Sex differences in the relationship between brain gray matter volume and psychological resilience in late adolescence.

Psychological resilience reflects an individual's ability to adapt and cope successfully in adverse environments and situations, making it a crucial trait in resisting stress-linked mental disorders and physical diseases. Although prior literature has consistently shown that males are more resilient than females, the sex-linked neuroanatomical correlates of psychological resilience are largely unknown. This study aims to explore the sex-specific relation between psychological resilience and brain gray matter volume (GMV) in adolescents via structural magnetic resonance imaging (s-MRI). A cohort of 231 healthy adolescents (121/110 females/males), aged 16 to 20 completed brain s-MRI scanning and Connor-Davidson Resilience Scale (CD-RISC) and other controlling behavioral tests. With s-MRI data, an optimized voxel-based morphometry method was used to estimate regional GMV, and a whole-brain condition-by-covariate interaction analysis was performed to identify the brain regions showing sex effects on the relation between psychological resilience and GMV. Male adolescents scored significantly higher than females on the CD-RISC. The association of psychological resilience with GMV differed between the two sex groups in the left ventrolateral prefrontal cortex extending to the adjacent anterior insula, with a positive correlation among males and a negative correlation among females. The sex-specific association between psychological resilience and GMV might be linked to sex differences in the hypothalamic-pituitary-adrenal axis and brain maturation during adolescence. This study may be novel in revealing the sex-linked neuroanatomical basis of psychological resilience, highlighting the need for a more thorough investigation of the role of sex in future studies of psychological resilience and stress-related illness.

Role of ventral subiculum neuronal ensembles in incubation of oxycodone craving after electric barrier-induced voluntary abstinence.

High relapse rate is a key feature of opioid addiction. In humans, abstinence is often voluntary due to negative consequences of opioid seeking. To mimic this human condition, we recently introduced a rat model of incubation of oxycodone craving after electric barrier-induced voluntary abstinence. Incubation of drug craving refers to time-dependent increases in drug seeking after cessation of drug self-administration. Here, we used the activity marker Fos, muscimol-baclofen (GABAa + GABAb receptor agonists) global inactivation, Daun02-selective inactivation of putative relapse-associated neuronal ensembles, and fluorescence-activated cell sorting of Fos-positive cells and quantitative polymerase chain reaction to demonstrate a key role of vSub neuronal ensembles in incubation of oxycodone craving after voluntary abstinence, but not homecage forced abstinence. We also used a longitudinal functional magnetic resonance imaging method and showed that functional connectivity changes in vSub-related circuits predict opioid relapse after abstinence induced by adverse consequences of opioid seeking.

Sex differences in the effect of chronic delivery of the buprenorphine analogue BU08028 on heroin relapse and choice in a rat model of opioid maintenance.

BACKGROUND AND PURPOSE: Maintenance treatment with opioid agonists (buprenorphine, methadone) decreases opioid use and relapse. We recently modelled maintenance treatment in rats and found that chronic delivery of buprenorphine or the µ opioid receptor partial agonist TRV130 decreased relapse to oxycodone seeking and taking. Here, we tested the buprenorphine analogue BU08028 on different heroin relapse-related measures and heroin versus food choice. EXPERIMENTAL APPROACH: For relapse assessment, we trained male and female rats to self-administer heroin (6 h·day-1 , 14 days) in Context A and then implanted osmotic minipumps containing BU08028 (0, 0.03 or 0.1 mg·kg-1 ·d-1 ). Effects of chronic BU08028 delivery were tested on (1) incubation of heroin-seeking in a non-drug Context B, (2) extinction responding reinforced by heroin-associated discrete cues in Context B, (3) reinstatement of heroin-seeking induced by re-exposure to Context A and (4) re-acquisition of heroin self-administration in Context A. For choice assessment, we tested the effect of chronic BU08028 delivery on heroin versus food choice. KEY RESULTS: Chronic BU08028 delivery decreased incubation of heroin seeking. Unexpectedly, BU08028 increased re-acquisition of heroin self-administration selectively in females. Chronic BU08028 had minimal effects on context-induced reinstatement and heroin versus food choice in both sexes. Finally, exploratory post hoc analyses suggest that BU08028 decreased extinction responding selectively in males. CONCLUSIONS AND IMPLICATIONS: Chronic BU08028 delivery had both beneficial and detrimental, sex-dependent, effects on different triggers of heroin relapse and minimal effects on heroin choice in both sexes. Results suggest that BU08028 would not be an effective opioid maintenance treatment in humans.

Incubation of palatable food craving is associated with brain-wide neuronal activation in mice.

Studies using rodent models have shown that relapse to drug or food seeking increases progressively during abstinence, a behavioral phenomenon termed "incubation of craving." Mechanistic studies of incubation of craving have focused on specific neurobiological targets within preselected brain areas. Recent methodological advances in whole-brain immunohistochemistry, clearing, and imaging now allow unbiased brain-wide cellular resolution mapping of regions and circuits engaged during learned behaviors. However, these whole-brain imaging approaches were developed for mouse brains, while incubation of drug craving has primarily been studied in rats, and incubation of food craving has not been demonstrated in mice. Here, we established a mouse model of incubation of palatable food craving and examined food reward seeking after 1, 15, and 60 abstinence days. We then used the neuronal activity marker Fos with intact-brain mapping procedures to identify corresponding patterns of brain-wide activation. Relapse to food seeking was significantly higher after 60 abstinence days than after 1 or 15 days. Using unbiased ClearMap analysis, we identified increased activation of multiple brain regions, particularly corticostriatal structures, following 60 but not 1 or 15 abstinence days. We used orthogonal SMART2 analysis to confirm these findings within corticostriatal and thalamocortical subvolumes and applied expert-guided registration to investigate subdivision and layer-specific activation patterns. Overall, we 1) identified brain-wide activity patterns during incubation of food seeking using complementary analytical approaches and 2) provide a single-cell resolution whole-brain atlas that can be used to identify functional networks and global architecture underlying the incubation of food craving.

Orbitofrontal cortex and dorsal striatum functional connectivity predicts incubation of opioid craving after voluntary abstinence.

We recently introduced a rat model of incubation of opioid craving after voluntary abstinence induced by negative consequences of drug seeking. Here, we used resting-state functional MRI to determine whether longitudinal functional connectivity changes in orbitofrontal cortex (OFC) circuits predict incubation of opioid craving after voluntary abstinence. We trained rats to self-administer for 14 d either intravenous oxycodone or palatable food. After 3 d, we introduced an electric barrier for 12 d that caused cessation of reward self-administration. We tested the rats for oxycodone or food seeking under extinction conditions immediately after self-administration training (early abstinence) and after electric barrier exposure (late abstinence). We imaged their brains before self-administration and during early and late abstinence. We analyzed changes in OFC functional connectivity induced by reward self-administration and electric barrier-induced abstinence. Oxycodone seeking was greater during late than early abstinence (incubation of oxycodone craving). Oxycodone self-administration experience increased OFC functional connectivity with dorsal striatum and related circuits that was positively correlated with incubated oxycodone seeking. In contrast, electric barrier-induced abstinence decreased OFC functional connectivity with dorsal striatum and related circuits that was negatively correlated with incubated oxycodone seeking. Food seeking was greater during early than late abstinence (abatement of food craving). Food self-administration experience and electric barrier-induced abstinence decreased or maintained functional connectivity in these circuits that were not correlated with abated food seeking. Opposing functional connectivity changes in OFC with dorsal striatum and related circuits induced by opioid self-administration versus voluntary abstinence predicted individual differences in incubation of opioid craving.

Effect of the dopamine stabilizer (-)-OSU6162 on potentiated incubation of opioid craving after electric barrier-induced voluntary abstinence.

In the classical incubation of drug craving rat model, drug seeking is assessed after homecage forced abstinence. However, human abstinence is often voluntary because negative consequences of drug seeking outweigh the desire for the drug. Here, we developed a rat model of incubation of opioid craving after electric barrier-induced voluntary abstinence and determined whether the dopamine stabilizer (-)-OSU6162 would decrease this new form of incubation. We trained male and female rats to self-administer oxycodone (0.1 mg/kg/infusion, 6 h/day) for 14 days. We then exposed them to either homecage forced abstinence or voluntary abstinence induced by an electric barrier of increasing intensity near the drug-paired lever. On abstinence days 1, 15, or 30, we tested the rats for oxycodone seeking without shock and drug. We also examined the effect of (-)-OSU6162 (7.5 and 15 mg/kg) on oxycodone seeking on abstinence day 1 or after 15 days of either voluntary or forced abstinence. Independent of sex, the time-dependent increase in oxycodone seeking after cessation of opioid self-administration (incubation of opioid craving) was stronger after voluntary abstinence than after forced abstinence. In males, (-)-OSU6162 decreased incubated (day 15) but not non-incubated (day 1) oxycodone seeking after either voluntary or forced abstinence. In females, (-)-OSU6162 modestly decreased incubated oxycodone seeking after voluntary but not forced abstinence. Results suggest that voluntary abstinence induced by negative consequences of drug seeking can paradoxically potentiate opioid craving and relapse. We propose the dopamine stabilizer (-)-OSU6162 may serve as an adjunct pharmacological treatment to prevent relapse in male opioid users.