Acid)
SB  - IM
MH  - Alcoholism/*drug therapy/metabolism/psychology
MH  - Animals
MH  - Drug-Seeking Behavior/drug effects
MH  - Glutamic Acid/*metabolism
MH  - Humans
MH  - Molecular Targeted Therapy/*methods
MH  - Protein Subunits
MH  - Receptors, AMPA/metabolism
MH  - Receptors, Kainic Acid/metabolism
MH  - Receptors, N-Methyl-D-Aspartate/metabolism
MH  - Substance Withdrawal Syndrome/metabolism/prevention & control/psychology
PMC - PMC3811052
MID - NIHMS520611
EDAT- 2013/09/03 06:00
MHDA- 2014/03/25 06:00
PMCR- 2014/10/01
CRDT- 2013/09/03 06:00
PHST- 2013/04/11 00:00 [received]
PHST- 2013/07/23 00:00 [accepted]
PHST- 2013/09/03 06:00 [entrez]
PHST- 2013/09/03 06:00 [pubmed]
PHST- 2014/03/25 06:00 [medline]
PHST- 2014/10/01 00:00 [pmc-release]
AID - 10.1007/s00213-013-3226-2 [doi]
PST - ppublish
SO  - Psychopharmacology (Berl). 2013 Oct;229(3):539-54. doi: 
      10.1007/s00213-013-3226-2. Epub 2013 Sep 1.