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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 shCtrl_PKCδ into 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 shCtrl_SOM into 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.

SUBMITTER: Venniro M

PROVIDER: S-EPMC7148559 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The goal of this study was to determine whether the plasma leptin, nesfatin-1, cortisol, brain-derived neurotrophic factor (BDNF), and inflammatory cytokines could be used as potential biomarkers for the degree of craving in the alcohol-dependent patients after 1 month of abstinence. A total of 83 patients with alcohol use disorder (AUD) and 61 healthy subjects were assessed. Patients with AUD were selected from Department of Material Dependence, Anhui Mental Health Center, and subjects in the control group were selected from healthy volunteers. The Alcohol Urge questionnaire Scale (AUQ) was used to evaluate the extent of craving for alcohol, and the Michigan Alcoholism Screening Test (MAST), the Fagerstrom Test for Nicotine Dependence (FTND), the Self-Rating Anxiety Scale (SAS), and the Self-Rating Depression Scale (SDS) were also assessed in patients with AUD. Enzyme-Linked Immunosorbent Assay (ELISA) was used for the measurement of plasma leptin, nesfatin-1, cortisol, BDNF, Interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-? (TNF-?) levels. Compare with healthy controls, the average leptin, leptin/BMI, IL-6, CRP, and TNF-? levels in patients with AUD were significantly increased, while the BDNF levels were significantly decreased. Moreover, the partial correlational analysis showed that the AUQ scores of the alcohol-dependent patients were positively correlated with the plasma leptin levels (r = 0.613, P < 0.001), rather than nesfatin-1 (r = 0.066, P = 0.569) after controlling for age as covariate. Furthermore, plasma nesfatin-1 levels were found to be correlated with the SDS scores (r = 0.366, P = 0.001) in the AUD group. In addition, plasma leptin levels were positively associated with the plasma IL-6 (r = 0.257, P = 0.033), CRP (r = 0.305, P = 0.011), and TNF-? (r = 0.311, P = 0.009) levels, and negatively associated with the BDNF levels (r = -0.245, P = 0.042) in patients with AUD. These results suggest that plasma leptin, but not nesfatin-1, might be a potential biomarker for the degree of craving in alcohol-dependent patients after 1 month of abstinence, the mechanism of which might be related to the dysfunction of the inflammatory cytokines and BDNF levels.

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Abstinence-dependent dissociable central amygdala microcircuits control drug craving.

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