The conditioned place preference (CPP) paradigm is a well-established model utilized to study the role of context associations in reward-related behaviors, including both natural rewards and drugs of abuse. In this review article, we discuss the basic history, various uses, and considerations that are tied to this technique. There are many potential takeaway implications of this model, including negative affective states, conditioned drug effects, memory, and motivation, which are all considered here. We also discuss the neurobiology of CPP including relevant brain regions, molecular signaling cascades, and neuromodulatory systems. We further examine some of our prior findings and how they integrate CPP with self-administration paradigms. Overall, by describing the fundamentals of CPP, findings from the past few decades, and implications of using CPP as a research paradigm, we have endeavored to support the case that the CPP method is specifically advantageous for studying the role of a form of Pavlovian learning that associates drug use with the surrounding environment.
Background: Our goal is to develop metrics that quantify the translation of performance from cadavers to patients. Our primary objective was to develop steps and error checklists from a Delphi questionnaire. Our second objective was to show that our test scores were valid and reliable. Methods: Sixteen UK experts identified 15 steps conducive to good performance and 15 errors to be avoided during interscalene block on the soft-embalmed cadaver and patients. Thereafter, six experts and six novices were trained, and then tested. Training consisted of psychometric assessment, an anatomy tutorial, volunteer scanning, and ultrasoundguided needle insertion on a pork phantom and on a soft-embalmed cadaver. For testing, participants conducted a single interscalene block on a dedicated soft-embalmed cadaver whilst wearing eye tracking glasses. Results: We developed a 15-step checklist and a 15-error checklist. The internal consistency of our steps measures were 0.83 (95% confidence interval [CI]: 0.78e0.89) and 0.90 (95% CI: 0.87e0.93) for our error measures. The experts completed more steps (mean difference: 3.2 [95% CI: 1.5e4.8]; P<0.001), had less errors (mean difference: 4.9 [95% CI: 3.5e6.3]; P<0.001), had better global rating scores (mean difference: 6.8 [95% CI: 3.6e10.0]; P<0.001), and more eye-gaze fixations (median of differences: 128 [95% CI: 0e288]; P¼0.048). Fixation count correlated negatively with steps (r¼e0.60; P¼0.04) and with errors (r¼0.64; P¼0.03). Conclusions: Our tests to quantify ultrasound-guided interscalene nerve block training and performance were valid and reliable.
The symptoms of 100 hospitalised cases of rotavirus infantile gastroenteritis are described. Most patients presented with high fever between the 2nd and 5th day, having started with diarrhoea or vomiting or both. 42% of the infants had upper respiratory tract symptoms. Severe electrolyte disturbance did not occur, although there was a suggestion of a correlation between the higher blood ureas and the number of rotavirus particles in the stools. The mean duration of illness of uncomplicated cases was 13.4 days. Infants were more severely affected when enteropathic coliforms were also present, the total duration of illness being extended to 23 days. It is suggested that rotavirus or similar virus infection may be an essential precursor in the majority of coliform gastroenteritis.
Summary
Visibility of the needle tip is difficult to maintain during ultrasound‐guided nerve block. A new needle has been developed that incorporates a piezo element 2–2.3 mm from the tip, activated by ultrasound. The electrical signal manifests as a coloured circle surrounding the needle tip, and allows real‐time tracking. We hypothesised that novice regional anaesthetists would perform nerve block better with the tracker turned on rather than off. Our primary objective was to evaluate the new needle by measuring the performance of novice anaesthetists conducting simulated sciatic block on the soft embalmed Thiel cadaver. Training consisted of a lecture, scanning in volunteers and practice on cadavers. Testing entailed scanning the sciatic nerve of a cadaver and conducting 20 in‐plane sciatic blocks in the mid‐to‐upper thigh region. Subjects were randomised equally, in groups of five, according to the sequence: tracker on/off/on/off; or tracker off/on/off/on. Video recordings were assessed by six raters for steps performed correctly and errors committed. Eight subjects were recruited and 160 videos were analysed. Using the tracking needle, five correct steps improved and one error reduced. The benefits included: better identification of the needle tip before advancing the needle, OR (95%CI) 3.4 (1.6–7.7; p < 0.001); better alignment of the needle to the transducer, 3.1 (1.3–8.7; p = 0.009); and better visibility of the needle tip 3.0 (1.4–7.3; p = 0.005). In conclusion, use of the tracker needle improved the sciatic block performance of novices on the soft embalmed cadaver.
Cocaine addicts display increased sensitivity to drug-associated cues, due in part to changes in the prelimbic prefrontal cortex (PL-PFC). The cellular mechanisms underlying cue-induced reinstatement of cocaine seeking remain unknown. Reinforcement learning for addictive drugs may produce persistent maladaptations in intrinsic excitability within sparse subsets of PFC pyramidal neurons. Using a model of relapse in male rats, we sampled >600 neurons to examine spike frequency adaptation (SFA) and afterhyperpolarizations (AHPs), two systems that attenuate low-frequency inputs to regulate neuronal synchronization. We observed that training to self-administer cocaine or nondrug (sucrose) reinforcers decreased SFA and AHPs in a subpopulation of PL-PFC neurons. Only with cocaine did the resulting hyperexcitability persist through extinction training and increase during reinstatement. In neurons with intact SFA, dopamine enhanced excitability by inhibiting Kv7 potassium channels that mediate SFA. However, dopamine effects were occluded in neurons from cocaine-experienced rats, where SFA and AHPs were reduced. Pharmacological stabilization of Kv7 channels with retigabine restored SFA and Kv7 channel function in neuroadapted cells. When microinjected bilaterally into the PL-PFC 10 min before reinstatement testing, retigabine reduced cue-induced reinstatement of cocaine seeking. Last, using cFos-GFP transgenic rats, we found that the loss of SFA correlated with the expression of cFos-GFP following both extinction and re-exposure to drug-associated cues. Together, these data suggest that cocaine self-administration desensitizes inhibitory Kv7 channels in a subpopulation of PL-PFC neurons. This subpopulation of neurons may represent a persistent neural ensemble responsible for driving drug seeking in response to cues. Long after the cessation of drug use, cues associated with cocaine still elicit drug-seeking behavior, in part by activation of the prelimbic prefrontal cortex (PL-PFC). The underlying cellular mechanisms governing these activated neurons remain unclear. Using a rat model of relapse to cocaine seeking, we identified a population of PL-PFC neurons that become hyperexcitable following chronic cocaine self-administration. These neurons show persistent loss of spike frequency adaptation, reduced afterhyperpolarizations, decreased sensitivity to dopamine, and reduced Kv7 channel-mediated inhibition. Stabilization of Kv7 channel function with retigabine normalized neuronal excitability, restored Kv7 channel currents, and reduced drug-seeking behavior when administered into the PL-PFC before reinstatement. These data highlight a persistent adaptation in a subset of PL-PFC neurons that may contribute to relapse vulnerability.
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