Alcohol-seeking behavior elicited by a discrete Pavlovian alcohol cue is invigorated by an alcohol context and requires AMPA glutamate receptors in the basolateral amygdala

Environmental cues associated with alcohol consumption can trigger craving and facilitate relapse in abstinent alcoholics. We hypothesized that alcohol-seeking behavior evoked by a discrete cue associated with alcohol, would be influenced by context and require glutamate transmission in the basolateral amygdala. Male, Long-Evans rats that had previously consumed ethanol (EtOH; 15%; v/v) received Pavlovian conditioning sessions in which a 10-sec auditory stimulus (CS; 15 trials per session) was paired with EtOH (0.2 ml/CS). Entries into a fluid port where EtOH was delivered were measured. Pavlovian conditioning occurred in a specific context (alcohol context) and was alternated with sessions in a different context (non-alcohol context) where neither the CS nor EtOH was presented. At test, the CS was presented without EtOH in either the alcohol context or the non-alcohol context. In a separate study, rats received a bilateral microinfusion (0.3 μl/hemisphere) of 0, 0.3, or 1.0 μg of the AMPA glutamate receptor antagonist NBQX [2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione)] in the BLA. The effect of NBQX administration in the CPu on alcohol-seeking behavior elicited by an alcohol-predictive CS was also tested in a non-alcohol context. Alcohol-seeking elicited by the CS was invigorated in the alcohol context relative to the non-alcohol context. NBQX in the BLA attenuated CS responding at test in both contexts, but had no effect when infused into the CPu. These data highlight an important role of context in modulating the vigor of Pavlovian-conditioned alcohol-seeking, and suggest that AMPA receptors within the BLA are required for the expression of this behavior

Comparing ABA, AAB, and ABC Renewal of Appetitive Pavlovian Conditioned Responding in Alcohol- and Sucrose-Trained Male Rats

Conditioned responding can be renewed by re-exposure to the conditioning context following extinction in a different context (ABA renewal) or by removal from the extinction context (AAB or ABC renewal). ABA renewal is robust in Pavlovian and operant conditioning paradigms. However, fewer studies have investigated AAB and ABC renewal of appetitive conditioning, and those that did predominantly used operant conditioning tasks. Renewal has theoretical relevance for extinction and for exposure-based treatments for substance use disorders that aim to extinguish reactivity to drug-predictive cues. We therefore investigated ABA, AAB, and ABC renewal of Pavlovian conditioned responding to cues that predicted either alcohol or sucrose. Male, Long-Evans rats (Charles River) were exposed to either 15% ethanol (Study 1: “alcohol”) or 10% sucrose (Study 2: “sucrose”) in their home cages. Next, they were trained to discriminate between two auditory stimuli (white noise and clicker; 10 s) in conditioning chambers equipped with distinct olfactory, visual, and tactile contextual stimuli (context A). One conditioned stimulus (CS+) was paired with fluid delivery (0.2 ml/CS+; 3.2 ml/session; alcohol or sucrose in separate experiments), and the second CS (CS−) was not. In all sessions (conditioning, extinction, and test), each CS was presented 16 times/session on a variable-time 67-s schedule, and entries into the fluid port were recorded. CS+ port entries were then extinguished by withholding fluid delivery either in context A or in a second, different context (context B). Next, we assessed ABA, AAB, and ABC renewal in the absence of fluid delivery. During extinction, CS+ port entries were initially elevated in context A relative to context B. ABA renewal of CS+ port entries occurred in both alcohol- and sucrose-trained rats. ABC renewal approached statistical significance when data from both experiments were combined. No AAB renewal was observed, and, in fact, alcohol-trained rats showed AAB suppression. These results corroborate the reliability of ABA renewal and suggest that ABC renewal is a modest effect that may require greater statistical power to detect. From a treatment perspective, the lack of AAB renewal suggests that exposure-based treatments for substance use disorders might benefit from implementation in real-world, drug-use contexts

The medial prefrontal cortex is required for responding to alcohol-predictive cues but only in the absence of alcohol delivery

Background: The prelimbic medial prefrontal cortex is implicated in promoting drug-seeking in relapse tests. However, drug-seeking behaviour is typically extinguished before a test and tests normally occur without drug delivery. Aims: We investigated the involvement of the prelimbic and the infralimbic cortex in responding elicited by a non-extinguished cue for alcohol that was presented without alcohol in an alcohol-associated context or a neutral context, and in responding to the same cue when it was paired with alcohol. Methods: Male, Long-Evans rats (220–240 g on arrival) were acclimated to 15% ethanol (v/v; ‘alcohol’) and then trained to associate a conditioned stimulus (10 s white noise; 15 trials/session) with alcohol delivery into a fluid port (0.2 mL/conditioned stimulus, 3 mL per session) for oral intake. Conditioning sessions occurred in a specific ‘alcohol context’ and were alternated daily with exposure to a second ‘neutral’ context that contained neither the conditioned stimulus nor alcohol. Results: At test, functional prelimbic cortex inactivation using baclofen/muscimol reduced fluid port entries elicited by a non-extinguished conditioned stimulus that was presented without alcohol, but had no subsequent impact on port entries when the conditioned stimulus was paired with alcohol. Similar results were obtained following infralimbic cortex inactivation; however, infralimbic cortex inactivation also non-specifically reduced port entries in the absence of alcohol. Conclusions: These data indicate that the prelimbic and infralimbic cortex are involved in responding to cues for alcoho

Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe

Background Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. Methods The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760. Findings Between April 1, 2014, and Jan 31, 2015, 31â127 anaesthetic procedures in 30â874 children with a mean age of 6·35 years (SD 4·50) were included. The incidence of perioperative severe critical events was 5·2% (95% CI 5·0â5·5) with an incidence of respiratory critical events of 3·1% (2·9â3·3). Cardiovascular instability occurred in 1·9% (1·7â2·1), with an immediate poor outcome in 5·4% (3·7â7·5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10â000. This was independent of type of anaesthesia. Age (relative risk 0·88, 95% CI 0·86â0·90; p<0·0001), medical history, and physical condition (1·60, 1·40â1·82; p<0·0001) were the major risk factors for a serious critical event. Multivariate analysis revealed evidence for the beneficial effect of years of experience of the most senior anaesthesia team member (0·99, 0·981â0·997; p<0·0048 for respiratory critical events, and 0·98, 0·97â0·99; p=0·0039 for cardiovascular critical events), rather than the type of health institution or providers. Interpretation This study highlights a relatively high rate of severe critical events during the anaesthesia management of children for surgical or diagnostic procedures in Europe, and a large variability in the practice of paediatric anaesthesia. These findings are substantial enough to warrant attention from national, regional, and specialist societies to target education of anaesthesiologists and their teams and implement strategies for quality improvement in paediatric anaesthesia. Funding European Society of Anaesthesiology

Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe

Background Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. Methods The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760. Findings Between April 1, 2014, and Jan 31, 2015, 31 127 anaesthetic procedures in 30 874 children with a mean age of 6.35 years (SD 4.50) were included. The incidence of perioperative severe critical events was 5.2% (95% CI 5.0-5.5) with an incidence of respiratory critical events of 3.1% (2.9-3.3). Cardiovascular instability occurred in 1.9% (1.7-2.1), with an immediate poor outcome in 5.4% (3.7-7.5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10 000. This was independent of type of anaesthesia. Age (relative risk 0.88, 95% CI 0.86-0.90; p<0.0001), medical history, and physical condition (1.60, 1.40-1.82; p<0.0001) were the major risk factors for a serious critical event. Multivariate analysis revealed evidence for the beneficial effect of years of experience of the most senior anaesthesia team member (0.99, 0.981-0.997; p<0.0048 for respiratory critical events, and 0.98, 0.97-0.99; p=0.0039 for cardiovascular critical events), rather than the type of health institution or providers. Interpretation This study highlights a relatively high rate of severe critical events during the anaesthesia management of children for surgical or diagnostic procedures in Europe, and a large variability in the practice of paediatric anaesthesia. These findings are substantial enough to warrant attention from national, regional, and specialist societies to target education of anaesthesiologists and their teams and implement strategies for quality improvement in paediatric anaesthesia