Relationship between transcranial magnetic stimulation markers of motor control and clinical recovery in obsessive compulsive disorder/Gilles de la Tourette syndrome: a proof of concept case study.

Background: Obsessive compulsive disorder (OCD) and Gilles de la Tourette syndrome (GTS) are neurodevelopmental disorders characterized by difficulties in controlling intrusive thoughts (obsessions) and undesired actions (tics), respectively. Both conditions have been associated with abnormal inhibition but a tangible deficit of inhibitory control abilities is controversial in GTS. Methods: Here, we examined a 25 years-old male patient with severe OCD symptoms and a mild form of GTS, where impairments in motor control were central. Transcranial magnetic stimulation (TMS) was applied over the primary motor cortex (M1) to elicit motor-evoked potentials (MEPs) during four experimental sessions, allowing us to assess the excitability of motor intracortical circuitry at rest as well as the degree of MEP suppression during action preparation, a phenomenon thought to regulate movement initiation. Results: When tested for the first time, the patient presented a decent level of MEP suppression during action preparation, but he exhibited a lack of intracortical inhibition at rest, as evidenced by reduced short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI). Interestingly, the patient's symptomatology drastically improved over the course of the sessions (reduced obsessions and tics), coinciding with feedback given on his good motor control abilities. These changes were reflected in the TMS measurements, with a significant strengthening of intracortical inhibition (SICI and LICI more pronounced than previously) and a more selective tuning of MEPs during action preparation; MEPs became even more suppressed, or selectively facilitated depending on the behavioral condition in which they we probed. Conclusion: This study highlights the importance of better understanding motor inhibitory mechanisms in neurodevelopmental disorders and suggests a biofeedback approach as a potential novel treatment.

Effect of virtual reality hypnosis on intraoperative sedation needs and functional recovery in knee arthroplasty: a prospective randomized clinical trial.

BACKGROUND AND OBJECTIVES: Perioperative psychological stress and pharmacological anxiolysis can negatively affect the quality of recovery after total knee arthroplasty. We aimed to assess whether hypnosis combined with virtual reality could reduce intraoperative pharmacological sedation and improve quality of recovery after total knee arthroplasty surgery. METHODS: In this prospective randomized clinical trial, 60 patients scheduled for total knee arthroplasty with spinal anesthesia were randomly divided into 2 groups of 30 patients each. Intraoperatively, intermittent boluses of midazolam 1 mg were administered at 5 min intervals at the patient's request, with a maximum driven by the clinical assessment of sedation depth. During surgery, patients received standard care (group control) or virtual reality hypnosis (group VRH). An unblinded observer recorded the total dose of midazolam administered during surgery, and changes in the Quality-of-Recovery 15-item score, comfort, fatigue, pain and anxiety before and 1, 3 and 7 days after surgery. RESULTS: Patients in the VRH group required a lower dose of midazolam (mg; median (range)) intraoperatively (group VRH: 0 (0-4) and group control: 2 (0-9), p<0.001). Quality-of-Recovery 15-item, anxiety, and pain were similar between groups. CONCLUSIONS: In total knee arthroplasty with spinal anesthesia, VRH reduces the requirement for intraoperative pharmacological sedation, without a change in the quality of recovery. TRIAL REGISTRATION NUMBER: NCT05707234.

Links between psychopathological symptoms and cortical thickness in men with severe alcohol use disorder: A Magnetic Resonance Imaging study.

BACKGROUND: Anxiety and depression are psychopathological states frequently co-occurring with severe alcohol use disorder (SAUD). These symptoms generally disappear with abstinence but may persist in some patients, increasing the relapse risk. METHODS: The cerebral cortex thickness of 94 male patients with SAUD was correlated with symptoms of depression and anxiety, both measured at the end (2-3 weeks) of the detoxification treatment. Cortical measures were obtained using surface-based morphometry implemented with Freesurfer. RESULTS: Depressive symptoms were associated with reduced cortical thickness in the superior temporal gyrus of the right hemisphere. Anxiety level was correlated with lower cortical thickness in the rostral middle frontal region, inferior temporal region, and supramarginal, postcentral, superior temporal, and transverse temporal regions of the left hemisphere, as well as with a large cluster in the middle temporal region of the right hemisphere. CONCLUSIONS: At the end of the detoxification stage, the intensity of depressive and anxiety symptoms is inversely associated with the cortical thickness of regions involved in emotions-related processes, and the persistence of the symptoms could be explained by these brain deficits.

Exploring the links between gut microbiota and excitatory and inhibitory brain processes in alcohol use disorder: A TMS study.

While the impact of the gut microbiota on brain and behavior is increasingly recognized, human studies examining this question are still scarce. The primary objective of the current study was to explore the potential relationships between the gut microbiota composition, motor cortical excitability at rest and during inhibitory control, as well as behavioral inhibition, in healthy volunteers and in patients suffering from alcohol use disorder. Motor cortical excitability was examined using a range of transcranial magnetic stimulation (TMS) measures probed at rest, including the recruitment curve, short and long intracortical inhibition, and intracortical facilitation within the primary motor cortex. Moreover, TMS was applied during a choice reaction time task to assess changes in motor excitability associated with inhibitory control. Finally, behavioral inhibition was investigated using a neuropsychological task (anti-saccade). Overall, our results highlight several interesting correlations between microbial composition and brain measures. Hence, higher bacterial diversity, as well as higher relative abundances of UGC-002 and Christensenellaceae R-7 group were correlated with stronger changes in motor excitability associated with inhibitory control. Also, higher abundance of Anaerostipes was associated with higher level of corticospinal excitability. Finally, relative abundances of Bifidobacterium and Faecalibacterium were positively related to performance in the neuropsychological task, suggesting that they might have a positive impact on behavioral inhibition. Although correlation is not causation, the present study suggests that excitatory and inhibitory brain processes might be related to gut microbiota composition. This article is part of the Special Issue on 'Microbiome & the Brain: Mechanisms & Maladies'.

Corticospinal Suppression Underlying Intact Movement Preparation Fades in Parkinson's Disease.

BACKGROUND: In Parkinson's disease (PD), neurophysiological abnormalities within the primary motor cortex (M1) have been shown to contribute to bradykinesia, but exact modalities are still uncertain. We propose that such motor slowness could involve alterations in mechanisms underlying movement preparation, especially the suppression of corticospinal excitability-called "preparatory suppression"-which is considered to propel movement execution by increasing motor neural gain in healthy individuals. METHODS: On two consecutive days, 29 PD patients (on and off medication) and 29 matched healthy controls (HCs) underwent transcranial magnetic stimulation over M1, eliciting motor-evoked potentials (MEPs) in targeted hand muscles, while they were either at rest or preparing a left- or right-hand response in an instructed-delay choice reaction time task. Preparatory suppression was assessed by expressing MEP amplitudes during movement preparation relative to rest. RESULTS: Contrary to HCs, PD patients showed a lack of preparatory suppression when the side of the responding hand was analyzed, especially when the latter was the most affected one. This deficit, which did not depend on dopamine medication, increased with disease duration and also tended to correlate with motor impairment, as measured by the Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III (both total and bradykinesia scores). CONCLUSIONS: Our novel findings indicate that preparatory suppression fades in PD, in parallel with worsening motor symptoms, including bradykinesia. Such results suggest that an alteration in this marker of intact movement preparation could indeed cause motor slowness and support its use in future studies on the relation between M1 alterations and motor impairment in PD. © 2022 International Parkinson and Movement Disorder Society.

Augmented tendency to act and altered impulse control in alcohol use disorders.

Action preparation relies on the operation of control processes that modulate the excitability of the corticospinal tract. On the one hand, excitatory processes prepare the motor system for the forthcoming response; the stronger these influences, the stronger the tendency to act. On the other hand, inhibitory influences allow to suppress inappropriate actions and, more generally, to ensure some sort of impulse control. Because an impairment in these processes could foster inappropriate drinking behavior, the present study aimed at evaluating the motor correlates of such excitatory and inhibitory influences in non-treatment seeking heavy drinkers (HDs) and inpatients suffering from severe alcohol use disorder (SAUDs). Besides, as cue-elicited craving might further alter these processes, we also assessed the impact of an alcohol-related exposure. To do so, 15 healthy controls (HCs), 15 HDs and 15 SAUDs performed a choice reaction time task after having been immersed in a neutral or an alcohol-related environment, using virtual reality videos. Importantly, single-pulse transcranial magnetic stimulation was applied over the left and the right primary motor cortex during the task to elicit motor-evoked potentials in a set of hand muscles allowing us to specifically probe the impact of excitatory and inhibitory processes on motor activity. Our data indicate that excitatory influences are particularly high in both HDs and SAUDs, especially in the dominant hand, an effect that was not observed in HCs. By contrast, inhibitory influences were found to be perfectly normal in HDs, while they were lacking in SAUDs. Furthermore, the alcohol-related exposure enhanced the level of self-reported craving, but this effect only arose in HDs and did not significantly alter the strength of excitatory and inhibitory influences. Overall, although these results have to be taken with caution due to the small sample sizes, this study suggests that enhanced excitatory processes characterize both HDs and SAUDs, while weaker inhibitory influences only concern SAUDs. Hence, an abnormally strong tendency to act could represent a common feature of hazardous drinking, leading individuals to excessive alcohol consumption, whereas deficient impulse control would be a hallmark of more severe forms of AUD, potentially due to the chronic neurotoxic effects of alcohol. Finally, although an alcohol-related exposure does not seem to affect excitatory and inhibitory processes at play during action preparation per se, future works should evaluate changes in corticospinal excitability during the preparation of responses specifically targeting alcohol-related cues.

Neural bases of inhibitory control: Combining transcranial magnetic stimulation and magnetic resonance imaging in alcohol-use disorder patients.

Inhibitory control underlies the ability to inhibit inappropriate responses and involves processes that suppress motor excitability. Such motor modulatory effect has been largely described during action preparation but very little is known about the neural circuit responsible for its implementation. Here, we addressed this point by studying the degree to which the extent of preparatory suppression relates to brain morphometry. We investigated this relationship in patients suffering from severe alcohol use disorder (AUD) because this population displays an inconsistent level of preparatory suppression and major structural brain damage, making it a suitable sample to measure such link. To do so, 45 detoxified patients underwent a structural magnetic resonance imaging (MRI) and performed a transcranial magnetic stimulation (TMS) experiment, in which the degree of preparatory suppression was quantified. Besides, behavioral inhibition and trait impulsivity were evaluated in all participants. Overall, whole-brain analyses revealed that a weaker preparatory suppression was associated with a decrease in cortical thickness of a medial prefrontal cluster, encompassing parts of the anterior cingulate cortex and superior-frontal gyrus. In addition, a negative association was observed between the thickness of the supplementary area (SMA)/pre-SMA and behavioral inhibition abilities. Finally, we did not find any significant correlation between preparatory suppression, behavioral inhibition and trait impulsivity, indicating that they represent different facets of inhibitory control. Altogether, the current study provides important insight on the neural regions underlying preparatory suppression and allows highlighting that the excitability of the motor system represents a valuable read-out of upstream cognitive processes.

Gut Microbiota-Induced Changes in ß-Hydroxybutyrate Metabolism Are Linked to Altered Sociability and Depression in Alcohol Use Disorder.

Patients with alcohol use disorder (AUD) present with important emotional, cognitive, and social impairments. The gut microbiota has been recently shown to regulate brain functions and behavior but convincing evidence of its role in AUD is lacking. Here, we show that gut dysbiosis is associated with metabolic alterations that affect behavioral (depression, sociability) and neurobiological (myelination, neurotransmission, inflammation) processes involved in alcohol addiction. By transplanting the gut microbiota from AUD patients to mice, we point out that the production of ethanol by specific bacterial genera and the reduction of lipolysis are associated with a lower hepatic synthesis of ß-hydroxybutyrate (BHB), which thereby prevents the neuroprotective effect of BHB. We confirm these results in detoxified AUD patients, in which we observe a persisting ethanol production in the feces as well as correlations among low plasma BHB levels and social impairments, depression, or brain white matter alterations.

Considering Motor Excitability During Action Preparation in Gambling Disorder: A Transcranial Magnetic Stimulation Study.

A lack of inhibitory control appears to contribute to the development and maintenance of addictive disorders. Among the mechanisms thought to assist inhibitory control, an increasing focus has been drawn on the so-called preparatory suppression, which refers to the drastic suppression observed in the motor system during action preparation. Interestingly, deficient preparatory suppression has been reported in alcohol use disorders. However, it is currently unknown whether this deficit also concerns behavioral, substance-free, addictions, and thus whether it might represent a vulnerability factor common to both substance and behavioral addictive disorders. To address this question, neural measures of preparatory suppression were obtained in gambling disorder patients (GDPs) and matched healthy control subjects. To do so, single-pulse transcranial magnetic stimulation was applied over the left and the right motor cortex to elicit motor-evoked potentials (MEPs) in both hands when participants were performing a choice reaction time task. In addition, choice and rapid response impulsivity were evaluated in all participants, using self-report measures and neuropsychological tasks. Consistent with a large body of literature, the MEP data revealed that the activity of the motor system was drastically reduced during action preparation in healthy subjects. Surprisingly, though, a similar MEP suppression was observed in GDPs, indicating that those subjects do not globally suffer from a deficit in preparatory suppression. By contrast, choice impulsivity was higher in GDPs than healthy subjects, and a higher rapid response impulsivity was found in the more severe forms of GD. Altogether, those results demonstrated that although some aspects of inhibitory control are impaired in GDPs, these alterations do not seem to concern preparatory suppression. Yet, the profile of individuals suffering of a GD is very heterogeneous, with only part of them presenting an impulsive disposition, such as in patients with alcohol use disorders. Hence, a lack of preparatory suppression may be only shared by this sub-type of addicts, an interesting issue for future investigation.

Preparatory inhibition: Impact of choice in reaction time tasks.

By applying transcranial magnetic stimulation (TMS) over primary motor cortex (M1) to elicit motor-evoked potentials (MEPs) in muscles of the contralateral hand during reaction time (RT) tasks, many studies have reported a strong global suppression of motor excitability during action preparation, a phenomenon called preparatory inhibition. Several hypotheses have been put forward regarding the role of this broad suppression, with the predominant view that it reflects inhibitory processes assisting action selection. However, this assumption is still a matter of debate. Here, we aimed at directly addressing this idea by comparing MEPs in a task that required subjects to select a finger response within a set of predefined options (choice RT task: left or right index finger abduction) or when subjects simply had to provide the same finger response on every trial, in the absence of choice (simple RT task). Moreover, we minimized any effect that could be associated with other forms of inhibition. In both versions of the task, TMS was applied on both M1 (double-coil protocol) at several time points between the go signal and the left or right index finger response, eliciting MEPs bilaterally in the prime mover (index finger agonist) and in an irrelevant muscle (pinky agonist). Overall, MEP suppression was moderate in this study compared to past research; it was only found for the irrelevant muscle. As such, MEPs in the index agonist were facilitated when elicited in a responding hand (e.g. left MEPs preceding left responses) and remained mostly unchanged in a non-responding hand (e.g. left MEPs preceding right responses). In contrast, MEPs were almost always suppressed in the pinky muscle when elicited in the non-responding hand. This finding contrasts with previous studies where preparatory inhibition usually concerns both relevant and irrelevant muscles. Yet importantly, the suppression was more consistent in the choice than in the simple RT task, supporting the view that preparatory inhibition may assist action selection.

Investigating the effect of anticipating a startling acoustic stimulus on preparatory inhibition.

OBJECTIVES: Motor-evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) show a profound suppression when elicited during the instructed-delay of reaction time (RT) tasks. One predominant hypothesis is that this phenomenon, called "preparatory inhibition", reflects the operation of processes that suppress motor activity to withhold prepared (but delayed) responses, a form of impulse control. In addition, a startling acoustic stimulus (SAS) - a loud and narrow sound - can trigger the release of prepared responses in RT tasks. We predicted that, if such premature release is clearly forbidden, then anticipating a SAS during delay periods may be associated with increased preparatory inhibition for greater impulse control. METHODS: Subjects performed a behavioural (n=16) and TMS (n=11) experiment. Both used a choice RT task that required subjects to choose a response based on a preparatory cue but to only release it after an imperative signal. SAS and TMS pulses were elicited at the end of the delay period and subjects were asked to do their best to only release their response after the imperative signal, even in the presence of SAS. SAS could be either rare or frequent, in separate blocks. RESULTS: Consistent with the literature, SAS shortened RTs, especially when they occurred frequently. Moreover, MEPs were suppressed when subjects delayed prepared responses but this preparatory inhibition did not depend on whether SAS were frequent or rare. DISCUSSION: The stronger RT shortening with frequent rather than rare SAS may be due to increased attention and/or reduced reactive inhibition to SAS, leaving preparatory inhibition unaffected.

Deficient inhibition in alcohol-dependence: let's consider the role of the motor system!

Impaired inhibitory control contributes to the development, maintenance, and relapse of alcohol-dependence, but the neural correlates of this deficit are still unclear. Because inhibitory control has been labeled as an executive function, most studies have focused on prefrontal areas, overlooking the contribution of more "primary" structures, such as the motor system. Yet, appropriate neural inhibition of the motor output pathway has emerged as a central aspect of healthy behavior. Here, we tested the hypothesis that this motor inhibition is altered in alcohol-dependence. Neural inhibitory measures of motor activity were obtained in 20 detoxified alcohol-dependent (AD) patients and 20 matched healthy subjects, using a standard transcranial magnetic stimulation procedure whereby motor-evoked potentials (MEPs) are elicited in a choice reaction time task. Moreover, behavioral inhibition and trait impulsivity were evaluated in all participants. Finally, the relapse status of patients was assessed 1 year after the experiment. As expected, AD patients displayed poorer behavioral inhibition and higher trait impulsivity than controls. More importantly, the MEP data revealed a considerable shortage of neural motor inhibition in AD patients. Interestingly, this neural defect was strongest in the patients who ended up relapsing during the year following the experiment. Our data suggest a strong motor component in the neural correlates of altered inhibitory control in AD patients. They also highlight an intriguing relationship with relapse and the perspective of a new biomarker to follow strategies aiming at reducing relapse in AD patients.

Comparison of Motor Inhibition in Variants of the Instructed-Delay Choice Reaction Time Task.

Using instructed-delay choice reaction time (RT) paradigms, many previous studies have shown that the motor system is transiently inhibited during response preparation: motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) over the primary motor cortex are typically suppressed during the delay period. This effect has been observed in both selected and non-selected effectors, although MEP changes in selected effectors have been more inconsistent across task versions. Here, we compared changes in MEP amplitudes in three different variants of an instructed-delay choice RT task. All variants required participants to choose between left and right index finger movements but the responses were either provided "in the air" (Variant 1), on a regular keyboard (Variant 2), or on a response device designed to control from premature responses (Variant 3). The task variants also differed according to the visual layout (more concrete in Variant 3) and depending on whether participants received a feedback of their performance (absent in Variant 1). Behavior was globally comparable between the three variants of the task although the propensity to respond prematurely was highest in Variant 2 and lowest in Variant 3. MEPs elicited in a non-selected hand were similarly suppressed in the three variants of the task. However, significant differences emerged when considering MEPs elicited in the selected hand: these MEPs were suppressed in Variants 1 and 3 whereas they were often facilitated in Variant 2, especially in the right dominant hand. In conclusion, MEPs elicited in selected muscles seem to be more sensitive to small variations to the task design than those recorded in non-selected effectors, probably because they reflect a complex combination of inhibitory and facilitatory influences on the motor output system. Finally, the use of a standard keyboard seems to be particularly inappropriate because it encourages participants to respond promptly with no means to control for premature responses, probably increasing the relative amount of facilitatory influences at the time motor inhibition is probed.

Concomitant Caffeine Increases Binge Consumption of Ethanol in Adolescent and Adult Mice, But Produces Additive Motor Stimulation Only in Adolescent Animals.

BACKGROUND: Binge co-consumption of highly caffeinated energy drinks with alcohol (ethanol [EtOH]) has become a common practice among adolescents/young adults and has been associated with an increased incidence of hazardous behaviors. Animal models are critical in advancing our understanding the neurobehavioral consequences of this form of binge drinking. Surprisingly, virtually no work has explored caffeine and EtOH co-consumption or its long-term consequences in adolescent animals. The primary objective of the current study was to extend a previously established mouse model of voluntary binge caffeine and EtOH co-consumption to explore adolescent consumption and responses compared to adults. METHODS: Adolescent and adult male C57BL/6J mice had daily limited access to caffeine (0.03% w/v), EtOH (20% v/v), a combined EtOH/caffeine solution, or water for 14 days via the binge-like drinking paradigm, drinking-in-the-dark (DID). Home cage locomotor activity was measured during DID in a subset of mice. Following DID, all mice rested for 18 days so that adolescents reached adulthood, whereupon all mice underwent 7 days of continuous access 2-bottle choice drinking for 10% (v/v) EtOH or water. RESULTS: Co-consumption with caffeine significantly increased EtOH intake and resultant blood ethanol concentrations in both adolescent and adult mice. In addition, adolescent mice exhibited a uniquely robust locomotor stimulant response to caffeine and EtOH co-consumption. Later EtOH intake and preference was not influenced, however, by prior fluid consumption history via DID. CONCLUSIONS: Together with findings from the human literature, our results suggest that caffeine co-consumption may positively influence binge alcohol consumption in adolescents/young adults. Importantly, this age group may be particularly sensitive to the additive stimulant effects of caffeinated alcohol consumption, an effect which may be related to the high incidence of associated negative outcomes in this population. These observations are particularly concerning considering the heightened plasticity of the adolescent brain.

A Double-Coil TMS Method to Assess Corticospinal Excitability Changes at a Near-Simultaneous Time in the Two Hands during Movement Preparation.

BACKGROUND: Many previous transcranial magnetic stimulation (TMS) studies have investigated corticospinal excitability changes occurring when choosing which hand to use for an action, one of the most frequent decision people make in daily life. So far, these studies have applied single-pulse TMS eliciting motor-evoked potential (MEP) in one hand when this hand is either selected or non-selected. Using such method, hand choices were shown to entail the operation of two inhibitory mechanisms, suppressing MEPs in the targeted hand either when it is non-selected (competition resolution, CR) or selected (impulse control, IC). However, an important limitation of this "Single-Coil" method is that MEPs are elicited in selected and non-selected conditions during separate trials and thus those two settings may not be completely comparable. Moreover, a more important problem is that MEPs are computed in relation to the movement of different hands. The goal of the present study was to test a "Double-Coil" method to evaluate IC and CR preceding the same hand responses by applying Double-Coil TMS over the two primary motor cortices (M1) at a near-simultaneous time (1 ms inter-pulse interval). METHODS: MEPs were obtained in the left (MEPLEFT) and right (MEPRIGHT) hands while subjects chose between left and right hand key-presses in blocks using a Single-Coil or a Double-Coil method; in the latter blocks, TMS was either applied over left M1 first (TMSLRM1 group, n = 12) or right M1 first (TMSRLM1 group, n = 12). RESULTS: MEPLEFT were suppressed preceding both left (IC) and right (CR) hand responses whereas MEPRIGHT were only suppressed preceding left (CR) but not right (IC) hand responses. This result was observed regardless of whether Single-Coil or Double-Coil TMS was applied in the two subject groups. However, in the TMSLRM1 group, the MEP suppression was attenuated in Double-Coil compared to Single-Coil blocks for both IC and CR, when probed with MEPLEFT (elicited by the second pulse). CONCLUSIONS: Although Double-Coil TMS may be a reliable method to assess bilateral motor excitability provided that a RM1-LM1 pulse order is used, further experiments are required to understand the reduced MEPLEFT changes in Double-Coil blocks when the LM1-RM1 pulse order was used.

Involvement of the GABAA Receptor in Age-Dependent Differences in Binge-Like Ethanol Intake.

BACKGROUND: Binge alcohol (ethanol [EtOH]) drinking is common during adolescence, a time characterized by many behavioral and neurobiological changes. Among them, the GABAA receptor system undergoes substantial modifications, including changes in the density, distribution, and subunit composition of the receptor. Based on its demonstrated role in EtOH consumption, this study aimed to investigate the effects of 2 different GABAA receptor agonists on binge-like EtOH intake in adolescent and adult mice using the Drinking-in-the-Dark model. METHODS: Three hours into their dark cycle, adolescent (postnatal day 28 [P28]) and adult (P63) male C57BL/6J mice were given daily access to 20% EtOH for 2 hours during 8 consecutive days. Immediately before the access on day 8, mice (P35 and P70) were systemically injected with 1 of 2 different GABAergic drugs. The effects of muscimol, a full GABAA agonist, were assessed in a first experiment. The second experiment tested for the more specific involvement of δ-containing extrasynaptic GABAA receptors through the administration of THIP (4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol). RESULTS: Adolescent mice consumed more EtOH than their adult counterparts. Following the administration of GABAA agonists, levels of EtOH intake were reduced at both ages. However, age-dependent differences were revealed following the administration of THIP, with adolescents exhibiting greater sensitivity to its suppressant effects, especially during the first 30 minutes of binge EtOH access. CONCLUSIONS: This study adds to the existing literature demonstrating the crucial role of the GABAA receptor in alcohol consumption. In addition, it suggests that age differences in the GABAA receptor modulation of binge alcohol drinking might be more dependent on extrasynaptic GABAA receptors.

Correlation between ethanol behavioral sensitization and midbrain dopamine neuron reactivity to ethanol.

Repeated ethanol injections lead to a sensitization of its stimulant effects in mice. Some recent results argue against a role for ventral tegmental area (VTA) dopamine neurons in ethanol behavioral sensitization. The aim of the present study was to test whether in vivo ethanol locomotor sensitization correlates with changes in either basal- or ethanol-evoked firing rates of dopamine neurons in vitro. Female Swiss mice were daily injected with 2.5 g/kg ethanol (or saline in the control group) for 7 days and their locomotor activity was recorded. At the end of the sensitization procedure, extracellular recordings were made from dopaminergic neurons in midbrain slices from these mice. Significantly higher spontaneous basal firing rates of dopamine neurons were recorded in ethanol-sensitized mice relative to control mice, but without correlations with the behavioral effects. The superfusion of sulpiride, a dopamine D2 antagonist, induced a stronger increase of dopamine neuron firing rates in ethanol-sensitized mice. This shows that the D2 feedback in dopamine neurons is preserved after chronic ethanol administration and argues against a reduced D2 feedback as an explanation for the increased dopamine neuron basal firing rates in ethanol-sensitized mice. Finally, ethanol superfusion (10-100 mM) significantly increased the firing rates of dopamine neurons and this effect was of higher magnitude in ethanol-sensitized mice. Furthermore, there were significant correlations between such a sensitization of dopamine neuron activity and ethanol behavioral sensitization. These results support the hypothesis that changes in brain dopamine neuron activity contribute to the behavioral sensitization of the stimulant effects of ethanol.

Differential effects of context on psychomotor sensitization to ethanol and cocaine.

Repeated drug injections lead to sensitization of their stimulant effects in mice, a phenomenon sometimes referred to as drug psychomotor sensitization. Previous studies showed that sensitization to cocaine is context dependent as its expression is reduced in an environment that was not paired with cocaine administration. In contrast, the effects of the test context on ethanol sensitization remain unclear. In the present study, female OF1 mice were repeatedly injected with 1.5 g/kg ethanol to test for both the effects of context novelty/familiarity and association on ethanol sensitization. A first group of mice was extensively pre-exposed to the test context before ethanol sensitization and ethanol injections were paired with the test context (familiar and paired group). A second group was not pre-exposed to the test context, but ethanol injections were paired with the test context (nonfamiliar and paired group). Finally, a third group of mice was not pre-exposed to the test context and ethanol was repeatedly injected in the home cage (unpaired group). Control groups were similarly exposed to the test context, but were injected with saline. In a second experiment, cocaine was used as a positive control. The same behavioral procedure was used, except that mice were injected with 10 mg/kg cocaine instead of ethanol. The results show a differential involvement of the test context in the sensitization to ethanol and cocaine. Cocaine sensitization is strongly context dependent and is not expressed in the unpaired group. In contrast, the expression of ethanol sensitization is independent of the context in which it was administered, but is strongly affected by the relative novelty/familiarity of the environment. Extensive pre-exposure to the test context prevented the expression of ethanol sensitization. One possible explanation is that expression of ethanol sensitization requires an arousing environment.

Higher long-lasting ethanol sensitization after adolescent ethanol exposure in mice.

RATIONALE: Due to their maturing brain, adolescents are suggested to be more vulnerable to the long-term consequences of chronic alcohol use. Increased sensitization to the stimulant effects of ethanol is a possible consequence of ethanol exposure during adolescence. OBJECTIVES: The aim of this study was to characterize the long-term alterations in the stimulant effects of ethanol and in the rate of ethanol sensitization in mice pre-exposed to ethanol during adolescence in comparison to mice pre-exposed to ethanol in adulthood. METHODS: Adolescent and adult female Swiss mice were injected with saline or ethanol (2.5 or 4 g/kg) during 14 consecutive days. After a 3-week period of ethanol abstinence, mice were tested as adults before and after a second exposure to daily repeated ethanol injections. RESULTS: All mice pre-exposed to ethanol as adults or adolescents showed higher stimulant effects when re-exposed to ethanol 3 weeks later. However, this enhanced sensitivity to the stimulant effects of ethanol was of significantly higher magnitude in mice repeatedly injected with high ethanol doses (4 g/kg) during adolescence. Furthermore, the increased expression of ethanol stimulant effects in these mice was maintained even after a second procedure of ethanol sensitization. CONCLUSIONS: Adolescence is a critical period for the development of a sensitization to ethanol stimulant properties providing that high intermittent ethanol doses are administered. These results might contribute to explain the relationship between age at first alcohol use and risks of later alcohol problems and highlight the dangers of repeated consumption of high alcohol amounts in young adolescents.