TY - JOUR
T1 - Prefrontal Regulation of Punished Ethanol Self-administration
AU - Halladay, Lindsay R.
AU - Kocharian, Adrina
AU - Piantadosi, Patrick T.
AU - Authement, Michael E.
AU - Lieberman, Abby G.
AU - Spitz, Nathen A.
AU - Coden, Kendall
AU - Glover, Lucas R.
AU - Costa, Vincent D.
AU - Alvarez, Veronica A.
AU - Holmes, Andrew
N1 - Funding Information:
This work was supported by National Institute on Alcohol Abuse and Alcoholism Intramural Research Program Grant No. ZIA-AA000401 (to AH), Intramural Programs of National Institute on Alcohol Abuse and Alcoholism and National Institute of Neurological Disorders and Stroke Grant No. ZIA-AA000421 (to VAA), a Postdoctoral Research Associate Training fellowship from the Center on Compulsive Behaviors (to PTP and MEA), and a National Institutes of Health Director's Challenge Award and DDIR Innovation Award (to VAA). The authors report no biomedical financial interests or potential conflicts of interest.
Funding Information:
This work was supported by National Institute on Alcohol Abuse and Alcoholism Intramural Research Program Grant No. ZIA-AA000401 (to AH), Intramural Programs of National Institute on Alcohol Abuse and Alcoholism and National Institute of Neurological Disorders and Stroke Grant No. ZIA-AA000421 (to VAA), a Postdoctoral Research Associate Training fellowship from the Center on Compulsive Behaviors (to PTP and MEA), and a National Institutes of Health Director’s Challenge Award and DDIR Innovation Award (to VAA). The authors report no biomedical financial interests or potential conflicts of interest.
Publisher Copyright:
© 2019 Society of Biological Psychiatry
PY - 2020/6/1
Y1 - 2020/6/1
N2 - Background: A clinical hallmark of alcohol use disorder is persistent drinking despite potential adverse consequences. The ventromedial prefrontal cortex (vmPFC) and dorsomedial prefrontal cortex (dmPFC) are positioned to exert top-down control over subcortical regions, such as the nucleus accumbens shell (NAcS) and basolateral amygdala, which encode positive and negative valence of ethanol (EtOH)-related stimuli. Prior rodent studies have implicated these regions in regulation of punished EtOH self-administration (EtOH-SA). Methods: We conducted in vivo electrophysiological recordings in mouse vmPFC and dmPFC to obtain neuronal correlates of footshock-punished EtOH-SA. Ex vivo recordings were performed in NAcS D1 receptor–expressing medium spiny neurons receiving vmPFC input to examine punishment-related plasticity in this pathway. Optogenetic photosilencing was employed to assess the functional contribution of the vmPFC, dmPFC, vmPFC projections to NAcS, or vmPFC projections to basolateral amygdala, to punished EtOH-SA. Results: Punishment reduced EtOH lever pressing and elicited aborted presses (lever approach followed by rapid retraction). Neurons in the vmPFC and dmPFC exhibited phasic firing to EtOH lever presses and aborts, but only in the vmPFC was there a population-level shift in coding from lever presses to aborts with punishment. Closed-loop vmPFC, but not dmPFC, photosilencing on a postpunishment probe test negated the reduction in EtOH lever presses but not in aborts. Punishment was associated with altered plasticity at vmPFC inputs to D1 receptor–expressing medium spiny neurons in the NAcS. Photosilencing vmPFC projections to the NAcS, but not to the basolateral amygdala, partially reversed suppression of EtOH lever presses on probe testing. Conclusions: These findings demonstrate a key role for the vmPFC in regulating EtOH-SA after punishment, with implications for understanding the neural basis of compulsive drinking in alcohol use disorder.
AB - Background: A clinical hallmark of alcohol use disorder is persistent drinking despite potential adverse consequences. The ventromedial prefrontal cortex (vmPFC) and dorsomedial prefrontal cortex (dmPFC) are positioned to exert top-down control over subcortical regions, such as the nucleus accumbens shell (NAcS) and basolateral amygdala, which encode positive and negative valence of ethanol (EtOH)-related stimuli. Prior rodent studies have implicated these regions in regulation of punished EtOH self-administration (EtOH-SA). Methods: We conducted in vivo electrophysiological recordings in mouse vmPFC and dmPFC to obtain neuronal correlates of footshock-punished EtOH-SA. Ex vivo recordings were performed in NAcS D1 receptor–expressing medium spiny neurons receiving vmPFC input to examine punishment-related plasticity in this pathway. Optogenetic photosilencing was employed to assess the functional contribution of the vmPFC, dmPFC, vmPFC projections to NAcS, or vmPFC projections to basolateral amygdala, to punished EtOH-SA. Results: Punishment reduced EtOH lever pressing and elicited aborted presses (lever approach followed by rapid retraction). Neurons in the vmPFC and dmPFC exhibited phasic firing to EtOH lever presses and aborts, but only in the vmPFC was there a population-level shift in coding from lever presses to aborts with punishment. Closed-loop vmPFC, but not dmPFC, photosilencing on a postpunishment probe test negated the reduction in EtOH lever presses but not in aborts. Punishment was associated with altered plasticity at vmPFC inputs to D1 receptor–expressing medium spiny neurons in the NAcS. Photosilencing vmPFC projections to the NAcS, but not to the basolateral amygdala, partially reversed suppression of EtOH lever presses on probe testing. Conclusions: These findings demonstrate a key role for the vmPFC in regulating EtOH-SA after punishment, with implications for understanding the neural basis of compulsive drinking in alcohol use disorder.
KW - Alcohol
KW - Amygdala
KW - Compulsive
KW - Corticostriatal
KW - Infralimbic
KW - Mouse
KW - Nucleus accumbens
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U2 - 10.1016/j.biopsych.2019.10.030
DO - 10.1016/j.biopsych.2019.10.030
M3 - Article
C2 - 31937415
AN - SCOPUS:85077724188
SN - 0006-3223
VL - 87
SP - 967
EP - 978
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 11
ER -