TY - JOUR
T1 - A neural substrate of compulsive alcohol use
AU - Domi, Esi
AU - Xu, Li
AU - Toivainen, Sanne
AU - Nordeman, Anton
AU - Gobbo, Francesco
AU - Venniro, Marco
AU - Shaham, Yavin
AU - Messing, Robert O.
AU - Visser, Esther
AU - Oever, Michel C. van den
AU - Holm, Lovisa
AU - Barbier, Estelle
AU - Augier, Eric
AU - Heilig, Markus
PY - 2021/8/18
Y1 - 2021/8/18
N2 - Alcohol intake remains controlled in a majority of users but becomes “compulsive,” i.e., continues despite adverse consequences, in a minority who develop alcohol addiction. Here, using a footshock-punished alcohol self-administration procedure, we screened a large population of outbred rats to identify those showing compulsivity operationalized as punishment-resistant self-administration. Using unsupervised clustering, we found that this behavior emerged as a stable trait in a subpopulation of rats and was associated with activity of a brain network that included central nucleus of the amygdala (CeA). Activity of PKCδ+ inhibitory neurons in the lateral subdivision of CeA (CeL) accounted for ~75% of variance in punishment-resistant alcohol taking. Activity-dependent tagging, followed by chemogenetic inhibition of neurons activated during punishment-resistant self-administration, suppressed alcohol taking, as did a virally mediated shRNA knockdown of PKCδ in CeA. These findings identify a previously unknown mechanism for a core element of alcohol addiction and point to a novel candidate therapeutic target.
AB - Alcohol intake remains controlled in a majority of users but becomes “compulsive,” i.e., continues despite adverse consequences, in a minority who develop alcohol addiction. Here, using a footshock-punished alcohol self-administration procedure, we screened a large population of outbred rats to identify those showing compulsivity operationalized as punishment-resistant self-administration. Using unsupervised clustering, we found that this behavior emerged as a stable trait in a subpopulation of rats and was associated with activity of a brain network that included central nucleus of the amygdala (CeA). Activity of PKCδ+ inhibitory neurons in the lateral subdivision of CeA (CeL) accounted for ~75% of variance in punishment-resistant alcohol taking. Activity-dependent tagging, followed by chemogenetic inhibition of neurons activated during punishment-resistant self-administration, suppressed alcohol taking, as did a virally mediated shRNA knockdown of PKCδ in CeA. These findings identify a previously unknown mechanism for a core element of alcohol addiction and point to a novel candidate therapeutic target.
UR - https://doi.org/10.1126/sciadv.abg9045
U2 - 10.1126/sciadv.abg9045
DO - 10.1126/sciadv.abg9045
M3 - Article
SN - 2375-2548
VL - 7
JO - Science Advances
JF - Science Advances
IS - 34
M1 - eabg9045
ER -