title: Dysregulated Glycine Signaling Contributes to Increased Impulsivity during Protracted Alcohol Abstinence.
abstract: Persons with alcoholism who are abstinent exhibit persistent impairments in the capacity for response inhibition, and this form of impulsivity is significantly associated with heightened relapse risk. Brain-imaging studies implicate aberrant prefrontal cortical function in this behavioral pathology, although the underlying mechanisms are not understood. Here we present evidence that deficient activation of glycine and serine release in the ventral medial prefrontal cortex (vmPFC) contributes to increased motor impulsivity during protracted abstinence from long-term alcohol exposure. Levels of 12 neurotransmitters were monitored in the rat vmPFC during the performance of a challenging variant of the five-choice serial reaction time task (5-CSRTT) in which alcohol-exposed rats exhibit excessive premature responding. Following long-term ethanol exposure, rats showed blunted task-related recruitment of vmPFC glycine and serine release, and the loss of an inverse relationship between levels of these neurotransmitters and premature responding normally evident in alcohol-naive subjects. Intra-vmPFC administration of the glycine transport inhibitor ALX5407 prevented excessive premature responding by alcohol-exposed rats, and this was reliant on NMDA glycine site availability. Alcohol-exposed rats and controls did not differ in their premature responding and glycine and serine levels in vmPFC during the performance of the standard 5-CSRTT. Collectively, these findings provide novel insight into cortical neurochemical mechanisms contributing to increased impulsivity following long-term alcohol exposure and highlight the NMDA receptor coagonist site as a potential therapeutic target for increased impulsivity that may contribute to relapse risk.SIGNIFICANCE STATEMENTPersons with alcoholism demonstrate increased motor impulsivity during abstinence; however, the neuronal mechanisms underlying these behavioral effects remain unknown. Here, we took advantage of an animal model that shows deficiencies in inhibitory control following prolonged alcohol exposure to investigate the neurotransmitters that are potentially responsible for dysregulated motor impulsivity following long-term alcohol exposure. We found that increased motor impulsivity is associated with reduced recruitment of glycine and serine neurotransmitters in the ventromedial prefrontal cortex (vmPFC) cortex in rats following long-term alcohol exposure. Administration of glycine transport inhibitor ALX5407 in the vmPFC alleviated deficits in impulse control.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, and cristin4@stanford.edu.
authors.forename: Cristina
authors.identifier: 0000-0001-6029-1055
authors.initials: C
authors.lastname: Irimia
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, and.|Virginia Tech School of Neuroscience, Blacksburg, Virginia 24061.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Buczynski
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, and.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Natividad
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, and.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Laredo
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, and.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Avalos
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, and.
authors.forename: Loren H
authors.initials: LH
authors.lastname: Parsons
mesh_terms: D064829:Alcohol Abstinence; D000428:Alcohol Drinking / Q000503:physiopathology*; D000818:Animals; D002492:Central Nervous System Depressants / Q000009:adverse effects; D002755:Choice Behavior / Q000187:drug effects; D004195:Disease Models, Animal; D000431:Ethanol / Q000009:adverse effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors; D005998:Glycine / Q000378:metabolism*; D007175:Impulsive Behavior / Q000502:physiology*; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism; D010775:Photic Stimulation; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D012521:Sarcosine / Q000031:analogs & derivatives / Q000494:pharmacology; D012694:Serine / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: C510369:(R)-(N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl))sarcosine; D002492:Central Nervous System Depressants; D018691:Excitatory Amino Acid Antagonists; D027342:Excitatory Amino Acid Transporter 2; D018377:Neurotransmitter Agents; D015363:Quinolones; D000431:Ethanol; D012694:Serine; C094635:L 701324; D005998:Glycine; D012521:Sarcosine
keywords: alcohol dependence; five-choice serial reaction time task; glycine; motor impulsivity