The roles of rat medial prefrontal and orbitofrontal cortices in relapse to cocaine-seeking: A comparison across methods for identifying neurocircuits

Mesa, Javier; Wesson, Daniel W.; Schwendt, Marek; Knackstedt, Lori A.

doi:10.1016/j.addicn.2022.100031

Cited by 12 publications

(4 citation statements)

References 119 publications

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“…Interestingly, mPFC activity has been implicated in several characteristics of addictive-like behaviors. Inhibition of mPFC accelerated acquisition of cocaine-taking 70 , and lesioning or inactivation of PL decreased cocaine seeking, but also stress-, cue-, context-or cocaine-induced reinstatement 71 , while inhibition or inactivation of IL increased drug-induced reinstatement 72 , and functional disconnection between IL and NAcS induced reinstatement of drug-seeking following extinction 73,74 . Together with our results, this suggests that hypoactivity in the fronto-striatal neurons may serve as a marker for both high motor impulsivity and vulnerability to drug consumption.…”

Section: Discussionmentioning

confidence: 99%

Activation of the mPFC-NAc pathway reduces motor impulsivity but does not affect risk-related decision-making in innately high-impulsive rats

Arrondeau,

Urueña-Méndez,

Marchessaux

et al. 2024

Preprint

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Attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUD) are characterized by exacerbated motor and risk-related impulsivities, which are associated with decreased cortical activity. In rodents, the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) have been separately implicated in impulsive behaviors, but studies on the specific role of the mPFC-NAc pathway in these behaviors are limited. Here, we investigated whether heightened impulsive behaviors are associated with reduced mPFC activity in rodents, and determined the involvement of the mPFC-NAc pathway in motor and risk-related impulsivities. We used the Roman High- (RHA) and Low-Avoidance (RLA) rat lines, which display divergent phenotypes in impulsivity. To investigate alterations in cortical activity in relation to impulsivity, regional brain glucose metabolism was measured using positron emission tomography and [18F]-fluorodeoxyglucose ([18F]FDG). Using chemogenetics, the activity of the mPFC-NAc pathway was either selectively activated in high-impulsive RHA rats or inhibited in low-impulsive RLA rats, and the effects of these manipulations on motor and risk-related impulsivity were concurrently assessed using the rat gambling task. We showed that basal [18F]FDG uptake was lower in the mPFC and NAc of RHA compared to RLA rats. Activation of the mPFC-NAc pathway in RHA rats reduced motor impulsivity, without affecting risk-related decision-making. Conversely, inhibition of the mPFC-NAc pathway had no effect in RLA rats. Our results suggest that the mPFC-NAc pathway controls motor impulsivity, but has limited involvement in risk-related decision-making. Our findings suggest that reducing fronto-striatal activity may help attenuate motor impulsivity in patients with impulse control dysregulation like ADHD or SUD.

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Section: Discussionmentioning

confidence: 99%

Activation of the mPFC-NAc pathway reduces motor impulsivity but does not affect risk-related decision-making in innately high-impulsive rats

Arrondeau,

Urueña-Méndez,

Marchessaux

et al. 2024

Preprint

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“…Pharmacological, chemogenetic, and optogenetic experiments have demonstrated that the dmPFC is a key site for driving cocaine seeking 30,[39][40][41] . Previous studies have demonstrated that inactivation of a small ensemble of neurons (less than 10% of total) in the dmPFC is sufficient to disrupt future cocaine seeking 42,43 .…”

Section: Discussionmentioning

confidence: 99%

Dissociable dorsal medial prefrontal cortex ensembles are necessary for cocaine seeking and fear conditioning in mice

Liu,

Nawarawong,

Liu

et al. 2024

Preprint

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The dmPFC plays a dual role in modulating drug seeking and fear-related behaviors. Learned associations between cues and drug seeking are encoded by a specific ensemble of neurons. This study explored the stability of a dmPFC cocaine seeking ensemble over two weeks and its influence on persistent cocaine seeking and fear memory retrieval. In the first series of experiments, we trained TetTag mice in cocaine self-administration and tagged strongly activated neurons with EGFP during the initial day 7 cocaine seeking session. Subsequently, a follow-up seeking test was conducted two weeks later to examine ensemble reactivation between two seeking sessions via c-Fos immunostaining. In the second series of experiments, we co-injected viruses expressing TRE-cre and a cre-dependent inhibitory PSAM-GlyR into the dmPFC of male and femalec-fos-tTA mice to enable “tagging” of cocaine seeking ensemble or cued fear ensemble neurons with an inhibitory chemogenetic receptors. Then we investigated their contribution to subsequent cocaine seeking and fear recall during inhibition of the tagged ensemble by administering uPSEM792s (0.3 mg/kg), a selective ligand for PSAM-GlyR. In both sexes, there was a positive association between the persistence of cocaine seeking and the proportion of reactivated EGFP+ neurons within the dmPFC. More importantly, inhibition of the cocaine seeking ensemble suppressed cocaine seeking, but not recall of fear memory, while inhibition of the fear ensemble reduced conditioned freezing but not cocaine seeking. The results demonstrate that cocaine and fear recall ensembles in the dmPFC are stable, but largely exclusive from one another.

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“…The positive correlation between alcohol intake and the number of PL c-Fos + cells observed here suggests that alcohol consumption modulates PL responding to the pharmacological effects of cocaine. PL activity drives reinstatement of cocaine seeking ( McFarland et al, 2003 ; McLaughlin and See, 2003 ; Stefanik et al, 2013 ; Mesa et al, 2022 ). If a non-contingent cocaine injection promotes cocaine seeking behaviors, PL cellular activation may serve as a precursor to those behaviors and alcohol may alter the capacity of those cells to respond to the cocaine experience.…”

Section: Discussionmentioning

confidence: 99%

Alcohol consumption modulates prelimbic cortex response to cocaine following sequential cocaine and alcohol polysubstance use in the rat

et al. 2023

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Polysubstance use (PSU), involves the consumption of more than one drug within a period of time and is prevalent among cocaine users. Ceftriaxone, a beta-lactam antibiotic, reliably attenuates reinstatement of cocaine seeking in pre-clinical models by restoring glutamate homeostasis following cocaine self-administration but fails to do so when rats consume both cocaine and alcohol (cocaine + alcohol PSU). We previously found that cocaine + alcohol PSU rats reinstate cocaine seeking similarly to cocaine-only rats, but demonstrate differences in reinstatement-induced c-Fos expression throughout the reward system, including a lack of change upon ceftriaxone treatment. Here, we used this model to determine if previous findings were caused by tolerance or sensitization to the pharmacological effects of cocaine. Male rats underwent intravenous cocaine self-administration immediately followed by 6 h of home cage access to water or unsweetened alcohol for 12 days. Rats subsequently underwent 10 daily instrumental extinction sessions, during which time they were treated with either vehicle or ceftriaxone. Rats then received a non-contingent cocaine injection and were perfused for later immunohistochemical analysis of c-Fos expression in the reward neurocircuitry. c-Fos expression in the prelimbic cortex correlated with total alcohol intake in PSU rats. There were no effects of either ceftriaxone or PSU on c-Fos expression in the infralimbic cortex, nucleus accumbens core and shell, basolateral amygdala, or ventral tegmental area. These results support the idea that PSU and ceftriaxone alter the neurobiology underlying drug-seeking behavior in the absence of pharmacological tolerance or sensitization to cocaine.

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The roles of rat medial prefrontal and orbitofrontal cortices in relapse to cocaine-seeking: A comparison across methods for identifying neurocircuits

Cited by 12 publications

References 119 publications

Activation of the mPFC-NAc pathway reduces motor impulsivity but does not affect risk-related decision-making in innately high-impulsive rats

Activation of the mPFC-NAc pathway reduces motor impulsivity but does not affect risk-related decision-making in innately high-impulsive rats

Dissociable dorsal medial prefrontal cortex ensembles are necessary for cocaine seeking and fear conditioning in mice

Alcohol consumption modulates prelimbic cortex response to cocaine following sequential cocaine and alcohol polysubstance use in the rat

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