Abstinence-dependent dissociable central amygdala microcircuits control drug craving

Abstract

We recently reported that social choice-induced voluntary abstinence prevents incubation of methamphetamine craving in rats. This inhibitory effect was associated with activation of protein kinase-Cδ (PKCδ)-expressing neurons in central amygdala lateral division (CeL). In contrast, incubation of craving after forced abstinence was associated with activation of CeL-expressing somatostatin (SOM) neurons. Here we determined the causal role of CeL PKCδ and SOM in incubation using short-hairpin RNAs against PKCδ or SOM that we developed and validated. We injected two groups with shPKCδ or shCtrlPKCδinto CeL and trained them to lever press for social interaction (6 d) and then for methamphetamine infusions (12 d). We injected two other groups with shSOM or shCtrlSOMinto CeL and trained them to lever press for methamphetamine infusions (12 d). We then assessed relapse to methamphetamine seeking after 1 and 15 abstinence days. Between tests, the rats underwent either social choice-induced abstinence (shPKCδ groups) or homecage forced abstinence (shSOM groups). After test day 15, we assessed PKCδ and SOM, Fos, and double-labeled expression in CeL and central amygdala medial division (CeM). shPKCδ CeL injections decreased Fos in CeL PKCδ-expressing neurons, increased Fos in CeM output neurons, and reversed the inhibitory effect of social choice-induced abstinence on incubated drug seeking on day 15. In contrast, shSOM CeL injections decreased Fos in CeL SOM-expressing neurons, decreased Fos in CeM output neurons, and decreased incubated drug seeking after 15 forced abstinence days. Our results identify dissociable central amygdala mechanisms of abstinence-dependent expression or inhibition of incubation of craving.

A neural substrate of compulsive alcohol use

“…A mechanistic role of CeA-PKC in punishment-resistant alcohol self-administration PKC has been used as a phenotypic marker to identify CeL-off cells, but is also of functional interest itself, as it is an intracellular signaling enzyme (40) and is involved in both alcohol potentiation of tonic GABA currents (41) and activation of adenylyl cyclase 7, which can, in turn, drive Fos induction (42). Elevated PKC expression in CeL of punishment-resistant rats suggests the possibility that up-regulated PKC signaling contributes to punishment resistance (39).…”

A balancing act: the role of pro‐ and anti‐stress peptides within the central amygdala in anxiety and alcohol use disorders

“…This caveat is explored in more detail in the Discussion. However, it should be noted that the precise actions of SST and/or PKCδ on anxiety and alcohol seeking TA B L E 1 Relative co-expression of markers across CeA subdivisions (Continues) (Venniro et al, 2020); however, whether similar actions are observed across drug classes requires examination.…”

Extinction blunts paraventricular thalamic contributions to heroin relapse

“…Importantly, evidence suggests the neural circuitry underlying these two forms of relapse is different. For instance, the central nucleus of the amygdala is critical for relapse after abstinence ( Venniro et al, 2017 , 2020 ), whereas the prefrontal cortex is recruited by extinction learning to regulate subcortical targets that drive drug seeking ( Peters et al, 2009 ).…”