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Despite the popularity of fiber photometry (FP), its integration with operant behavior paradigms is progressing slowly. This can be attributed to the complex protocols in operant behavior – resulting in a combination of diverse non-predictable behavioral responses and scheduled events, thereby complicating data analysis. To overcome this, we developed Pyfiber , an open-source python library which facilitates the merge of FP with operant behavior by relating changes in fluorescent signals within a neuronal population to behavioral responses and events. Pyfiber helps to 1. Extract events and responses that occur in operant behavior, 2. Extract and process the FP signals, 3. Select events of interest and align them to the corresponding FP signals, 4. Apply appropriate signal normalization and analysis according to the type of events, 5. Run analysis on multiple individuals and sessions, 6. Collect results in an easily readable format. Pyfiber is suitable for use with many different fluorescent sensors and operant behavior protocols. It was developed using Doric lenses FP systems and Imetronic behavioral systems, but it possesses the capability to process data from alternative systems. This work sets a solid foundation for analyzing the relationship between different dimensions of complex behavioral paradigms with fluorescent signals from brain regions of interest.

RationaleOver the last decade, oxycodone has become one of the most widely abused drugs in the USA. Oxycodone use disorder (OUD) is a serious health problem that has prompted a need to develop animal models of OUD that have both face and predictive validity. Oxycodone use in humans is more prevalent in women and leads to pronounced hyperalgesia and irritability during withdrawal. However, unclear is whether current animal models of oxycodone self-administration recapitulate these characteristics in humans.ObjectivesWe assessed the face validity of a model of extended-access oxycodone self-administration in rats by examining the escalation of oxycodone intake and behavioral symptoms of withdrawal, including irritability-like behavior and mechanical nociception, in male and female Wistar rats.ResultsBoth male and female rats escalated their oxycodone intake over fourteen 12-h self-administration sessions. After escalation, female rats administered more drug than male rats. No differences in plasma oxycodone levels were identified, but males had a significantly higher level of oxycodone in the brain at 30 min. Extended access to oxycodone significantly decreased aggressive-like behavior and increased defensive-like behaviors when tested immediately after a 12-h self-administration session, followed by a rebound increase in aggressive-like behavior 12 h into withdrawal. Tests of mechanical nociception thresholds during withdrawal indicated pronounced hyperalgesia. No sex differences in irritability-like behavior or pain sensitivity were observed.ConclusionsThe present study demonstrated the face validity of the extended access model of oxycodone self-administration by identifying sex differences in the escalation of oxycodone intake and pronounced changes in pain and affective states.

Addiction is commonly characterized by escalation of drug intake, compulsive drug seeking, and continued use despite harmful consequences. However, the factors contributing to the transition from moderate drug use to these problematic patterns remain unclear, particularly regarding the role of sex. Many preclinical studies have been limited by small sample sizes, low genetic diversity, and restricted drug access, making it challenging to model significant levels of intoxication or dependence and translate findings to humans. To address these limitations, we characterized addiction-like behaviors in a large sample of >500 outbred heterogeneous stock (HS) rats using an extended cocaine self-administration paradigm (6 hr/daily). We analyzed individual differences in escalation of intake, progressive ratio (PR) responding, continued use despite adverse consequences (contingent foot shocks), and irritability-like behavior during withdrawal. Principal component analysis showed that escalation of intake, progressive ratio responding, and continued use despite adverse consequences loaded onto a single factor that was distinct from irritability-like behaviors. Categorizing rats into resilient, mild, moderate, and severe addiction-like phenotypes showed that females exhibited higher addiction-like behaviors, with a lower proportion of resilient individuals compared to males. These findings suggest that, in genetically diverse rats with extended drug access, escalation of intake, continued use despite adverse consequences, and PR responding are highly correlated measures of a shared underlying construct. Furthermore, our results highlight sex differences in resilience to addiction-like behaviors.

Addiction is commonly characterized by escalation of drug intake, compulsive drug seeking, and continued use despite harmful consequences. However, the factors contributing to the transition from moderate drug use to these problematic patterns remain unclear, particularly regarding the role of sex. Many preclinical studies have been limited by small sample sizes, low genetic diversity, and restricted drug access, making it challenging to model significant levels of intoxication or dependence and translate findings to humans. To address these limitations, we characterized addiction-like behaviors in a large sample of >500 outbred heterogeneous stock (HS) rats using an extended cocaine self-administration paradigm (6 hr/daily). We analyzed individual differences in escalation of intake, progressive ratio (PR) responding, continued use despite adverse consequences (contingent foot shocks), and irritability-like behavior during withdrawal. Principal component analysis showed that escalation of intake, progressive ratio responding, and continued use despite adverse consequences loaded onto a single factor that was distinct from irritability-like behaviors. Categorizing rats into resilient, mild, moderate, and severe addiction-like phenotypes showed that females exhibited higher addiction-like behaviors, with a lower proportion of resilient individuals compared to males. These findings suggest that, in genetically diverse rats with extended drug access, escalation of intake, continued use despite adverse consequences, and PR responding are highly correlated measures of a shared underlying construct. Furthermore, our results highlight sex differences in resilience to addiction-like behaviors.

Addiction is commonly characterized by escalation of drug intake, compulsive drug seeking, and continued use despite harmful consequences. However, the factors contributing to the transition from moderate drug use to these problematic patterns remain unclear, particularly regarding the role of sex. Many preclinical studies have been limited by small sample sizes, low genetic diversity, and restricted drug access, making it challenging to model significant levels of intoxication or dependence and translate findings to humans. To address these limitations, we characterized addiction-like behaviors in a large sample of >500 outbred heterogeneous stock (HS) rats using an extended cocaine self-administration paradigm (6 h/daily). We analyzed individual differences in escalation of intake, progressive-ratio (PR) responding, continued use despite adverse consequences (contingent foot shocks), and irritability-like behavior during withdrawal. Principal component analysis showed that escalation of intake, progressive ratio responding, and continued use despite adverse consequences loaded onto a single factor that was distinct from irritability-like behaviors. Categorizing rats into resilient, mild, moderate, and severe addiction-like phenotypes showed that females exhibited higher addiction-like behaviors, with a lower proportion of resilient individuals compared to males. These findings suggest that, in genetically diverse rats with extended drug access, escalation of intake, continued use despite adverse consequences, and PR responding are highly correlated measures of a shared underlying construct. Furthermore, our results highlight sex differences in resilience to addiction-like behaviors.

Background- Advances in in vivo fluorescent imaging have exploded with the recent developments of genetically encoded calcium indicators (GECIs) and fluorescent biosensors. Their use with a bulk imaging technique such as fiber photometry (FP) can be highly beneficial in identifying neuronal signatures in behavioral neuroscience experiments. Popularity of FP has grown rapidly. Initially applied to classical conditioning, its integration into operant behavior paradigms is progressing. However, in operant behavior, protocols can be complex including numerous scheduled events, while behavioral responses can occur in diverse and non-predictable manners. To optimize data processing and analysis, there is a need for a flexible tool to extract and relate behavioral and fiber photometry data occurring over operant sessions. New Method- Applied to cocaine intravenous self-administration (using ImetronicR polymodal apparati) and FP recordings in the prelimbic cortex (using Doric Lenses photometry system) in the rat, we established Pyfiber, an outline and open source data analysis python library that facilitates the merge of fiber photometry (using Doric Lenses) with operant behavior (using ImetronicR). It allows relating activity changes within a neuronal population to the various behavioral responses and events occurring during operant behavior. Results- We show some of the possibilities and benefits of the analytical tool Pyfiber, which helps to: 1. Extract the different types of events that occur in an operant session, 2. Extract and process the fiber photometry signals, 3. Select events of interest and align them to the corresponding fiber photometry signals, 4. Apply the most appropriate type of FP signal normalization and signal analysis according to the studied type of event or behavioral response, 5. Run data extraction and analysis on multiple individuals and sessions at the same time, 6. Collect results in an easily readable format for statistical analysis. From our data and through the use of Pyfiber, we show that we can successfully record and easily analyze calcium transients surrounding events occurring during a cocaine self-administration paradigm in the rat. Comparison with Existing Method(s)- While other analytical tools can be used for streamlined fiber photometry analysis, they are either too rigid and specific or too flexible, requiring extensive coding to properly fit the data sets. Additionally, current tools do not permit easy exploration of multiple types of events in parallel- something that is possible with Pyfiber. Conclusions- This work established an open source resource that facilitates the pairing of fiber photometry recordings (using Doric Lenses photometry system) with operant behavior (using ImetronicR polymodal apparati), setting a solid foundation in analyzing the relationship between different dimensions of operant behavior with fluorescent signals from brain regions of interest. Competing Interest Statement The authors have declared no competing interest.

Previous studies showed that the glyoxalase 1 (Glo1) gene modulates anxiety-like behavior, seizure susceptibility, depression-like behavior, and alcohol drinking in the drinking-in-the-dark paradigm in nondependent mice. Administration of the small-molecule GLO1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG) decreased alcohol drinking in nondependent mice, suggesting a possible therapeutic strategy. However, the preclinical therapeutic efficacy of pBBG in animal models of alcohol dependence remains to be demonstrated. We tested the effect of pBBG (7.5 and 25 mg/kg) on operant alcohol self-administration in alcohol-dependent and nondependent rats. Wistar rats were trained to self-administer 10% alcohol (v/v) and made dependent by chronic intermittent passive exposure to alcohol vapor for 5 weeks. Pretreatment with pBBG dose-dependently reduced alcohol self-administration in both nondependent and dependent animals, without affecting water self-administration. pBBG treatment was more effective in dependent rats than in nondependent rats. These data extend previous findings that implicated Glo1 in alcohol drinking in nondependent mice by showing even more profound effects in alcohol-dependent rats. These results suggest that the pharmacological inhibition of GLO1 is a relevant therapeutic target for the treatment of alcohol use disorders.

Cocaine use disorder (CUD) is a major public health crisis with detrimental individual and societal effects. The specific genes mediating CUD remain largely unknown. We conducted a genome-wide association study (GWAS) using outbred N/NIH Heterogeneous Stock (HS; n = 836, female = 415, male = 421) rats. We examined multiple CUD-related phenotypes that captured acquisition of self-administration, escalation of intake, and compulsive-like responding. Consistent with the existing literature, these traits were phenotypically and genetically correlated and exhibited modest heritability (h = 0.07 - 0.16). We identified six genome-wide significant associations. One locus on chromosome 16 was associated with the variable time between cocaine infusions (post infusion interval) and contains several carboxylesterase genes that are orthologous to the human gene; notably, carboxylesterases metabolize cocaine. Three non-synonymous coding variants in the genes and were in perfect linkage disequilibrium with this locus, suggesting that one or more of them might be the causal SNP. The other 5 loci also contained promising coding and expression variants, including a gene previously associated with CUD in human GWAS and , , and which have been associated with alcohol and tobacco use disorder. This is the largest genetic study of cocaine self-administration ever conducted in any species. Our results replicate previous loci associated with CUD in humans and provide several novel biological insights including the potential of pharmacological strategies targeting carboxylesterases for the treatment of CUD.

A major limitation of the most widely used current animal models of alcohol dependence is that they use forced exposure to ethanol including ethanol-containing liquid diet and chronic intermittent ethanol (CIE) vapor to produce clinically relevant blood alcohol levels (BAL) and addiction-like behaviors. We recently developed a novel animal model of voluntary induction of alcohol dependence using ethanol vapor self-administration (EVSA). In this model, naive outbred rats given intermittent access to alcohol vapor self-administration exhibit BAL in the 150-300 mg% range and develop somatic signs of withdrawal during acute abstinence. However, it is unknown whether EVSA leads to an escalation of alcohol drinking per se, and whether such escalation is associated with neuroadaptations in brain regions related to stress, reward, and habit. To address these issues, we compared the levels of alcohol drinking during withdrawal between rats passively exposed to alcohol (CIE) or voluntarily exposed to EVSA and measured the number of Fos+ neurons during acute withdrawal (16 h) in the central nucleus of the amygdala (CeA), dorsomedial striatum (DMS), dorsolateral striatum (DLS), nucleus accumbens core (Nacc), periaqueducal grey area (PAG), lateral Habenula (HbL), and the paraventricular nucleus of the thalamus (PVT). The rats were first trained to orally self-administer alcohol in standard operant chambers and then divided in 4 groups (CIE, CI-Air, EVSA and Air-SA) and exposed to intermittent ethanol vapor (passive or active) or intermittent air (passive or active) for 8 h/day, 3 days a week. CIE and EVSA rats exhibited similar BAL (150-300 mg% range) and similar escalation of alcohol drinking during withdrawal, while no changes in terms of drinking were observed in the air exposed rats. CIE and EVSA also increased the motivation for alcohol compared to their respective air control groups under a progressive ratio schedule of reinforcement. Acute withdrawal from EVSA and CIE recruited a similar number of Fos+ neurons in the CeA, however, acute withdrawal from EVSA recruited a higher number of Fos+ neurons in every other brain region analyzed compared to acute withdrawal from CIE. Moreover, acute withdrawal from EVSA specifically recruited the DMS and PVT, a pattern not observed in CIE rats. In summary, these results demonstrate that EVSA produces similar escalation of alcohol drinking, motivation to drink, and blood-alcohol levels than the CIE model, while letting animals voluntary initiate alcohol exposure and maintain alcohol dependence. Moreover, while the behavioral measures of alcohol dependence between the voluntary (EVSA) and passive (CIE) model was similar, the recruitment of neuronal ensembles during acute withdrawal was very different with a higher recruitment of Fos+ neurons in key brain regions important for stress, reward and habit-related processes. The EVSA model may be particularly useful to unveil the neuronal networks and pharmacology responsible for the voluntary induction and maintenance of alcohol dependence and may improve translational studies by providing preclinical researchers with an animal model with better face validity for alcohol use disorder. Competing Interest Statement The authors have declared no competing interest.

The gut-brain axis is a bi-directional communication system through which microbial communities in the gut interact with the nervous system. Disruptions in microbiome composition, known as dysbiosis, appear to be associated with neuropsychiatric disorders, perhaps including drug abuse. This study used behavioral data and biological samples from the Cocaine Biobank to test the hypothesis that the gut microbiota can predict and reflect susceptibility to cocaine reinforcement. Adult male heterogenous (HS) rats were catheterized and allowed to self-administer cocaine in daily short-access sessions (2 hr/day, 10 days, 0.5 mg/kg per intravenous infusion), followed by progressive ratio (PR) testing. Rats were transitioned to daily long-access sessions (6 hr/day, 14 days), followed by a PR test and alternating blocks of footshock testing, long-access, and PR. Fecal samples were collected at three time points and bacterial 16s rRNA genes were sequenced to profile the microbiota and compare low vs. high responders to cocaine. Bacterial taxa identified in baseline samples in drug-naive animals were used to test whether specific bacterial abundance could predict future cocaine susceptibility. As expected, levels of cocaine-related behavior varied across individual subjects, such that a quartile split identified low and high responders on each measure, as well as an overall addiction index. Although beta diversity in the gut microbiota at baseline and after short access did not predict membership in high or low addiction quartiles, linear discriminant analysis (LDA) identified certain taxa that were more robustly represented in either low or high responders. Beta diversity after long access did reveal a difference in microbiota profiles between low and high responders, and LDA identified specific populations that differed between groups. Plotting baseline samples identified using LDA on a Receiver Operating Characteristic (ROC) curve revealed that high relative abundance of Akkermansia muciniphila predicted future low response rates. This study is the first to report that microbiota variability reflects levels of cocaine intake and that the microbiota might facilitate diagnosis and identify risk factors predictive of future drug vulnerability. Competing Interest Statement The authors have declared no competing interest.