Apolipoprotein E4 allele is genetically associated with risk of the short- and medium-term postoperative cognitive dysfunction: A meta-analysis and trial sequential analysis.

The aim of systematic review and meta-analysis was to investigate whether APOE4 was associated with postoperative neurologic dysfunction occurrence in short- or medium-term among surgical patients and to study the potential genetic association among these two entities. We searched electronic databases for reserch studies to evaluate the association of APOE4 with postoperative delirium (POD) or short- and medium term postoperative cognitive dysfunction (POCD). Twenty-two trials (16 prospective and six retrospective) with 6734 patients were included. APOE4 alleles was shown significantly associated with POCD within 1 week (odds ratio, OR, 1.89, 95% confidence interval, CI, 1.36 to 2.6278, p < 0.01) in the random-effects model. A significant association was also noted between APOE4 and POCD in medium-term, 1-3 months, after surgery (OR: 1.67, 95% CI: 1.003-2.839, p = 0.049). However, APOE4 was not significantly associated with POCD 1 year after surgery (OR: 0.98, 95% CI: 0.57-1.70, p = 0.9449) and POD (OR: 1.28, 95% CI: 0.85-1.91, p = 0.23). In conclusion, APOE4 alleles was genetically associated with short- and medium-term postoperative neurological dysfunction and future screening or preventive strategies derived is highly potential to improve outcomes.

Efficacy and safety of remifentanil for endoscopic ultrasound-guided tissue acquisition: a single center retrospective study.

BACKGROUND: Remifentanil is a rapid onset and rapid recovery opioid. The combination of remifentanil and propofol for deep sedation decreases the incidents of movement, cough, and hiccup. We evaluated the efficacy and safety of remifentanil during endoscopic ultrasound-guided tissue acquisition. METHODS: We retrospectively reviewed patients in whom endoscopic ultrasound-guided tissue acquisition was performed for solid mass lesions of the upper gastrointestinal tract and adjacent organs. All patients were premedicated with midazolam (2 mg), and target-controlled infusion of propofol, opioid, and Bispectral Index (BIS) monitoring were administered as necessary to maintain moderate-to-deep sedation. The opioids used were a bolus of alfentanil or remifentanil infusion. The discharge time, consumption of propofol and opioid, adverse events, diagnostic accuracy, and sensitivity and specificity for malignancy, were compared. RESULTS: Tissue acquisition was achieved in 123 patients (alfentanil group, n = 64; remifentanil group, n = 59). The discharge time of the remifentanil group (16.5 ± 3.2 min) was significantly shorter than that of the alfentanil group (19.0 ± 4.9 min, P = 0.001). The consumption of propofol, adverse events, diagnostic accuracy, sensitivity, and specificity for malignancy in the alfentanil group were not significantly different from those in the remifentanil group. CONCLUSIONS: Use of alfentanil or remifentanil for target-controlled infusion of propofol-BIS monitoring can provide good sedative and diagnostic quality for endoscopic ultrasound-guided tissue acquisition. However, remifentanil resulted in faster recovery than alfentanil.

A survey of one-lung ventilation device in lung resection surgeries in Taiwan-A population-based nationwide cohort study.

BACKGROUND: Double-lumen endotracheal tubes and bronchial blockers are the two lung separation devices most commonly used for lung resection. The preference and outcomes of choosing different lung separation devices have not been discussed in the literature. METHODS: This study was conducted using the data of 2 million patients randomly chosen from the National Health Insurance Research Database between 2011 and 2016. We selected patients who underwent lung resection surgery and surveyed their demographic data and trends of double-lumen endotracheal tube and bronchial blocker use. To determine the influence of endotracheal tubes on clinical outcomes, we computed multiple linear regressions of the number of deaths within 30 days after surgery, intensive care unit stay, hospital stay, and medical cost. RESULTS: The use of bronchial blockers in Taiwan has steadily increased from 6.13% to 11.33% from 2011 to 2016. Anaesthesiologists working in regions with higher thoracic surgery volumes preferred bronchial blockers over double-lumen endotracheal tubes. Bronchial blockers were the preferred choice in women, elderly individuals, patients with more comorbidities, and those undergoing video-assisted thoracoscopic surgeries. After adjustment for sex, age, Charlson Comorbidity Index, and video-assisted thoracoscopic surgeries, we found that patients in whom bronchial blockers were applied had shorter hospital stays. CONCLUSION: The use of bronchial blockers is increasing as the experience of anaesthesiologists increases. Although double-lumen endotracheal tubes remain the principal choice for lung separation in Taiwan, clinical outcomes of the bronchial blocker group were not inferior to those of the double-lumen endotracheal tube group.

Target-controlled propofol infusion with or without bispectral index monitoring of sedation during advanced gastrointestinal endoscopy.

BACKGROUND AND AIM: Target-controlled infusion (TCI) uses averaged pharmacokinetic datasets derived from population samples to automatically control the infusion rate. Bispectral index (BIS) technology non-invasively measures levels of consciousness during surgical procedures. We compared the efficacy and safety of propofol TCI with or without BIS monitoring for sedation during advanced gastrointestinal endoscopy. METHODS: This prospective study enrolled 200 patients who were premedicated with midazolam 2 mg and alfentanil 0.4 mg before undergoing advanced gastrointestinal endoscopy. The initial target blood concentration of propofol was set at 1.0 µg/mL, and adjustments of 0.2 µg/mL were made as necessary to maintain moderate-to-deep sedation. Patients were randomized to either the BIS-blind group and evaluated for depth of anesthesia by monitoring scores of 1-2 on the Modified Observer's Assessment of Alertness/Sedation scale (n = 100) or to the BIS-open group and monitored by BIS scores of 60-80 (n = 100). The primary outcome was the total amount of propofol required to maintain anesthesia. Secondary outcomes were sedation-induced adverse events, recovery, and quality of sedation (endoscopist and patient satisfaction). RESULTS: The mean propofol infusion rate was significantly higher in patients not monitored by BIS scores than in those who were (5.44 ± 2.12 vs 4.76 ± 1.84 mg/kg/h; P = 0.016). Levels of satisfaction were higher for endoscopists who used BIS monitoring than in those who did not. CONCLUSIONS: Mean infusion rates were higher in propofol TCI without BIS monitoring compared with propofol TCI with BIS during advanced gastrointestinal endoscopy. Endoscopists expressed satisfaction with BIS monitoring.

Inhibiting the LPS-induced enhancement of mEPSC frequency in superficial dorsal horn neurons may serve as an electrophysiological model for alleviating pain.

Pain is a major primary health care problem. Emerging studies show that inhibition of spinal microglial activation reduces pain. However, the precise mechanisms by which microglial activation contributes to nociceptive synaptic transmission remain unclear. In this study, we measured spontaneous synaptic activity of miniature excitatory postsynaptic currents (mEPSCs) in rat spinal cord superficial dorsal horn (SDH, laminae I and II) neurons. Lipopolysaccharide (LPS) and adenosine triphosphate (ATP) increased the frequency, but not amplitude, of mEPSCs in SDH neurons. Microglial inhibitors minocycline and paeonol, as well as an astrocyte inhibitor, a P2Y1 receptor (P2Y1R) antagonist, and a metabotropic glutamate receptor 5 (mGluR5) antagonist, all prevented LPS-induced enhancement of mEPSC frequency. In mouse behavioral testing, minocycline and paeonol effectively reduced acetic acid-induced writhing and LPS-induced hyperalgesia. These results indicate that LPS-activated microglia release ATP, which stimulates astrocyte P2Y1Rs to release glutamate, triggering presynaptic mGluR5 receptors and increasing presynaptic glutamate release, leading to an increase in mEPSC frequency and enhancement of nociceptive transmission in SDH neurons. We propose that these effects can serve as a new electrophysiological model for evaluating pain. Moreover, we predict that pharmacologic agents capable of inhibiting the LPS-induced enhancement of mEPSC frequency in SDH neurons will have analgesic effects.

Platelet activation in diabetic mice models: the role of vascular endothelial cell-derived protein disulfide isomerase-mediated GP IIb/IIIa receptor activation.

GP IIb/IIIa receptor activation plays an important role in thrombosis. The mechanism of early activation of GP IIb/IIIa receptors in diabetic conditions remains unknown. The purpose of this study was to investigate the release of Endothelial microparticle (EMP)-associated protein disulfide isomerase (PDI) after endothelial cell injury induced in diabetes and the changes in platelet activation. We produced an animal model of type 2 diabetes mellitus using ApoE-/- mice. Normal ApoE-/- and diabetic mice were allocated to four groups (n = 15): normal diet, normal diet plus rutin, diabetic, and diabetes plus rutin. The EMP-PDI content and GP IIb/IIIa expression of mice platelets were determined. In addition, EMPs obtained from the four groups were pretreated with the PDI inhibitor rutin; then, their effects on the platelets of normal C57 mice were characterized. Compared with the normal diet group, the diabetic group had significantly increased plasma EMP-PDI content and accelerated platelet activation by increased GP IIb/IIIa expression. In conclusion, EMP-PDI promotes early platelet activation through glycoprotein (GP) IIb/IIIa receptors present on platelet surface in the diabetic state. However, this process could be partially suppressed by the administration of rutin.

Manual acupuncture relieves bile acid-induced itch in mice: the role of microglia and TNF-α.

Pruritus, or itch, is a frequent complaint amongst patients with cholestatic hepatobiliary disease and is difficult to manage, with many patients refractory to currently available antipruritic treatments. In this study, we examined whether manual acupuncture (MA) at particular acupoints represses deoxycholic acid (DCA)-induced scratching behavior and microglial activation and compared these effects with those induced by another pruritogen, 5'-guanidinonaltrindole (GNTI, a kappa opioid receptor antagonist). MA at Hegu (LI4) and Quchi (LI11) acupoints significantly attenuated DCA- and GNTI-induced scratching, whereas no such effects were observed at the bilateral Zusanli acupoints (ST36). Interestingly, GNTI-induced scratching was reduced similarly by both MA and electroacupuncture (EA) at the LI4 and LI11 acupoints. MA at non-acupoints did not affect scratching behavior. Intraperitoneal injection of minocycline (a microglial inhibitor) reduced GNTI- and DCA-induced scratching behavior. In Western blot analysis, subcutaneous DCA injection to the back of the neck increased spinal cord expression of ionized calcium-binding adapter molecule 1 (Iba1) and tumor necrosis factor-alpha (TNF-α) as compared with saline injection, while MA at LI4 and LI11 reduced these DCA-induced changes. Immunofluorescence confocal microcopy revealed that DCA-induced Iba1-positive cells with thicker processes emanated from the enlarged cell bodies, while this effect was attenuated by pretreatment with MA. It is concluded that microglia and TNF-α play important roles in the itching sensation and MA reduces DCA-induced scratching behavior by alleviating spinal microglial activation. MA may be an effective treatment for cholestatic pruritus.

Decreased Parasympathetic Activity of Heart Rate Variability During Anticipation of Night Duty in Anesthesiology Residents.

BACKGROUND: In residency programs, it is well known that autonomic regulation is influenced by night duty due to workload stress and sleep deprivation. A less investigated question is the impact on the autonomic nervous system of residents before or when anticipating a night duty shift. In this study, heart rate variability (HRV) was evaluated as a measure of autonomic nervous system regulation. METHODS: Eight residents in the Department of Anesthesiology were recruited, and 5 minutes of electrocardiography were recorded under 3 different conditions: (1) the morning of a regular work day (baseline); (2) the morning before a night duty shift (anticipating the night duty); and (3) the morning after a night duty shift. HRV parameters in the time and frequency domains were calculated. Repeated measures analysis of variance was performed to compare the HRV parameters among the 3 conditions. RESULTS: There was a significant decrease of parasympathetic-related HRV measurements (high-frequency power and root mean square of the standard deviation of R-R intervals) in the morning before night duty compared with the regular work day. The mean difference of high-frequency power between the 2 groups was 80.2 ms (95% confidence interval, 14.5-146) and that of root mean square of the standard deviation of R-R intervals was 26 milliseconds (95% confidence interval, 7.2-44.8), with P = .016 and .007, respectively. These results suggest that the decrease of parasympathetic activity is associated with stress related to the condition of anticipating the night duty work. On the other hand, the HRV parameters in the morning after duty were not different from the regular workday. CONCLUSIONS: The stress of anticipating the night duty work may affect regulation of the autonomic nervous system, mainly manifested as a decrease in parasympathetic activity. The effect of this change on the health of medical personnel deserves our concern.

Pretreatment serum lactate level as a prognostic biomarker in patients undergoing supratentorial primary brain tumor resection.

INTRODUCTION: Malignant primary brain tumors are one of the most aggressive cancers. Pretreatment serum nonneuronal biomarkers closely associated with postoperative outcomes are of high clinical relevance. The present study aimed to identify potential pretreatment serum biomarkers that may influence oncological outcomes in patients with primary brain tumors. METHODS: A total of 74 patients undergoing supratentorial primary brain tumor resection were enrolled. Before tumor resection, serum neuronal biomarkers, namely neuron-specific enolase (NSE), S100ß, and glial fibrillary acidic protein (GFAP), and serum nonneuronal biomarkers, namely neutrophil gelatinase-associated lipocalin (NGAL), lactate dehydrogenase (LDH), and lactate, were measured and associated postoperative oncological outcomes, including brain tumor grading, progression-free survival (PFS), and overall survival (OS), were compared. RESULTS: Patients with high-grade brain tumors had significantly higher pretreatment serum lactate levels (p = 0.011). By contrast, other biomarkers were comparable between patients with high-grade and low-grade brain tumors. Receiver operating characteristic curve analysis of serum lactate levels yielded an area under the curve of 0.71 for differentiating between high-grade and low-grade brain tumors. Kaplan-Meier survival analysis revealed patients with high serum lactate levels (≧2.0 mmol/L) had shorter PFS and OS (p = 0.021 and p = 0.093, respectively). In a multiple regression model, only elevated serum lactate levels were associated with poor PFS and OS (p = 0.021 and p = 0.048, respectively). CONCLUSIONS: An elevated pretreatment serum lactate level is a prognostic biomarker of high-grade primary brain tumors and is significantly associated with poor PFS in patients with supratentorial brain tumors undergoing tumor resection. By contrast, other serum biomarkers are not significantly associated with oncological outcomes.

Long-term outcomes of totally implantable venous access devices.

PURPOSE: Identifying risk factors for premature totally implantable venous access device (TIVAD) catheter removal is crucial; however, because of the diversity of study methodologies, there is no consensus on such factors. The objective of the present study was to identify such risk factors by applying a cohort design study with a long-term follow-up period. METHODS: For this cohort study, we selected cancer patients who had newly implanted TIVADs between July 2008 and December 2008. The follow-up period lasted until September 2012. Univariate analysis was performed for age, gender, cancer type, TIVAD brand, puncture site, sidedness of puncture, and catheter tip position. The hazard ratio (HR) of potential risk factors was calculated using the Cox proportional hazards regression model, and Kaplan-Meier curves were applied for catheter survival analysis. RESULTS: Our study consisted of 240 people, with 5 people lost to follow-up. The cumulative premature catheter removal rate of all TIVADs was 9.8%, with the most common reason for premature removal being port-associated blood stream infection (PABSI), which proved to be highest in patients with hematology cancer (27.8%) and upper gastrointestinal cancer (19.4%). Suboptimal tip position (HR 5.13, 95% confidence interval 1.73-15.21) was also a risk factor for premature removal, and it was correlated with symptomatic TIVAD occlusion (p = 0.0004). CONCLUSIONS: PABSI was the most common reason for premature catheter removal, with a varied incidence rate between different cancer types. Suboptimal tip position was also a risk factor. Confirming the final tip position after implantation is crucial. Infection control is important for TIVAD care, especially in high-risk cancer patients.

The effects of different epidural analgesia formulas on labor and mode of delivery in nulliparous women.

OBJECTIVES: Patient-controlled epidural analgesia (PCEA) and continuous epidural infusion (CEI) are popular and effective methods for pain relief during labor; however, there are concerns about increasing rates of cesarean section (C/S) and instrumental delivery. This prospective study investigated the effect of PCEA and CEI with different formulas on labor and the mode of delivery in nulliparous women. MATERIALS AND METHODS: A total of 480 nulliparous women were randomized into four groups, with 120 in each. Group A received a loading dose of 10 mL of 1 mg/mL ropivacaine with 2 µg/mL fentanyl, then an intermittent bolus of 5 mL with a background infusion of 5 mL/hour by PCEA. Group B received the same PCEA formula as Group A with 0.8 mg/mL bupivacaine. Group C received the same formula as Group A by CEI with 1 mg/mL ropivacaine at a rate of 10 mL/hour. Group D received the same formula as Group C with 0.8 mg/mL bupivacaine. The rates of C/S and instrumental delivery and the incidence of side effects were recorded. RESULTS: The rates of C/S were significantly different between Groups A and C, Groups A and D, and Groups B and D. The rates of instrumental delivery for normal spontaneous delivery were significantly different between Groups A and B, A and D, B and C, and C and D. CONCLUSION: The C/S rate was higher in Groups C and D; however, the instrumental delivery rate was lower in Groups A and C. We conclude that PCEA with 1 mg/mL ropivacaine might provide the greatest benefit for labor analgesia.

Relationship of abdominal circumference and trunk length with spinal anesthesia level in the term parturient.

BACKGROUND: We hypothesized that body shape metrics influence the anatomy of spinal canal and intraabdominal pressure in three dimensions. We explored the effects of abdominal circumference, trunk length, and their combination on the level of spinal anesthesia in the term parturient in this study. METHODS: Thirty term parturients, ASA class I-II, from 20 to 41 years of age, scheduled for cesarean section were enrolled in this observational study. Abdominal circumference (AC) and trunk length (TL) were recorded preoperatively. Spinal anesthesia was performed with 10 mg 0.5% hyperbaric bupivacaine at the L4-L5 intervertebral space in all parturients. Correlation between maximal sensory spinal anesthesia level and physical parameters was analyzed with Spearman rank correlation coefficients. The calculated r value was compared with r = 0 with p < 0.05 as the significant level. The prediction power of these physical parameters for spinal level was evaluated by prediction probability. RESULTS: The parameter TL/AC2 was statistically correlated with maximal sensory level (Spearman correlation coefficient, -0.45 with p < 0.02). The prediction probability of TL/AC2 for the dermatomal level was P K = 0.685. If the dermatomal levels were lumped as higher (above T2) and lower (below T3) levels, the prediction probability of TL/AC2 was as high as P K = 0.856. CONCLUSIONS: TL/AC2, which simulated the ratio of the long axis and transection area of the abdomen, was correlated with maximal spinal level, and parturients with low TL/AC2 values tended to have higher dermatomal levels during spinal anesthesia.

Patient -controlled epidural ropivacaine as a post-Cesarean analgesia: a comparison with epidural morphine.

OBJECTIVE: Conventional, intermittent, epidural morphine is widely applied as a post-Cesarean delivery analgesia. We compared the analgesic efficacy, motor weakness, and side effects of administering a patient-controlled epidural analgesia (PCEA) of pure ropivacaine versus the intermittent administration of epidural morphine after Cesarean delivery. MATERIALS AND METHODS: This randomized, double-blind study included 120 full-term parturients who underwent elective Cesarean delivery and received either PCEA with pure ropivacaine or an intermittent bolus epidural of 2 mg/10 mL morphine in normal saline twice per day. The efficacy of pain relief, post-Cesarean side effects, motor blockades, time to first ambulation, and global satisfaction scores were evaluated. RESULTS: Pain scores were recorded at the four evaluation times (2, 12, 24, and 48 hours post-Cesarean delivery), and the time to first ambulation did not statistically differ between the two groups. Patients in the ropivacaine group experienced more motor weakness at 2 and 12 hours, fewer side effects, and higher global satisfaction scores than those in the morphine group (p < 0.05). CONCLUSION: The analgesic efficacy after cesarean delivery was almost equivalent between two groups. PCEA with pure ropivacaine induced significant motor blockade during the first 12 hours, but without delaying the time to first ambulation. Patients in the ropivacaine group reported higher patient satisfaction scores due to the significant reduction of annoying side effects, such as pruritus, nausea, vomiting, and urinary retention.

Action potential bursts in central snail neurons elicited by paeonol: roles of ionic currents.

AIM: to investigate the effects of 2'-hydroxy-4'-methoxyacetophenone (paeonol) on the electrophysiological behavior of a central neuron (right parietal 4; RP4) of the giant African snail (Achatina fulica Ferussac). METHODS: intracellular recordings and the two-electrode voltage clamp method were used to study the effects of paeonol on the RP4 neuron. RESULTS: the RP4 neuron generated spontaneous action potentials. Bath application of paeonol at a concentration of ≥ 500 micromol/L reversibly elicited action potential bursts in a concentration-dependent manner. Immersing the neurons in Co(2+)-substituted Ca(2+)-free solution did not block paeonol-elicited bursting. Pretreatment with the protein kinase A (PKA) inhibitor KT-5720 or the protein kinase C (PKC) inhibitor Ro 31-8220 did not affect the action potential bursts. Voltage-clamp studies revealed that paeonol at a concentration of 500 micromol/L had no remarkable effects on the total inward currents, whereas paeonol decreased the delayed rectifying K(+) current (I(KD)) and the fast-inactivating K(+) current (I(A)). Application of 4-aminopyridine (4-AP 5 mmol/L), an inhibitor of I(A), or charybdotoxin 250 nmol/L, an inhibitor of the Ca(2+)-activated K(+) current (I(K(Ca))), failed to elicit action potential bursts, whereas tetraethylammonium chloride (TEA 50 mmol/L), an I(KD) blocker, successfully elicited action potential bursts. At a lower concentration of 5 mmol/L, TEA facilitated the induction of action potential bursts elicited by paeonol. CONCLUSION: paeonol elicited a bursting firing pattern of action potentials in the RP4 neuron and this activity relates closely to the inhibitory effects of paeonol on the I(KD).

Coronary artery dissection in a patient with traumatic femoral shaft fracture.

We report a 24-year-old man who developed postoperative pulmonary edema and desaturation, after open reduction with internal fixation for left femoral shaft fracture sustained in a motorcycle accident. Cardiac catheterization revealed a left anterior descending coronary artery dissection. Review of his present history, showed that he neither had chest discomfort nor suffered from hemodynamic decompensation preoperatively. Only the abnormal 12-lead ECG with moderate tachycardia was suggestive of myocardial ischemia. Coronary artery dissection, although uncommon, is a disastrous complication following blunt chest trauma, and needs thorough preoperative evaluation to exclude its occurrence.

Action potential bursts in central snail neurons elicited by procaine: roles of ionic currents.

The role of ionic currents on procaine-elicited action potential bursts was studied in an identifiable RP1 neuron of the African snail, Achatina fulica Ferussac, using the two-electrode voltage clamp method. The RP1 neuron generated spontaneous action potentials and bath application of procaine at 10 mM reversibly elicited action potential bursts in a concentration-dependent manner. Voltage clamp studies revealed that procaine at 10 mM decreased [1] the Ca2+ current, [2] the Na+ current, [3] the delayed rectifying K+ current I(KD), and [4] the fast-inactivating K+ current (I(A)). Action potential bursts were not elicited by 4-aminopyridine (4-AP), an inhibitor of I(A), whereas they were seen after application of tetraethylammonium chloride (TEA), a blocker of the I(K)(Ca) and I(KD) currents, and tacrine, an inhibitor of I(KD). Pretreatment with U73122, a phospholipase C inhibitor, blocked the action potential bursts elicited by procaine. U73122 did not affect the I(KD) of the RP1 neuron; however, U73122 decreased the inhibitory effect of procaine on the I(KD). Tacrine decreased the TEA-sensitive I(KD) of RP1 neuron but did not significantly affect the I(A). Tacrine also successfully induced action potential bursts in the RP1 neuron. It is concluded that the inhibition on the I(KD) is responsible for the generation of action potential bursts in the central snail RP1 neuron. Further, phospholipase C activity is involved in the procaine-elicited I(KD) inhibition and action potential bursts.

Ecstasy and methamphetamine elicit action potential bursts via different mechanisms in a central snail neuron.

This study sought to determine the effects of (+) methamphetamine (METH) and its ring-substituted analog (+/-)3,4-methylenedioxymethamphetamine (MDMA; ecstasy) on electrophysiological behavior and their relationships to second messenger systems in an identifiable RP4 neuron of the African snail, Achatina fulica Ferussac. Extracellular application of MDMA at 1mM and METH at 3mM elicited action potential bursts that were not blocked after immersing the neurons in Ca(2+)-free solution. Notably, MDMA- (1mM) elicited action potential bursts were blocked by pretreatment with the protein kinase C (PKC) inhibitors chelerythrine (20 microM) and Ro 31-8220 (20 microM), but not by the PKA inhibitors KT-5720 (10 microM) and H89 (10 microM). The PKC activator phorbol 12,13-dibutyrate (PDBu; 3 microM), but not the PKA activator forskolin (50 microM), facilitated the induction of bursts elicited by MDMA at a lower concentration (0.3mM). In contrast, METH- (3mM) elicited action potential bursts were blocked by pretreatment with KT-5720 (10 microM) and H89 (10 microM), but not by chelerythrine (20 microM) and Ro 31-8220 (20 microM). Forskolin (50 microM), but not PDBu (3 microM) facilitated the induction of bursts elicited by METH at a lower concentration (1mM). Tetraethylammonium chloride (TEA), a blocker of the delayed rectifying K(+) current (I(KD)), did not elicit bursts at a concentration of 5mM but did facilitate the induction of action potential bursts elicited by both METH and MDMA. Voltage clamp studies revealed that both METH and MDMA decreased the TEA-sensitive I(KD) of the RP4 neuron. Forskolin (50 microM) or dibutyryl cAMP (1mM), a membrane-permeable cAMP analog, alone did not elicit action potential bursts. However, co-administration with forskolin (50 microM) and TEA (5mM) or co-administration with dibutyryl cAMP (1mM) and TEA (50mM) elicited action potential bursts in the presence of the PKC inhibitor chelerythrine (20 microM). Similarly, PDBu (10 microM) or phorbol 12-myristate 13-acetate (PMA; 3 microM) alone did not elicit action potential bursts. However, co-administration with PDBu (10 microM) and TEA (5mM) or co-administration with PMA (3 microM) and TEA (5mM) elicited action potential bursts in the presence of the PKA inhibitor KT-5720 (10 microM). These data suggest that action potential bursts in the RP4 neuron were not due to Ca(2+)-dependent synaptic effects. Rather, action potential bursts may be elicited through (1) combined activation of the cAMP-PKA signaling pathway and inhibition of the I(KD) and (2) combined activation of PKC and inhibition of the I(KD).