Fos-expressing neuronal ensemble in rat ventromedial prefrontal cortex encodes cocaine seeking but not food seeking in rats.

Neuronal ensembles in ventromedial prefrontal cortex (vmPFC) play a role in both cocaine and palatable food seeking. However, it is unknown whether similar or different vmPFC neuronal ensembles mediate food and cocaine seeking. Here, we used the Daun02 inactivation procedure to assess whether the neuronal ensembles mediating food and cocaine seeking can be functionally distinguished. We trained male and female Fos-LacZ rats to self-administer palatable food pellets and cocaine on alternating days for 18 days. We then exposed the rats to a brief nonreinforced food- or cocaine-seeking test to induce Fos and ß-gal in neuronal ensembles associated with food or cocaine seeking, respectively and infused Daun02 into vmPFC to ablate the ß-gal-expressing ensembles. Two days later, we tested the rats for food or cocaine seeking under extinction conditions. Although inactivation of the food-seeking ensemble did not influence food or cocaine seeking, inactivation of the cocaine-seeking ensemble reduced cocaine seeking but not food seeking. Results indicate that the neuronal ensemble activated by cocaine seeking in vmPFC is functionally separate from the ensemble activated by food seeking.

Separate vmPFC Ensembles Control Cocaine Self-Administration Versus Extinction in Rats.

Recent studies suggest that the ventral medial prefrontal cortex (vmPFC) encodes both operant drug self-administration and extinction memories. Here, we examined whether these opposing memories are encoded by distinct neuronal ensembles within the vmPFC with different outputs to the nucleus accumbens (NAc) in male and female rats. Using cocaine self-administration (3 h/d for 14 d) and extinction procedures, we demonstrated that vmPFC was similarly activated (indexed by Fos) during cocaine-seeking tests after 0 (no-extinction) or 7 extinction sessions. Selective Daun02 lesioning of the self-administration ensemble (no-extinction) decreased cocaine seeking, whereas Daun02 lesioning of the extinction ensemble increased cocaine seeking. Retrograde tracing with fluorescent cholera toxin subunit B injected into NAc combined with Fos colabeling in vmPFC indicated that vmPFC self-administration ensembles project to NAc core while extinction ensembles project to NAc shell. Functional disconnection experiments (Daun02 lesioning of vmPFC and acute dopamine D1-receptor blockade with SCH39166 in NAc core or shell) confirm that vmPFC ensembles interact with NAc core versus shell to play dissociable roles in cocaine self-administration versus extinction, respectively. Our results demonstrate that neuronal ensembles mediating cocaine self-administration and extinction comingle in vmPFC but have distinct outputs to the NAc core and shell that promote or inhibit cocaine seeking.SIGNIFICANCE STATEMENT Neuronal ensembles within the vmPFC have recently been shown to play a role in self-administration and extinction of food seeking. Here, we used the Daun02 chemogenetic inactivation procedure, which allows selective inhibition of neuronal ensembles identified by the activity marker Fos, to demonstrate that different ensembles for cocaine self-administration and extinction memories coexist in the ventral mPFC and interact with distinct subregions of the nucleus accumbens.

'Hot' vs. 'cold' behavioural-cognitive styles: motivational-dopaminergic vs. cognitive-cholinergic processing of a Pavlovian cocaine cue in sign- and goal-tracking rats.

Discrete Pavlovian reward cues acquire more potent incentive motivational properties (incentive salience) in some animals (sign-trackers; STs) compared to others (goal-trackers; GTs). Conversely, GTs appear to be better than STs in processing more complex contextual cues, perhaps reflecting their relatively greater bias for goal-directed cue processing. Here, we investigated the activity of two major prefrontal neuromodulatory input systems, dopamine (DA) and acetylcholine (ACh), in response to a discrete Pavlovian cue that was previously paired with cocaine administration in STs and GTs. Rats underwent Pavlovian training in which light cue presentations were either paired or unpaired with an intravenous cocaine infusion. Following a 10-day abstinence period, prefrontal dialysates were collected in STs and GTs during cue presentations in the absence of cocaine. In STs, the cue previously paired with cocaine significantly increased prefrontal DA levels. DA levels remained elevated over baseline across multiple cue presentation blocks, and DA levels and approaches to the cue were significantly correlated. In STs, ACh levels were unaffected by cue presentations. In contrast, in GTs, presentations of the cocaine cue increased prefrontal ACh, but not DA, levels. GTs oriented towards the cue at rates similar to STs, but they did not approach it and elevated ACh levels did not correlate with conditioned orientation. The results indicate a double dissociation between the role of prefrontal DA and ACh in STs and GTs, and suggest that these phenotypes will be useful for studying the role of neuromodulator systems in mediating opponent behavioural-cognitive styles.

Dual-substance use disorder couples: An integrative review and proposed theoretical model.

Committed romantic relationships between two individuals with Substance Use Disorder (or dual-SUD couples) are prevalent. Dual-SUD couples have poor treatment engagement and outcomes. Research has established a reciprocal link between relationship dynamics (e.g., conflict, intimacy) and substance use. Thus, the couple's relationship presents a distinct social context for both partner's substance use. Dual-SUD couples face unique challenges due to substance use being a shared behavior that may serve as a rewarding source of compatibility, closeness, and short-term relationship satisfaction despite it being at the cost of other alternative sources of substance-free reinforcement. Yet, treatment options for these couples are scarce. Dual-maladaptive health behaviors (e.g., dual-substance use) are challenging to treat; however, theory and preliminary research suggests that transformation of couple's joint motivation toward adaptive health behavior change may result in a more satisfying relationship and improved treatment outcomes for both individuals. The current paper reviews the extant literature on dual-SUD couples from theoretical, empirical, and treatment research and proposes an expanded paradigm regarding how we understand dual-SUD couples with the aim of informing basic research and treatment development.

The impact of spiritual well-being and social support on substance use treatment outcomes within a sample of predominantly Black/African American adults.

INTRO: Substance use and associated problems often return following treatment for substance use disorder (SUD), which disproportionally impact Black/African American (AA) individuals. Social support and spiritual well-being are sources of recovery capital identified as particularly important among Black/AA adults. Social support and spiritual well-being are also posited mechanisms in 12-step; thus, this study tested the effects of social support and spiritual well-being on substance use outcomes over time, distinct from 12-step involvement, among Black/AA adults post-SUD treatment. The study hypothesized that social support and spiritual well-being would demonstrate significant interactions with time, respectively, on substance use frequency and substance use consequences, above the effect of 12-step involvement. METHOD: The study drew data from a study of 262 adults (95.4 % Black/AA) entering residential SUD treatment (NCT#01189552). Assessments were completed at pretreatment and at 3-, 6-, and 12-months posttreatment. Two generalized linear mixed models (GLMM) tested the effects of social support and spiritual well-being, above the effect of 12-step involvement, on substance use frequency and substance use consequences over the course of 12-months posttreatment. RESULTS: Higher spiritual well-being predicted significantly less frequent substance use during recovery (ß = 0.00, p = .03). Greater 12-step involvement predicted significantly fewer substance use consequences during recovery (ß = 0.00, p = .02). In post hoc analyses the effect of spiritual well-being and 12-step involvement dissipated by 3.5- and 6.6-months posttreatment, respectively. The study found no significant effects of social support over time. DISCUSSION: Spiritual well-being and 12-step involvement are associated with lower substance use and substance use consequences, respectively, in the early months of posttreatment recovery among Black/AA adults. These findings contribute to the growing recovery capital literature informing paths to recovery and sources of support outside of 12-step affiliation. However, these effects diminish over time.

Harm reduction-focused behavioral activation for people who inject drugs: Mixed methods outcomes from a pilot open trial.

INTRODUCTION: People who inject drugs (PWID) experience high rates of mental health problems and drug-related harms. Harm reduction-focused interventions aim to reduce harms associated with drug use and are an important approach for engaging people who are not seeking traditional abstinence-focused treatment. Yet, few studies to date have examined the effectiveness of harm reduction psychosocial treatment for drug use. We evaluated the outcomes of a harm reduction-focused behavioral activation (BA) intervention from pretreatment to a 1-month follow-up. METHODS: A total of N = 23 PWID (65.2 % White; 52.2 % women; mean age 35.4 ± 7.8 years) were recruited from syringe services programs and n = 19 received the intervention via teletherapy. Assessment of study outcome measures occurred at pre- and posttreatment and a one-month follow-up. RESULTS: Results reflected post-intervention increases in behavioral activation and readiness to change drug use, as well as decreases in substance use, depression, and HIV risk behaviors. There were mixed outcomes on substance-related problems with increases at follow-up, possibly reflecting increased problem recognition. CONCLUSIONS: These results suggest initial promise for the harm reduction-focused treatment. Additional research with randomized designs and larger sample sizes is needed, and more intensive treatment may be required to support sustained treatment gains in this population.

Food-Seeking Behavior Is Mediated by Fos-Expressing Neuronal Ensembles Formed at First Learning in Rats.

Neuronal ensembles in the infralimbic cortex (IL) develop after prolonged food self-administration training. However, rats demonstrate evidence of learning the food self-administration response as early as day 1, with responding quickly increasing to asymptotic levels. Since the contribution of individual brain regions to task performance shifts over the course of training, it remains unclear whether IL ensembles are gradually formed and refined over the course of extensive operant training, or whether functionally-relevant ensembles might be recruited and formed as early as the initial acquisition of food self-administration behavior. Here, we aimed to determine the role of IL ensembles at the earliest possible point after demonstrable learning of a response-outcome association. We first allowed rats to lever press for palatable food pellets and stopped training rats once their behavior evidenced the response-outcome association (learners). We compared their food-seeking behavior and neuronal activation (Fos protein expression) to similarly trained rats that did not form this association (non-learners). Learners had greater food-seeking behavior and neuronal activation within the medial prefrontal cortex (mPFC), suggesting that mPFC subregions might encode initial food self-administration memories. To test the functional relevance of mPFC Fos-expressing ensembles to subsequent food seeking, we tested region-wide inactivation of the IL using muscimol+baclofen and neuronal ensemble-specific ablation using the Daun02 inactivation procedure. Both region-wide inactivation and ensemble-specific inactivation of the IL significantly decreased food seeking. These data suggest that IL neuronal ensembles form during initial learning of food self-administration behavior, and furthermore, that these ensembles play a functional role in food seeking.