Abstinence-dependent dissociable central amygdala microcircuits control drug craving

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 shCtrlPKCδ 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 shCtrlSOM 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

Abstinence-dependent dissociable central amygdala microcircuits control drug craving

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 shCtrlPKCδ 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 shCtrlSOM 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

Age-Related Differences in Alcohol Intake and Control Over Alcohol Seeking in Rats

Alcohol use disorder (AUD) is characterized by excessive and persistent alcohol use, despite adverse consequences. AUD often originates during adolescence, as do other substance use disorders. However, despite periods of excessive alcohol intake, many adolescents reduce their alcohol use by early adulthood. Brain development, social context, personality traits, and genetic makeup are thought to play an important role in these age-dependent fluctuations in alcohol use. However, studies that directly investigate age-related differences in the effects of alcohol exposure on brain and behavior are sparse. Therefore, to better understand the relationship between adolescent alcohol consumption and AUD-like behavior, this study compared the degree of control over alcohol seeking in rats that differed in terms of age of onset of alcohol drinking and in their level of alcohol consumption. We hypothesized that control over alcohol seeking is more prominent in adolescent-onset rats than in adult-onset rats, and that control over alcohol seeking is related to the consumed amount of alcohol. To test this hypothesis, alcohol seeking in the presence of a conditioned aversive stimulus was assessed after 2 months of intermittent alcohol access (IAA) in rats that consumed alcohol from postnatal day 42 (adolescence) or day 77 (adulthood). The rats were subdivided into low (LD), medium (MD), or high (HD) alcohol drinking rats, in order to assess the impact of the extent of alcohol intake on control over alcohol seeking. The adolescent-onset animals consumed slightly, but significantly less alcohol compared to the adult-onset rats. In adult-onset rats, we found that conditioned suppression of alcohol seeking, i.e., reduction of alcohol seeking by presentation of a conditioned aversive stimulus, was most pronounced in LD. By contrast, in the adolescent-onset rats, MD and HD showed increased alcohol seeking compared to LD, which was suppressed by conditioned aversive stimuli. Taken together, these findings reveal a complex relationship between the age of onset and level of alcohol intake with control over alcohol seeking, whereby adolescent rats consume less alcohol than adults. In adult rats, control over alcohol seeking is negatively related to preceding levels of alcohol intake. By contrast, adolescent rats appear to retain control over alcohol seeking, even after a history of high levels of alcohol intake

Motivational and Control Mechanisms Underlying Adolescent versus Adult Alcohol Use

Increased motivation towards alcohol use and suboptimal behavioral control are suggested to predispose adolescents to alcohol use disorders (AUDs). Paradoxically however, most adolescent AUDs resolve over time without any formal intervention, suggesting adolescent resilience to AUDs. Importantly, studies directly comparing adolescent and adult alcohol use are largely missing. We therefore aimed to unravel the moderating role of age in the relation between alcohol use and motivational and control-related cognitive processes in 45 adolescent drinkers compared to 45 adults. We found that enhancement drinking motives and impulsivity related positively to alcohol use. Although enhancement drinking motives and impulsivity were higher in adolescents, the strength of the relation between these measures and alcohol use did not differ between age groups. None of the alcohol use-related motivational measures (i.e., craving, attentional bias, and approach bias) and behavioral control measures (i.e., interference control, risky decision making, and working-memory) were associated with alcohol use or differed between age groups. These findings support the role of impulsivity and affective sensitivity in adolescent drinking but question the moderating role of age therein. The current study contributes towards understanding the role of age in the relation between alcohol use and cognition