title: D-Serine and D-Cycloserine Reduce Compulsive Alcohol Intake in Rats.
abstract: There is considerable interest in NMDAR modulators to enhance memory and treat neuropsychiatric disorders such as addiction, depression, and schizophrenia. D-serine and D-cycloserine, the NMDAR activators at the glycine site, are of particular interest because they have been used in humans without serious adverse effects. Interestingly, D-serine also inhibits some NMDARs active at hyperpolarized potentials (HA-NMDARs), and we previously found that HA-NMDARs within the nucleus accumbens core (NAcore) are critical for promoting compulsion-like alcohol drinking, where rats consume alcohol despite pairing with an aversive stimulus such as quinine, a paradigm considered to model compulsive aspects of human alcohol use disorders (AUDs). Here, we examined the impact of D-serine and D-cycloserine on this aversion-resistant alcohol intake (that persists despite adulteration with quinine) and consumption of quinine-free alcohol. Systemic D-serine reduced aversion-resistant alcohol drinking, without altering consumption of quinine-free alcohol or saccharin with or without quinine. Importantly, D-serine within the NAcore but not the dorsolateral striatum also selectively reduced aversion-resistant alcohol drinking. In addition, D-serine inhibited EPSCs evoked at -70 mV in vitro by optogenetic stimulation of mPFC-NAcore terminals in alcohol-drinking rats, similar to reported effects of the NMDAR blocker AP5. Further, D-serine preexposure occluded AP5 inhibition of mPFC-evoked EPSCs, suggesting that D-serine reduced EPSCs by inhibiting HA-NMDARs. Systemic D-cycloserine also selectively reduced intake of quinine-adulterated alcohol, and D-cycloserine inhibited NAcore HA-NMDARs in vitro. Our results indicate that HA-NMDAR modulators can reduce aversion-resistant alcohol drinking, and support testing of D-serine and D-cycloserine as immediately accessible, FDA-approved drugs to treat AUDs.
authors: Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
authors: Taban
authors: T
authors: Seif
authors: Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
authors: Jeffrey A
authors: JA
authors: Simms
authors: Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
authors: Kelly
authors: K
authors: Lei
authors: Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
authors: Scott
authors: S
authors: Wegner
authors: 1] NIDA Intramural Research Program, Baltimore, MD, USA [2] Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
authors: Antonello
authors: A
authors: Bonci
authors: 1] Department of Neurology, University of California at San Francisco, San Francisco, CA, USA [2] The University of Texas at Austin, College of Pharmacy, Austin, TX, USA.
authors: Robert O
authors: RO
authors: Messing
authors: Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
authors: F Woodward
authors: FW
authors: Hopf
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy* / Q000503:physiopathology*; D000818:Animals; D003192:Compulsive Behavior / Q000188:drug therapy* / Q000209:etiology*; D003523:Cycloserine / Q000627:therapeutic use*; D000431:Ethanol / Q000009:adverse effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D008297:Male; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012439:Saccharin / Q000378:metabolism; D012694:Serine / Q000627:therapeutic use*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D000431:Ethanol; D012694:Serine; C056639:2-amino-5-phosphopentanoic acid; D003523:Cycloserine; D012439:Saccharin; D014633:Valine