Biology subjects
Publications and source records attributed to Degoulet, M..
High-frequency stimulation of the subthalamic nucleus (STN) has shown therapeutic potential in preclinical models of addiction. However, its rewarding properties remain unclear. Here, we show that cocaine withdrawal enhances STN intracranial self-stimulation, revealing a reward-based mechanism that may contribute to the beneficial effects of STN deep brain stimulation in addiction and related neuropsychiatric disorders.
When does compulsive-like drug seeking emerge? Despite decades of research, and critical advances in our understanding of brain processes leading to addiction, this question remains widely unanswered. So far, behavioral models assessing compulsive-like cocaine seeking following an extended access to cocaine failed to capture the development of its compulsive seeking. In fact, compulsive-like animals immediately displayed pathological seeking when facing its negative consequences of drug seeking, usually materialized by an unescapable mild electric shock on the paws. Here, we designed a new task, Punished Seeking during Extended access (PSE), by inserting punished seeking trials within the sessions of extended access to cocaine. We show that compulsive-like cocaine seeking progressively emerges after several PSE sessions, once cocaine intake has been escalated. We thus provide the addiction community a pertinent model to explore brain mechanisms sustaining the emergence of compulsive-like cocaine seeking.
RationalThe immediate social context significantly influences alcohol consumption in humans. Recent studies have revealed that peer presence could modulate drugs use in rats. The most efficient condition to reduce cocaine intake is the presence of a stranger peer, naive to drugs. Deep brain stimulation (DBS) of the Subthalamic Nucleus (STN), which was shown to have beneficial effects on addiction to cocaine or alcohol, also modulate the protective influence of peers presence on cocaine use. ObjectivesThis study aimed to: 1) explore how the presence of an alcohol-naive stranger peer affects recreational and escalated alcohol intake, and 2) assess the involvement of STN on alcohol use and in the modulation induced by the presence of an alcohol-naive stranger peer. MethodsRats with STN DBS and control animals self-administered 10% (v/v) ethanol in presence, or absence, of an alcohol-naive stranger peer, before and after escalation of ethanol intake (observed after intermittent alcohol (20% (v/v) ethanol) access). ResultsNeither STN DBS nor the presence of an alcohol-naive stranger peer modulated significantly recreational alcohol intake. After the escalation procedure, STN DBS gradually reduced ethanol consumption. The presence of an alcohol-naive stranger peer increased consumption only in low drinkers, which effect was suppressed by STN DBS. ConclusionsThese results highlight the influence of a peers presence on escalated alcohol intake, and confirm the role of STN in addiction-like alcohol intake and in the social influence on drug consumption.
The immediate social context critically modulates drug consumption. The presence of an unfamiliar conspecific, naive to the drug, at the time of consumption reduces cocaine self-administration in male rats during short-access sessions, as well as drug intake in human cocaine users. The subthalamic nucleus (STN), a brain structure involved in cocaine addiction and limbic processes, has been proposed to mediate such social influence on this limited level of drug intake. Whether this influence extends to escalated drug consumption remains an open question. In this study, we compared the effect of the presence of an unfamiliar peer, naive to cocaine, on cocaine self-administration in rats having been exposed to either short (2h) or long-access sessions (6h). We showed that the presence of the peer drastically reduced both limited and escalated cocaine intake in males, while it had no effect on females during short-access sessions. Assessing the effect of STN photo-inhibition or high frequency (HF) stimulation in male rats, we demonstrated that it had no effect in the absence of the conspecific in short-access sessions, STN photo-manipulation suppressed the influence of the peers presence. Moreover, STN photo-inhibition and HF stimulation decreased drug consumption in long-access sessions, but no additive effect was observed when associated with the peers presence, confirming an overriding effect of STN manipulation. Taken together, these results highlight the potential influence of socially oriented manipulations on cocaine intake and further position the STN as a critical mediator of the effect of social presence on addictive-like behaviors.
Most behavioral studies in animals investigate risk using outcome probabilities larger than 10%. However, real-world Decision-Making often requires evaluating events that are both extremely unlikely and highly consequential. To address this gap, we developed an experimental and computational framework to quantify how rats detect and adapt to rare (probability <1%) and extreme (deviation from mean >10 standard deviations) outcomes (REE). Using a four-armed bandit task, animals chose between options associated with probabilistic rewards (sugar pellets) or punishments (time-out delays). Depending on the animals choice, REE can occur or not, allowing us to probe how rats integrate information across both common and fat-tailed event distributions. Across subjects, behavior showed restricted diversification (typically two out of four options) and clear sensitivity to REE, expressed as a systematic avoidance of rare and extreme punishments (Black Swans) combined with partial exposure to rare and extreme gains (Jackpots). The dominant behavioral phenotype displayed a near-complete suppression of exposure to Black Swans, whereas exposure to Jackpots remained only moderate. This asymmetric sensitivity came at a cost: these animals accepted smaller frequent gains and larger frequent losses to avoid catastrophic outcomes. To account for these behaviors, we implemented an augmented reinforcement learning model in which REE are weighted separately from frequent events. Fitting this model to individual behavioral data captured subjects decision patterns far better than standard Q-learning, which systematically failed to reproduce the observed asymmetry. The best-fitting model suggests that the rat brain segregates information from the central outcome distribution and the distribution tails, assigning distinct value weights to REE during action selection. This work provides the first evidence that rodents spontaneously adapt their learning strategies to avoid extreme punishments while partially maintaining exposure to rare and extreme gains, suggesting that frequent outcomes are treated separately from rare and extreme ones through different weights in Decision-Making.
Although deep brain stimulation (DBS) is now a widely used therapeutic strategy, its precise mechanism remains largely unclear. Since this approach is progressively extended to treat non-motor disorders such as depression, obsessive-compulsive disorders, the comprehension of its effects on motivated behaviors appears of the upmost importance for a possible application for addiction. In intact rats, we used inhibition and high frequency optogenetic activation of subthalamic nucleus (STN) neurons to test whether or not we could reproduce the effects of electric deep brain stimulation on rats motivation for sweet food and cocaine. Rats motivation was assessed using fixed-ratio 5 and progressive ratio schedules of reinforcement for both rewards and illumination was applied during behavioral testing. Efficiency of optogenetic manipulations has been validated using in-vitro electrophysiological recordings. Optogenetic inhibition of STN increased motivation for food and reduced motivation for cocaine. In contrast, optogenetic high frequency stimulation reduced the motivation for food without impacting motivation for cocaine. Optical inhibition mimics the effect of electric deep brain stimulation on food and cocaine motivation, confirming that the effects observed under electric DBS result from a specific inactivation of the STN. In contrast, optogenetic high frequency stimulation induces opposite effects to those of electric one, suggesting a stimulation of the STN that only seems to affect food motivation.
Cocaine seeking despite a foot-shock contingency is used to model compulsive drug seeking, a core component of drug addiction, in rodents. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is efficient on other addiction criteria models and we show here that 30-Hz STN stimulation reduces pathological cocaine seeking in compulsive-like rats. This confirms STN DBS as a potential strategy to treat addiction. We also observed that only compulsive-like rats displayed a progressive increase in STN low frequency oscillations, especially in the alpha/theta band (6-13 Hz), during cocaine escalation. Conversely, applying 8-Hz STN DBS to mimic alpha/theta oscillations in non-compulsive animals changed them into compulsive ones. We have thus identified a predictive neuronal biomarker of compulsivity. Since one critical challenge in addiction research is to identify vulnerable individuals before they transition to harmful drug consumption pattern, our results could lead to new diagnostic tools and prevention strategies.