Alcohol abuse and alcohol dependence are key factors in the development of alcohol use disorder, which is a pervasive societal problem with substantial economic, medical, and psychiatric consequences. Although our understanding of the neurocircuitry that underlies alcohol use has improved, novel brain regions that are involved in alcohol use and novel biomarkers of alcohol use need to be identified. The present study used a single-cell whole-brain imaging approach to 1) assess whether abstinence from alcohol in an animal model of alcohol dependence alters the functional architecture of brain activity and modularity, 2) validate our current knowledge of the neurocircuitry of alcohol abstinence, and 3) discover brain regions that may be involved in alcohol use. Alcohol abstinence resulted in the whole-brain reorganization of functional architecture in mice and a pronounced decrease in modularity that was not observed in nondependent moderate drinkers. Structuring of the alcohol abstinence network revealed three major brain modules: 1) extended amygdala module, 2) midbrain striatal module, and 3) cortico-hippocampo-thalamic module, reminiscent of the three-stage theory. Many hub brain regions that control this network were identified, including several that have been previously overlooked in alcohol research. These results identify brain targets for future research and demonstrate that alcohol use and dependence remodel brain-wide functional architecture to decrease modularity. Further studies are needed to determine whether the changes in coactivation and modularity that are associated with alcohol abstinence are causal features of alcohol dependence or a consequence of excessive drinking and alcohol exposure.

Over the last decade oxycodone has become one of the most widely abused drugs. The emergence of oxycodone dependence as a serious health crisis has prompted a major need for animal models of oxycodone dependence with face and predictive validity. Oxycodone use in humans is more prevalent in women (Administration, 2014) and leads to pronounced hyperalgesia and irritability. However, it is unclear if the current animal model of oxycodone self-administration recapitulates these characteristics. We assessed the face validity of an extended access oxycodone self-administration model in rats by examining escalation of oxycodone intake and behavioral symptoms of withdrawal including irritability like behavior and mechanical nociception in male and female rats. We found that male and female rats escalated oxycodone intake over the course of 14 self-administration sessions, however, female rats escalated took more drug than male rats once escalated. When we assessed irritability-like behavior we found no differences between baseline or withdrawal, however when tested immediately after a 12-h self-administration session rats showed a decreased number of aggressive responses and a increased number of defensive responses. When tested for mechanical threshold during withdrawal rats showed pronounced hyperalgesia that was only partially reversed by oxycodone self-administration. The results of the present study demonstrate the face validity of the extended access model of oxycodone self-administration by identifying sex differences in the escalation of oxycodone intake and demonstrating pronounced changes to pain and affective states.

Background Alcohol binge drinking in humans is thought to increase the risk for alcohol use disorder. Unclear is whether drinking patterns (e.g., binge-like or stable drinking) differentially affect the transition to compulsive-like drinking in dependent individuals. We examined whether chronic binge-like drinking facilitates the transition to compulsive-like drinking in rats. Methods Male Wistar rats were given 5 months of intermittent access to ethanol (IAE) or continuous access to ethanol (CAE) in a two-bottle choice paradigm. Then rats were given chronic intermittent ethanol (CIE) vapor exposure. Escalation of ethanol intake and compulsive-like responding for ethanol, using a progressive-ratio schedule of reinforcement and quinine-adulterated ethanol, were measured. Results IAE rats escalated ethanol drinking after 2 weeks of two-bottle choice, whereas CAE rats exhibited stable ethanol drinking for 5 months. After 8 weeks of CIE, both IAE+CIE and CAE+CIE rats escalated their ethanol intake. However, IAE rats escalated their ethanol intake weeks sooner than CAE rats and exhibited greater ethanol intake. No differences in compulsive-like responding were found between IAE+CIE and CAE+CIE rats. However, both IAE+CIE and CAE+CIE rats showed strong compulsive-like responding compared with rats without prior IAE or CAE. Conclusions Chronic ethanol drinking at stable or escalated levels for several months is associated with more compulsive-like responding for ethanol in rats that are exposed to CIE compared with rats without a prior history of ethanol drinking. Moreover, IAE facilitated the transition to compulsive-like responding for ethanol after CIE exposure, reflected by the escalation of ethanol intake. These results suggest that IAE may facilitate the transition to alcohol use disorder. The present study indicates that despite a moderate level of ethanol drinking, the IAE animal model is highly relevant to early stages of alcohol abuse and suggests that it may be associated with neuroadaptations that produce a faster transition to alcohol dependence.

Numerous brain regions have been identified as contributing to withdrawal behaviors, but unclear is the way in which these brain regions as a whole lead to withdrawal. The search for a final common brain pathway that is involved in withdrawal remains elusive. To address this question, we implanted osmotic minipumps containing either saline, nicotine (24 mg/kg/day), cocaine (60 mg/kg/day), or methamphetamine (4 mg/kg/day) for 1 week in male C57BL/6J mice.After 1 week the minipumps were removed and brains collected 8 hours (saline, nicotine and cocaine) or 12 hours (methamphetamine) after removal. We then performed single-cell wholebrain imaging of neural activity during the withdrawal period when brains were collected. We used hierarchical clustering and graph theory to identify similarities and differences in brain functional architecture. Although methamphetamine and cocaine shared some network similarities, the main common neuroadaptation between these psychostimulant drugs was a dramatic decrease in modularity, with a shift from a cortical-to subcortical-driven network, including a decrease in total hub brain regions. These results demonstrate that psychostimulant withdrawal produces the drug-dependent remodeling of functional architecture of the brain and suggest that the decreased modularity of brain functional networks and not a specific set of brain regions may represent the final common pathway associated with withdrawal. Significance StatementA key aspect of treating drug abuse is understanding similarities and differences of how drugs of abuse affect the brain. In the present study we examined how the brain is altered during withdrawal from psychostimulants. We found that each drug produced a unique pattern of activity in the brain, but that brains in withdrawal from cocaine and methamphetamine shared 3 similar features. Interestingly, we found the major common link between withdrawal from all psychostimulants, when compared to controls, was a shift in the broad organization of the brain in the form of reduced modularity. Reduced modularity has been shown in several brain disorders, including traumatic brain injury, and dementia, and may be the common link between drugs of abuse.