Lower Abnormal Fecal Immunochemical Test Cut-Off Values Improve Detection of Colorectal Cancer in System-Level Screens.

BACKGROUND & AIMS: Noninvasive tests used in colorectal cancer screening, such as the fecal immunochemical test (FIT), are more acceptable but detect neoplasias with lower levels of sensitivity than colonoscopy. We investigated whether lowering the cut-off concentration of hemoglobin for designation as an abnormal FIT result increased the detection of advanced neoplasia in a mailed outreach program. METHODS: We performed a prospective study of 17,017 uninsured patients, age 50 to 64 years, who were not current with screening and enrolled in a safety-net system in Texas. We reduced the cut-off value for an abnormal FIT result from 20 or more to 10 or more µg hemoglobin/g feces a priori. All patients with abnormal FIT results were offered no-cost diagnostic colonoscopy. We compared proportions of patients with abnormal FIT results and neoplasia yield for standard vs lower cut-off values, as well as absolute hemoglobin concentration distribution among 5838 persons who completed the FIT. Our primary aim was to determine the effects of implementing a lower hemoglobin concentration cut-off value on colonoscopy demand and yield, specifically colorectal cancer (CRC) and advanced neoplasia detection, compared with the standard, higher, hemoglobin concentration cut-off value. RESULTS: The proportions of patients with abnormal FIT results were 12.3% at the 10 or more µg hemoglobin/g feces and 6.6% at the standard 20 or more µg hemoglobin/g feces cut-off value (P = .0013). Detection rates for the lower vs the standard threshold were 10.2% vs 12.7% for advanced neoplasia (P = .12) and 0.9% vs 1.2% for CRC (P = .718). The positive predictive values were 18.9% for the lower threshold vs 24.4% for the standard threshold for advanced neoplasia (P = .053), and 1.7% vs 2.4% for CRC (P = .659). The number needed to screen to detect 1 case with advanced neoplasia was 45 at the lower threshold compared with 58 at the standard threshold; the number needed to scope to detect 1 case with advanced neoplasia increased from 4 to 5. Most patients with CRC (72.7%) or advanced adenoma (67.3%) had hemoglobin concentrations of 20 or more µg/g feces. In the group with 10 to 19 µg hemoglobin/g feces, there were 3 patients with CRC (3 of 11; 27.3%) and 36 with advanced adenoma (36 of 110; 32.7%) who would not have been detected at the standard positive threshold (advanced neoplasia Pcomparison < .001). The proportion of patients found to have no neoplasia after an abnormal FIT result (false positives) was not significantly higher with the lower cut-off value (44.4%) than the standard cut-off value (39.1%) (P = .1103). CONCLUSIONS: In a prospective study of 17,017 uninsured patients, we found that reducing the abnormal FIT result cut-off value (to ≥10 µg hemoglobin/g feces) might increase detection of advanced neoplasia, but doubled the proportion of patients requiring a diagnostic colonoscopy. If colonoscopy capacity permits, health systems that use quantitative FITs should consider lowering the abnormal cut-off value to optimize CRC detection and prevention. (ClinicalTrials.gov no: NCT01946282.).

Patient-Reported Barriers to Completing a Diagnostic Colonoscopy Following Abnormal Fecal Immunochemical Test Among Uninsured Patients.

BACKGROUND: For colorectal cancer (CRC) screening to improve survival, patients with an abnormal fecal immunochemical test (FIT) must follow-up with a diagnostic colonoscopy. Adherence to follow-up is low and patient-level barriers for suboptimal adherence have yet to be explored. OBJECTIVE: To characterize barriers for non-completion of diagnostic colonoscopy after an abnormal FIT reported by under- and uninsured patients receiving care in a safety-net health system. DESIGN: A longitudinal, cohort study of CRC screening outreach to 8565 patients using mailed FIT kits. Patients with abnormal FIT results received telephonic navigation to arrange for a no-cost diagnostic colonoscopy. PATIENTS: Adults aged 50-64 years receiving care at a North Texas safety-net health system. APPROACH: Descriptive analyses characterized the patient sample and reasons for lack of follow-up after abnormal FIT over the 3-year outreach program. Thematic qualitative analyses characterized reasons for lack of follow-up with a colonoscopy after the abnormal FIT. KEY RESULTS: Of 689 patients with an abnormal FIT, 45% (n = 314) did not complete a follow-up colonoscopy. Among the 314 non-completers, 184 patients reported reasons for not completing a follow-up colonoscopy included health insurance-related challenges (38%), comorbid conditions (37%), social barriers such as transportation difficulties and lack of social support (29%), concerns about FIT/colonoscopy process (12%), competing life priorities (12%), adverse effects of bowel preparation (3%), and poor health literacy (3%). Among the 314 non-completers, 131 patients did not report a barrier, as 51% reported that that had completed a previous colonoscopy in the past 10 years, 10% refused with no reason, and 10% were never reached by phone. CONCLUSIONS: Future studies aimed at improving FIT screening and subsequent colonoscopy rates need to address the unique needs of patients for effective and sustainable screening programs. TRIAL REGISTRATION: NCT01946282.

Prehospital sepsis alert notification decreases time to initiation of CMS sepsis core measures.

OBJECTIVE: To determine if prehospital identification of sepsis will affect time to Centers for Medicare and Medicaid services (CMS) sepsis core measures and improve clinical outcomes. METHODS: We conducted a retrospective cohort study among septic patients who were identified as "sepsis alerts" in the emergency department (ED). Metrics including time from ED registration to fluid resuscitation, blood cultures, serum lactate draws, and antibiotics administration were compared between those who had pre-arrival notification by EMS versus those that did not. Additionally, outcomes such as mortality and intensive care unit (ICU) admission were recorded. RESULTS: Of the 272 total patients, 162 had pre-arrival notification (prehospital sepsis alerts) and 110 did not. The prehospital sepsis alert group had significantly lower times to intravenous fluid administration (6 min 95%CI 4-9 min vs 41 min 95%CI 24-58 min, p < 0.001), blood cultures drawn (12 min 95%CI 10-14 min vs 34 min 95%CI 20-48 min, p = 0.003), lactate levels drawn (12 min 95%CI 10-15 min vs 34 min 95%CI 20-49 min, p = 0.003), and administration of antibiotics (33 min 95%CI 26-40 min vs 61 min 95%CI 44-78 min, p = 0.004). Patients with prehospital sepsis alerts also had a higher admission rate (100% vs 95%, p = 0.006), and a lower ICU admission rate (33% vs 52%, p = 0.003). There was no difference in mortality (11% vs 14%, p = 0.565) between groups. CONCLUSIONS: Prehospital sepsis alert notification may decrease time to specific metrics shown to improve outcomes in sepsis.

Financial Incentives for Promoting Colorectal Cancer Screening: A Randomized, Comparative Effectiveness Trial.

OBJECTIVES: Offering financial incentives to promote or "nudge" participation in cancer screening programs, particularly among vulnerable populations who traditionally have lower rates of screening, has been suggested as a strategy to enhance screening uptake. However, effectiveness of such practices has not been established. Our aim was to determine whether offering small financial incentives would increase colorectal cancer (CRC) screening completion in a low-income, uninsured population. METHODS: We conducted a randomized, comparative effectiveness trial among primary care patients, aged 50-64 years, not up-to-date with CRC screening served by a large, safety net health system in Fort Worth, Texas. Patients were randomly assigned to mailed fecal immunochemical test (FIT) outreach (n=6,565), outreach plus a $5 incentive (n=1,000), or outreach plus a $10 incentive (n=1,000). Outreach included reminder phone calls and navigation to promote diagnostic colonoscopy completion for patients with abnormal FIT. Primary outcome was FIT completion within 1 year, assessed using an intent-to-screen analysis. RESULTS: FIT completion was 36.9% with vs. 36.2% without any financial incentive (P=0.60) and was also not statistically different for the $10 incentive (34.6%, P=0.32 vs. no incentive) or $5 incentive (39.2%, P=0.07 vs. no incentive) groups. Results did not differ substantially when stratified by age, sex, race/ethnicity, or neighborhood poverty rate. Median time to FIT return also did not differ across groups. CONCLUSIONS: Financial incentives, in the amount of $5 or $10 offered in exchange for responding to mailed invitation to complete FIT, do not impact CRC screening completion.

Enhancement of Odor Sensitivity Following Repeated Odor and Visual Fear Conditioning.

Odor detection sensitivity can be rapidly altered by fear conditioning; whether this effect is augmented over time is not known. The present study aimed to test whether repeated conditioning sessions induce changes in odor detection threshold as well as in conditioned responses and whether olfactory stimuli evoke stronger conditioned responses than visual stimuli. The repeated conditioning group participated in repeated sessions over 2 weeks whereas the single conditioning group participated in 1 conditioning session; both groups were presented with visual and olfactory stimuli, were paired with an electric shock (CS+) and 2 matched control stimuli not paired with shock (CS-) while olfactory detection threshold and skin conductance responses (SCRs) were measured before and after the last session. We found increased sensitivity for the CS+ odor in the repeated but not in the single conditioning group, consistent with changes in olfactory sensitivity following repeated aversive learning and of a similar magnitude to what has previously been demonstrated in the periphery. SCR to the visual and olfactory CS+ were similar between groups, indicating that sensory thresholds can change without corresponding change in conditioned responses. In conclusion, repeated conditioning increases detection sensitivity and reduces conditioned responses, suggesting that segregated processes influence perception and conditioned responses.

Mind over age--stereotype activation and olfactory function.

Given that context affects olfaction and the elderly exhibit olfactory deficits, the current study tested whether a subtle change in internal context, evoked by priming the elderly stereotype, would affect performance in a variety of olfactory tasks including odor sensitivity, discrimination, and identification (Experiment 1), as well as perceived odor intensity, pleasantness and familiarity, and an odor reaction time task (Experiment 2). Such internalization of the elderly stereotype has been demonstrated with slower walking speeds and fewer words recalled in a memory task. In the current study, 76 participants first listened to a presentation about age-related declines in olfaction and then participated in 3 language tasks which, unbeknownst to them, served as the elderly stereotype priming manipulation. This priming manipulation was effective at decreasing walking speed and word recall, confirming the findings of previous researchers; however, olfaction was not affected. Whether olfaction is resistant to stereotype priming is discussed.

End-tidal carbon dioxide measured at emergency department triage outperforms standard triage vital signs in predicting in-hospital mortality and intensive care unit admission.

OBJECTIVES: This study assessed the ability of end-tidal carbon dioxide (ETCO2 ) in predicting in-hospital mortality and intensive care unit (ICU) admission compared to standard vital signs at ED triage as well as comparing to measures of metabolic acidosis. METHODS: This prospective study enrolled adult patients presenting to the ED of a tertiary care Level I trauma center over 30 months. Patients had standard vital signs measured along with exhaled ETCO2 at triage. Outcome measures included in-hospital mortality; ICU admission; and correlations with lactate, sodium bicarbonate (HCO3 ), and anion gap. RESULTS: There were 1136 patients enrolled and 1091 patients with outcome data available. There were 26 (2.4%) patients who did not survive to hospital discharge. Mean ETCO2 levels were 34 (33-34) in survivors and 22 (18-26) nonsurvivors (p < 0.001). The area under the curve (AUC) for predicting in-hospital mortality for ETCO2 was 0.82 (0.72-0.91). In comparison the AUC for temperature was 0.55 (0.42-0.68), respiratory rate (RR) 0.59 (0.46-0.73), systolic blood pressure (SBP) 0.77 (0.67-0.86), diastolic blood pressure (DBP) 0.70 (0.59-0.81), heart rate (HR) 0.76 (0.66-0.85), and oxygen saturation (SpO2 ) 0.53 (0.40-0.67). There were 64 (6%) patients admitted to the ICU, and the ETCO2 AUC for predicting ICU admission was 0.75 (0.67-0.80). In comparison the AUC for temperature was 0.51, RR 0.56, SBP 0.64, DBP 0.63, HR 0.66, and SpO2 0.53. Correlations between expired ETCO2 and serum lactate, anion gap, and HCO3 were rho = -0.25 (p < 0.001), rho = -0.20 (p < 0.001), and rho = 0.330 (p < 0.001), respectively. CONCLUSIONS: ETCO2 was a better predictor of in-hospital mortality and ICU admission than the standard vital signs at ED triage. ETCO2 correlated significantly with measures of metabolic acidosis.

Implementation and Uptake of Rural Lung Cancer Screening.

OBJECTIVE: Given the higher rates of tobacco use along with increased mortality specific to lung cancer in rural settings, low-dose CT (LDCT)-based lung cancer screening could be particularly beneficial to such populations. However, limited radiology facilities and increased geographical distance, combined with lower income and education along with reduced patient engagement, present heightened barriers to screening initiation and adherence. METHODS: In collaboration with community leaders and stakeholders, we developed and implemented a community-based lung cancer screening program, including telephone-based navigation and tobacco cessation counseling support, serving 18 North Texas counties. Funding was available to support clinical services costs where needed. We collected data on LDCT referrals, orders, and completion. RESULTS: To raise awareness for lung cancer screening, we leveraged our established collaborative network of more than 700 community partners. In the first year of operation, 107 medical providers referred 570 patients for lung cancer screening, of whom 488 (86%) were eligible for LDCT. The most common reasons for ineligibility were age (43%) and insufficient tobacco history (20%). Of 381 ordered LDCTs, 334 (88%) were completed. Among screened patients, 61% were current smokers and 36% had insurance coverage for the procedure. The program cost per patient was $430. DISCUSSION: Implementation, uptake, and completion of LDCT-based lung cancer screening is feasible in rural settings. Community outreach, health promotion, and algorithm-based navigation may support such efforts. Given low lung cancer screening rates nationally and heightened lung cancer risk in rural populations, similar programs in other regions may be particularly impactful.

The effect of deadlines on cancer screening completion: a randomized controlled trial.

Cancer is the second leading cause of death in the United States. Although screening facilitates prevention and early detection and is one of the most effective approaches to reducing cancer mortality, participation is low-particularly among underserved populations. In a large, preregistered field experiment (n = 7711), we tested whether deadlines-both with and without monetary incentives tied to them-increase colorectal cancer (CRC) screening. We found that all screening invitations with an imposed deadline increased completion, ranging from 2.5% to 7.3% relative to control (ps < .004). Most importantly, individuals who received a short deadline with no incentive were as likely to complete screening (9.7%) as those whose invitation included a deadline coupled with either a small (9.1%) or large declining financial incentive (12.0%; ps = .57 and .04, respectively). These results suggest that merely imposing deadlines-especially short ones-can significantly increase CRC screening completion, and may also have implications for other forms of cancer screening.

Mere odor exposure learning in the rat neonate immediately after birth and 1 day later.

Rat pups are more resistant to retroactive associative interference 3 hr after birth than 24 hr later [Cheslock et al. [2004] Developmental Science, 7, 581-598]. The present experiments tested the effect of age, retention interval and dam presence during the retention interval on odor-induced motor activity subsequent to mere odor exposure. Rats were exposed to an hour of odor immediately after birth or approximately 1 day later and tested after a given retention interval (3 or 27 hr [Exp 1]; 0, 30, 75, or 180 min [Exp. 2]). They spent the retention interval either in the presence or absence of a foster dam (Exp. 1 and 3). After the retention interval, pups were tested in a 4-min activity test including a 2-min baseline period and 2 min of odor exposure. Overall activity was scored during tape-playback. Odor-exposed pups were more active than nonexposed pups during reexposure to the odor during testing, but this was true only for P0 pups. In contrast, P1 pups without prior odor exposure were active during testing and behaviorally quieted in the presence of the odor they were previously exposed to. Though 1 day apart, newborn rats just hours old lack many of the experiences that a 1-day-old has had including nursing, huddling, and being groomed. These experiences are associated with, among other stimuli, a barrage of olfactory cues (e.g., colostrum, saliva, dander, feces, and urine). P0 and P1 pups also differ in their proximity from the birthing experience and associated neurochemical changes. The age-related pattern of responding to odors based on previous odor exposure was discussed in relation to these and other possibilities.

Olfactory learning in the rat immediately after birth: Unique salience of first odors.

An infant rat's chance of survival is increased when it remains close to the nest. Early olfactory learning supports such adaptive behavior. Previous experiments indicated that non-associative odor exposure immediately after birth promoted later attachment to a similarly scented artificial nipple. The goal of the current experiments was to extend these findings on olfactory learning in the hours after birth by: exposing pups to more than one odor exposure (Experiment 1), dissecting the role of timing versus order of odor exposure (Experiment 2), testing the odor specificity of these effects (Experiments 3 and 4), and evaluating associative odor conditioning soon after birth (Experiment 5). Without explicit prior odor experience, pups only hours old do not respond much to a novel odor. Prior non-associative odor experience increases later motor activity to that same odor and to novel odors. Furthermore, these findings may be specific to certain amodal dimensions of the (in our case) lemon odor exposure. Single odor non-associative and associative conditioning was equally effective immediately after birth and during the third postnatal hour. Nevertheless, pups given two mere odor exposures responded to the first one more than the second at test, regardless of whether the exposures began immediately or 2 hr after birth. Possible mechanisms for these findings concerning early olfactory learning are discussed.

Financial Incentives to Promote Colorectal Cancer Screening: A Longitudinal Randomized Control Trial.

BACKGROUND: Financial incentives may improve health behaviors. We tested the impact of offering financial incentives for mailed fecal immunochemical test (FIT) completion annually for 3 years. METHODS: Patients, ages 50 to 64 years, not up-to-date with screening were randomized to receive either a mailed FIT outreach (n = 6,565), outreach plus $5 (n = 1,000), or $10 (n = 1,000) incentive for completion. Patients who completed the test were reinvited using the same incentive the following year, for 3 years. In year 4, patients who returned the kit in all preceding 3 years were reinvited without incentives. Primary outcome was FIT completion among patients offered any incentive versus outreach alone each year. Secondary outcomes were FIT completion for groups offered $5 versus outreach alone, $10 versus outreach alone, and $5 versus $10. RESULTS: Year 1 FIT completion was 36.9% with incentives versus 36.2% outreach alone (P = 0.59) and was not statistically different for $10 (34.6%; P = 0.31) or $5 (39.2%; P = 0.070) versus outreach alone. Year 2 completion was 61.6% with incentives versus 60.8% outreach alone (P = 0.75) and not statistically different for $10 or $5 versus outreach alone. Year 3 completion was 79.4% with incentives versus 74.8% outreach alone (P = 0.080), and was higher for $10 (82.4%) versus outreach alone (P = 0.033), but not for $5 versus outreach alone. Completion was similar across conditions in year 4 (no incentives). CONCLUSIONS: Offering small incentives did not increase FIT completion relative to standard outreach. IMPACT: This was the first longitudinal study testing the impact of repeated financial incentives, and their withdrawal, on FIT completion.

Safety and Efficacy of Prehospital Diltiazem for Atrial Fibrillation with Rapid Ventricular Response.

INTRODUCTION: Atrial fibrillation (AFIB) with rapid ventricular response (RVR) is a common tachydysrhythmia encountered by Emergency Medical Services (EMS). Current guidelines suggest rate control in stable, symptomatic patients. PROBLEM: Little is known about the safety or efficacy of rate-controlling medications given by prehospital providers. This study assessed a protocol for prehospital administration of diltiazem in the setting of AFIB with RVR for provider protocol compliance, patient clinical improvement, and associated adverse events. METHODS: This was a retrospective, cohort study of patients who were administered diltiazem by providers in the Orange County EMS System (Florida USA) over a two-year period. The protocol directed a 0.25mg/kg dose of diltiazem (maximum of 20mg) for stable, symptomatic patients in AFIB with RVR at a rate of >150 beats per minute (bpm) with a narrow complex. Data collected included patient characteristics, vital signs, electrocardiogram (ECG) rhythm before and after diltiazem, and need for rescue or additional medications. Adverse events were defined as systolic blood pressure <90mmHg or administration of intravenous fluid after diltiazem administration. Clinical improvement was defined as a heart rate decreased by 20% or less than 100bmp. Original prehospital ECG rhythm interpretations were compared to physician interpretations performed retrospectively. RESULTS: Over the study period, 197 patients received diltiazem, with 131 adhering to the protocol. The initial rhythm was AFIB with RVR in 93% of the patients (five percent atrial flutter, two percent supraventricular tachycardia, and one percent sinus tachycardia). The agreement between prehospital and physician rhythm interpretation was 92%, with a Kappa value of 0.454 (P <.001). Overall, there were 22 (11%) adverse events, and 112 (57%) patients showed clinical improvement. When diltiazem was given outside of the existing protocol, the patients had higher rates of adverse events (18% versus eight percent; P = .033). Patients who received diltiazem in adherence with protocols were more likely to show clinical improvement (63% versus 46%; P = .031). CONCLUSION: This study suggests that prehospital diltiazem administration for AFIB with RVR is safe and effective when strict protocols are followed.Rodriguez A, Hunter CL, Premuroso C, Silvestri S, Stone A, Miller S, Zuver C, Papa L. Safety and efficacy of prehospital diltiazem for atrial fibrillation with rapid ventricular response. Prehosp Disaster Med. 2019;34(3):297-302.

Olfactory learning in the rat neonate soon after birth.

The first hours of a newborn rat's life entail locating and attaching to the mother's nipple not only for nutrition but also for protection and warmth. The present study sought to characterize olfactory learning in the rat neonate immediately after birth. Newborn rats were exposed to an odor at various time periods soon after birth and tested for behavioral activation and attachment to a surrogate nipple in the presence of this odor at 4-5 hr postpartum. Regardless of when pups were presented the odor (0, 1, or 2 hr after birth) motor activity was greater among pups previously exposed to the odor than pups with no odor experience. Similarly, latency to attach to the nipple in the presence of the odor was lower among odor-preexposed pups, especially when odor exposure began within an hour of cesarean delivery. Odor exposure immediately after birth for just 15 min was sufficient to increase motor activity and to decrease latency to attach to a similarly scented surrogate nipple. These results suggest that olfactory experience very soon after birth can shape subsequent olfactory responses. The relative importance of the dearth of postnatal experience or of elevated neurochemicals immediately after birth and possible associative mechanisms underlying this learning is discussed.

Aversive learning increases sensory detection sensitivity.

Increased sensitivity to specific cues in the environment is common in anxiety disorders. This increase in sensory processing can emerge through attention processes that enhance discrimination of a cue from other cues as well as through augmented senses that reduce the absolute intensity of sensory stimulation needed for detection. Whereas it has been established that aversive conditioning can enhance odor quality discrimination, it is not known whether it also changes the absolute threshold at which an odor can be detected. In two separate experiments, we paired one odor of an indistinguishable odor pair with an aversive outcome using a classical conditioning paradigm. Ability to discriminate and to detect the paired odor was assessed before and after conditioning. The results demonstrate that aversive conditioning increases absolute sensory sensitivity to a predictive odor cue in an odor-specific manner, rendering the conditioned odor detectable at a significantly lower (20%) absolute concentration. As animal research has found long-lasting change in behavior and neural signaling resulting from conditioning, absolute threshold was also tested eight weeks later. Detection threshold had returned to baseline level at the eight week follow-up session suggesting that the change in detection threshold was mediated by a transient reorganization. Taken together, we can for the first time demonstrate that increasing the biological salience of a stimulus augments the individual's absolute sensitivity in a stimulus-specific manner outside conscious awareness. These findings provide a unique framework for understanding sensory mechanisms in anxiety disorders as well as further our understanding of mechanisms underlying classical conditioning.

Early operant learning is unaffected by socio-economic status and other demographic factors: a meta-analysis.

The relation between SES (socioeconomic status) and academic achievement in school-aged children is well established; children from low SES families have more difficulty in school. However, few studies have been able to establish a link between SES and learning in infancy, and thus the developmental onset of SES effects remains unknown. The limited studies that have been conducted to explore the link between SES and learning in infancy have generated mixed results; some demonstrate a link between SES and learning in infants as young as 6-9 months (Smith, Fagan, & Ulvund, 2002) while others do not. Further, studies examining the genetic as well as environmental contributors to learning in infancy and early childhood suggest that the effect of SES is likely cumulative and that as children develop, the effect of a low SES environment will become more pronounced (Tucker-Drob, Rhemtulla, Harden, Turkheimer, & Fask, 2011). Using aggregated data from 790 infants collected across 18 studies, we examined the contribution of SES and other demographic factors to learning of an operant kicking task in 2-4-month-old infants in a meta-analysis. Results indicated that, at least with respect to operant conditioning, an infant is an infant; that is SES did not affect learning rate or ability to learn in infants under 4-months of age. SES effects may therefore be better characterized as cumulative, with tangible effects emerging sometime later in life.

Social isolation and stress related hormones modulate the stimulating effect of ethanol in preweanling rats.

Preweanling rats are highly sensitive to the locomotor stimulation induced by relatively high ethanol doses. In adult mice this ethanol effect is modulated by stress. The goal of the present study was to analyze the role of stress and corticosterone in the stimulating effect of ethanol in preweanling rats. In Experiment 1 15-day-old rats were separated from the mother during a period of 4h in which subjects remained isolated or paired with a littermate. In a third condition pups remained in the home-cage with the dam. After this isolation period pups were given ethanol (0 or 2.5 g/kg) and were tested in a novel environment. Previous data have shown that a similar period of isolation is enough to increase corticosterone levels in preweanling rats. Experiment 2 evaluated the effect of exogenous administration of corticosterone (0, 3 or 6 mg/kg) along with ethanol, and Experiment 3 tested ethanol-mediated locomotor activation in adrenalectomized preweanling rats. The last experiment aimed to test the role of corticotropic releasing factor 1 (CRF1) receptors in locomotion induced by ethanol in isolated pups. According to our results there is a synergism between stress or corticosterone and ethanol in preweanling rats. The interaction between stress (induced by social isolation) and ethanol seems to be mediated by CRF, since blockade of CRF1 receptors cancelled the effect of ethanol in isolated pups. This study highlights the importance of considering stress as a possible intervening variable in studies evaluating ethanol effects in developing animals when maternal separation is used in the experimental procedure.

Novelty modulates the stimulating motor effects of ethanol in preweanling rats.

During early ontogeny heterogeneous rats are sensitive to ethanol's stimulating effects. In adulthood locomotor activity in a novel environment is a valuable predictor of acute sensitivity to the activating effects of various drugs, including ethanol. Environmental novelty modulates response to ethanol and other drugs in adult rats. The present study analyzed the role of novelty in the acute locomotor response induced by ethanol earlier in development, during the preweanling period, a stage characterized by enhanced sensitivity to ethanol's reinforcing effects. In Experiment 1 we evaluated the predictive value of baseline locomotor activity upon ethanol-induced locomotor effects in 12-day-old rats. In Experiment 2 we tested whether repeated familiarization with the testing environment would reduce the stimulating effects induced by ethanol on postnatal day 12. Individual differences in response to an inescapable novel environment significantly predicted the locomotor activating effects of ethanol, but not other acute effects of the drug, such as hypothermia, motor impairment or sedation. Behavioral activation induced by ethanol during the preweanling period was attenuated after familiarization with the testing environment, suggesting that environmental novelty is critical for activating effects of ethanol.