Biology subjects
Publications and source records attributed to Pelloux, Y..
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.
The inability to suppress actions despite adverse consequences is a hallmark of compulsive behaviors and is amygdala dependent. To study the amygdalas role in responding despite adverse consequences, we compared single-unit activity in the basolateral (BLA) or central (CeA) amygdala before and after reward-seeking under punishment threat. Rats started each trial by pressing an initial lever, which triggered an outcome-specific 5-s auditory cue (white noise, pure tone, or clicker), signaling one of three reinforcement conditions: 100% sucrose reward, 20% reward/80% omission, or 80% reward/20% footshock punishment. Next, the active and inactive levers were extended, and pressing on the active lever terminated the auditory cue and triggered an outcome-specific 1-s visual cue predicting either reward, reward omission, or shock. After training, we implanted eight tetrodes in the BLA (n=7) or CeA (n=5) and recorded single-unit activity of [~]100 neurons per region during task performance. CeA neurons, and to a lesser extent BLA neurons, responded differently to the distinct auditory cues and outcomes. The discrimination between conditions partially explained the capacity of neuronal activity to predict the latency to lever press to complete the trial. The failure to suppress reward-seeking behavior in the face of punishment coincided with the reactivation of reward-seeking-sensitive and the loss of inhibition of punishment-sensitive neuronal populations. In conclusion, we found that after extended training, opposing populations of activated and inhibited neurons in CeA, and to a lesser extent in BLA, control completion of reward-seeking despite punishment.
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.
Stimulant use, including cocaine, often occurs in a social context whose influence is important to understand to decrease intake and reduce associated harms. Given the regulatory role of the subthalamic nucleus (STN) on cocaine intake and emotions, we investigate its role on such influence of social context on cocaine intake. We explored the influence of peer presence and familiarity on the frequency of self-administered cocaine and its neurobiological basis. We first compared cocaine intake in various conditions (alone or with peers with different characteristics: observing or self-administering, familiar or not, cocaine-naive or not, dominant or subordinate) in rats (n=90). The risk of drug consumption was reduced when a peer was present, observing or self-administering as well, and further diminished when the peer was unfamiliar (vs familiar). The presence of a cocaine-naive peer further decreased cocaine consumption. The presence of a non-familiar and drug-naive peer represents thus key conditions to diminish cocaine intake. We tested the effects of STN lesions in these various conditions and also conducted social experiments to validate the role of STN in social cognition. The STN lesion by itself reduced cocaine intake to the level reached in presence of a stranger naive peer and affected social cognition, positioning the STN as one neurobiological substrate of social influence on drug intake. Finally, with a translational research approach, we compared the drug intake in these conditions in human drug users (n=77). This human study confirmed the beneficial effect of social presence, especially of strangers. Our results indirectly support the use of social interventions and harm reduction strategies, in particular supervised consumption rooms for stimulant users.
While the term "language" is used for human and non-human primates, "vocal communication" is rather used for rodents or other species. The main difference is that there is, to date, no evidence for a vocal signature in the well-known 50- and 22-kHz ultrasonic vocalizations (USV) emitted by rats. Here, we show that rats can recognize the identity of the USV emitter since they self-administer preferentially playback of 50-kHz USV emitted by a stranger rat over those emitted by their cage-mate. In a second experiment, we show that the familiarity with the USV emitter also modulate the effect of USV playback during cocaine self-administration, since only stranger, but not familiar, 50-kHz USV decrease drug intake. Finally, to study the neurobiological substrate of those processes, we have tested the effects of the subthalamic nucleus (STN) lesion on these various conditions. STN-lesioned rats did not lever press much for any USV playback, whatever their emotional valence, nor did they seem able to differentiate familiar from stranger peer. Advocating for the existence of a vocal signature in rats, these results highlight the importance of ultrasonic communication in socio-affective influence of behavior, such as the influence of proximal social factors on drug consumption and confirm the role of the subthalamic nucleus on this influence.
Drug intake is known to be under the influence of social context. We have recently shown that presence of a peer influences drug intake in both rats and humans. Whether or not social acoustic communications between the peers play a role during cocaine or sucrose self-administration (SA) was investigated here, using playback of ultrasonic vocalizations (USV) at 50- and 22-kHz, conveying respectively positive and negative internal affective states in adult rats. To assess the neurobiological substrate of a potential USV influence on drug and food intake, we tested the effects of subthalamic nucleus (STN) lesions, given its role in emotional and motivational processes. In sham-control rats, playback of USV associated with positive affective states induced long-term decreased cocaine consumption, while USV associated with negative affective states induced short-term increase. Interestingly, no effect of USV playback was observed on sucrose intake, whatever the frequency. STN lesions abolished the influence of USV on cocaine intake, highlighting the influence of STN in emotional processes induced by USV emitted by a peer. These results show how acoustic social communication is important to regulate drug intake in rats and how STN modulation could interfere with addiction processes.
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.
Social environment influences drug consumption, its persistence and evolution. Little is known regarding the influence of the presence of a peer during drug consumption and especially how the relationship between peers (familiarity and dominance) can influence drug consumption. We used here a translational and transdisciplinary approach to explore the influence of peer presence and peer familiarity in rats and humans that self-administer stimulants. In rats, cocaine intake was compared when rats were alone with intake when peers with different characteristics (familiar or not, cocaine naive or not, dominant or subordinate) were present. In humans, 77 cocaine and/or methylphenidate users were asked to detail their most recent drug use episodes and their relationship with peers present at consumption. The results show that in both humans and rats, the risk of cocaine/stimulant consumption was significantly reduced by 37% and 32%, respectively, when a peer was present. Moreover, the lowest risk of consumption was consistently observed when the peer was unfamiliar (vs familiar) with a further 38% and 17% risk reduction, respectively. In rats, a decreased risk of consumption was greater when the peer was cocaine naive (vs non-cocaine naive).\n\nThe presence of a non-familiar and possibly drug-naive peer is the most efficient condition to diminish stimulant intake. Our results indirectly support the use of harm reduction strategies, in particular supervised consumption rooms for stimulant users.