Perinatal outcomes in women with sickle cell disease: a matched cohort study from London, UK.

There are limited data on contemporary outcomes for women with sickle cell disease (SCD) in pregnancy. We conducted a single-site matched cohort study, comparing 131 pregnancies to women with SCD between 2007 and 2017 to a comparison group of 1310 pregnancies unaffected by SCD. Restricting our analysis to singleton pregnancies that reached 24 weeks of gestation, we used conditional Poisson regression to estimate adjusted risk ratios (aRRs) for perinatal outcomes. Infants born to mothers with SCD were more likely to be small for gestational age [aRR 1·69, 95% confidence interval (CI) 1·13-2·48], preterm (aRR 2·62, 95% CI 1·82-3·78) and require Neonatal Unit (NNU) admission (aRR 3·59, 95% CI 2·18-5·90). Pregnant women with SCD were at higher risk of pre-eclampsia/eclampsia (aRR 3·53, 95% CI 2·00-6·24), more likely to receive induction of labour (aRR 2·50, 95% CI 1·82-1·76) and caesarean birth (aRR 1·44, 95% CI 1·18-1·76). In analysis stratified by genotype, the risk of adverse outcomes was highest in haemoglobin SS (HbSS) pregnancies (n = 80). There was no strong evidence that haemoglobin SC (HbSC) pregnancies (n = 46) were at higher risk of preterm birth, caesarean delivery, or NNU admission. Pre-eclampsia/eclampsia was more frequently observed in HbSC pregnancies. Despite improvements in the care of pregnant women with SCD, the increased risk of adverse perinatal outcomes remains.

Maternal iron deficiency anaemia in pregnancy: Lessons from a national audit.

We describe the management and the prevalence of iron deficiency anaemia (IDA) during pregnancy by comparison to standards. A cross-sectional national cohort study of women who had given birth six weeks prior to data collection was conducted at maternity units in the UK and Ireland. Participating centres collected data from 10 consecutive pregnant women. Analysis was descriptive to define the prevalence of IDA in pregnancy and the puerperium, and to compare the outcomes in women who had IDA with women who did not have anaemia anytime during pregnancy. Eighty-six maternity units contributed data on 860 pregnancies and births. The overall prevalence of IDA during pregnancy was 30.4% and in the puerperium 20%. Anaemic women were more likely to be from ethnic minorities, odds ratio 2.23 (1.50, 3.32). Adherence to national guidance was suboptimal, and the prevalence of anaemia in pregnancy remains very high. There is pressing need to explore barriers to early identification and effective management of iron deficiency. IDA should be considered a major public health problem in the UK.

How we manage Philadelphia-negative myeloproliferative neoplasms in pregnancy.

The combined incidence of classical Philadelphia-negative myeloproliferative neoplasm (MPN) is 6-9/100 000 with a peak frequency between 50 and 70 years. MPN is less frequent in women of reproductive age. However, for essential thrombocythaemia (ET) in particular there is a second peak in women of reproductive age and 15% of polycythaemia vera (PV) patients are less than 40 years of age at the time of diagnosis. Thus these diseases are encountered in women of reproductive potential and may be diagnosed in pregnancy or in women being investigated for recurrent pregnancy loss. The incidence of MPN pregnancies is 3·2/100 000 maternities per year in the UK. The majority of data regarding Philadelphia-negative MPNs relates to patients with ET, for which the literature suggests significant maternal morbidity and poor fetal outcome; specifically maternal thrombosis and haemorrhage, miscarriage, pre-eclampsia, intrauterine growth restriction (IUGR), stillbirth and premature delivery as summarised in the recent systematic review and meta-analysis in Blood, 2018, 132, 3046. The literature for PV is more sparse but increasing and is concordant with ET pregnancy outcomes. The literature regarding primary myelofibrosis (PMF) is even more scarce. Treatment options include aspirin, venesection, low molecular weight heparin (LMWH) and cytoreductive therapy. Data and management recommendations are often extrapolated from other pro-thrombotic conditions or from ET to PV and PMF. Women of reproductive age with a diagnosis of MPN should receive information and assurance regarding management and outcome of future pregnancies. From pre-conceptual planning to the post-partum period, women should have access to joint care from an obstetrician with experience of high-risk pregnancies and a haematologist in a multidisciplinary setting. This paper provides an update with regards to Philadelphia-negative MPN in pregnancy, details local practise in an internationally recognised centre for patients with MPN and outlines a future research strategy.

Blood component use in critical care in patients with COVID-19 infection: a single-centre experience.

There has been a significant surge in admissions to critical care during the coronavirus disease 2019 (COVID-19) pandemic. At present, the demands on blood components have not been described. We reviewed their use during the first 6 weeks of the outbreak from 3 March 2020 in a tertiary-level critical care department providing venovenous extracorporeal membrane oxygenation (vv-ECMO). A total of 265 patients were reviewed, with 235 not requiring ECMO and 30 requiring vv-ECMO. In total, 50 patients required blood components during their critical care admission. Red cell concentrates were the most frequently transfused component in COVID-19-infected patients with higher rates of use during vv-ECMO. The use of fresh frozen plasma, cryoprecipitate and platelet transfusions was low in a period prior to the use of convalescent plasma.

Risk of venous thromboembolism in pregnant women with essential thrombocythemia: a systematic review and meta-analysis.

We performed a meta-analysis to evaluate the risk of venous thromboembolism (VTE) in pregnant women with essential thrombocythemia. Twenty-one trials and 756 pregnancies met inclusion criteria. The absolute VTE risk in the antepartum period is not above a threshold where low-molecular-weight heparin (LMWH) prophylaxis is clearly indicated or below a threshold where LMWH should be withheld (2.5%; 95% CI, 1.3-4.3). Postpartum, the absolute VTE risk is above a threshold where postpartum LMWH prophylaxis should be considered (4.4%; 95% CI, 1.2-9.5).

The opioid system and brain development: effects of methadone on the oligodendrocyte lineage and the early stages of myelination.

Oligodendrocytes express opioid receptors throughout development, but the role of the opioid system in myelination remains poorly understood. This is a significant problem as opioid use and abuse continue to increase in two particular populations: pregnant addicts (in whom drug effects could target early myelination in the fetus and newborn) and adolescents and young adults (in whom late myelination of 'higher-order' regions takes place). Maintenance treatments for opioid addicts include the long-lasting opioids methadone and buprenorphine. Similar to our previous findings on the effects of buprenorphine, we have now found that early myelination in the developing rat brain is also altered by perinatal exposure to therapeutic doses of methadone. Pups exposed to this drug exhibited elevated brain levels of the 4 major splicing variants of myelin basic protein, myelin proteolipid protein, and myelin-oligodendrocyte glycoprotein. Consistent with the enrichment and function of these proteins in mature myelin, analysis of the corpus callosum in these young animals also indicated an elevated number of axons with already highly compacted myelin sheaths. Moreover, studies in cultured cells showed that methadone exerts direct effects at specific stages of the oligodendrocyte lineage, stimulating the proliferation of progenitor cells while on the other hand accelerating the maturation of the more differentiated but still immature preoligodendrocytes. While the long-term effects of these observations remain unknown, accelerated or increased oligodendrocyte maturation and myelination could both disrupt the complex sequence of synchronized events leading to normal connectivity in the developing brain. Together with our previous observations on the effects of buprenorphine, the present findings further underscore a crucial function of the endogenous opioid system in the control of oligodendrocyte development and the timing of myelination. Interference with these regulatory systems by opioid use or maintenance treatments could disrupt the normal process of brain maturation at critical stages of myelin formation.

Managing sickle cell disease and related complications in pregnancy: results of an international Delphi panel.

ABSTRACT: Data to guide evidence-based management of pregnant people with sickle cell disease (SCD) are limited. This international Delphi panel aimed to identify consensus among multidisciplinary experts for SCD management during pregnancy. The 2-round Delphi process used questionnaires exploring 7 topics (antenatal care, hydroxyurea use, transfusion, prevention of complications, treatment of complications, delivery and follow-up, and bottlenecks and knowledge gaps) developed by a steering committee. Thirteen panelists (hematologists, physiologists, obstetricians, maternal fetal medicine, and transfusion medicine physicians) from the United States, the United Kingdom, Turkey, and France completed the first survey; 12 panelists completed the second round. Anonymized responses were collected and summarized by a contract research organization (Akkodis Belgium). Consensus and strong consensus were predefined as 75% to 90% (9-10 of 12) and >90% (≥11 of 12) of panelists, respectively, agreeing or disagreeing on a response to a predefined clinical scenario or statement. In several areas of SCD management, consensus was achieved: experts recommended performing at least monthly multidisciplinary antenatal follow-up, administering prophylactic aspirin for preeclampsia prevention between gestational weeks 12 and 36, initiating prophylactic transfusion therapy in certain cases, or choosing automated red blood cell exchange over other transfusion methods for patients with iron overload or severe acute chest syndrome. No consensus was reached on several topics including the prophylactic aspirin dose, indications for starting infection prophylaxis, routine use of prophylactic transfusions, or use of prophylactic transfusions for preventing fetal complications. These recommendations could inform clinical care for patients with SCD who are pregnant in the absence of large clinical trials involving this population; the identified knowledge gaps can orient future research.

Oligodendrocyte responses to buprenorphine uncover novel and opposing roles of µ-opioid- and nociceptin/orphanin FQ receptors in cell development: implications for drug addiction treatment during pregnancy.

Although the classical function of myelin is the facilitation of saltatory conduction, this membrane and the oligodendrocytes, the cells that make myelin in the central nervous system (CNS), are now recognized as important regulators of plasticity and remodeling in the developing brain. As such, oligodendrocyte maturation and myelination are among the most vulnerable processes along CNS development. We have shown previously that rat brain myelination is significantly altered by buprenorphine, an opioid analogue currently used in clinical trials for managing pregnant opioid addicts. Perinatal exposure to low levels of this drug induced accelerated and increased expression of myelin basic proteins (MBPs), cellular and myelin components that are markers of mature oligodendrocytes. In contrast, supra-therapeutic drug doses delayed MBP brain expression and resulted in a decreased number of myelinated axons. We have now found that this biphasic-dose response to buprenorphine can be attributed to the participation of both the µ-opioid receptor (MOR) and the nociceptin/orphanin FQ receptor (NOP receptor) in the oligodendrocytes. This is particularly intriguing because the NOP receptor/nociceptin system has been primarily linked to behavior and pain regulation, but a role in CNS development or myelination has not been described before. Our findings suggest that balance between signaling mediated by (a) MOR activation and (b) a novel, yet unidentified pathway that includes the NOP receptor, plays a crucial role in the timing of oligodendrocyte maturation and myelin synthesis. Moreover, exposure to opioids could disrupt the normal interplay between these two systems altering the developmental pattern of brain myelination.

Maternal sickle cell disease and twin pregnancy: a case series and review of the literature.

OBJECTIVES: Maternal sickle cell disease (SCD) and multiple gestations are well known separately as causes of high-risk pregnancies, however, there is sparse information available on maternal and perinatal outcome when both conditions occur together. This case series describes the outcomes of women with maternal SCD and twin pregnancy in the largest single-center case series to date. METHODS: Retrospective identification of all twin pregnancies in maternal SCD patients between 2006 and 2016 at Guy's and St. Thomas' Hospital, United Kingdom Results: Eight women were included: seven with HbSS and one with HbSC. Our cohort experienced common SCD-related and pregnancy-related complications such as painful vaso-occlusive crises (VOC), acute chest syndrome (ACS), and pre-eclampsia and less common complications such as peri-partum cardiomyopathy and delayed hemolytic transfusion reaction. Only two out of eight women had relatively uncomplicated pregnancies. Seven out of eight women required transfusion antenatally and there was no maternal or perinatal mortality. A review of the available literature highlighted the lack of available information on this uncommon cohort. It was evident that outcomes have improved over the years, where historical studies demonstrate higher rates of maternal and perinatal mortality. DISCUSSION: The antenatal and postnatal complications described in our study and literature review highlights the significant morbidity and mortality associated with these high-risk pregnancies. CONCLUSION: Our case series highlights the advantage of closer monitoring and comprehensive multidisciplinary care in delivering improved clinical outcomes.

Opioid addiction and pregnancy: perinatal exposure to buprenorphine affects myelination in the developing brain.

Buprenorphine is a mu-opioid receptor partial agonist and kappa-opioid receptor antagonist currently on trials for the management of pregnant opioid-dependent addicts. However, little is known about the effects of buprenorphine on brain development. Oligodendrocytes express opioid receptors in a developmentally regulated manner and thus, it is logical to hypothesize that perinatal exposure to buprenorphine could affect myelination. To investigate this possibility, pregnant rats were implanted with minipumps to deliver buprenorphine at 0.3 or 1 mg/kg/day. Analysis of their pups at different postnatal ages indicated that exposure to 0.3 mg/kg/day buprenorphine caused an accelerated and significant increase in the brain expression of all myelin basic protein (MBP) splicing isoforms. In contrast, treatment with the higher dose caused a developmental delay in MBP expression. Examination of corpus callosum at 26-days of age indicated that both buprenorphine doses cause a significant increase in the caliber of the myelinated axons. Surprisingly, these axons have a disproportionately thinner myelin sheath, suggesting alterations at the level of axon-glial interactions. Analysis of myelin associated glycoprotein (MAG) expression and glycosylation indicated that this molecule may play a crucial role in mediating these effects. Co-immunoprecipitation studies also suggested a mechanism involving a MAG-dependent activation of the Src-family tyrosine kinase Fyn. These results support the idea that opioid signaling plays an important role in regulating myelination in vivo and stress the need for further studies investigating potential effects of perinatal buprenorphine exposure on brain development.

Epidemiological consequences of an incursion of highly pathogenic H5N1 avian influenza into the British poultry flock.

Highly pathogenic avian influenza and in particular the H5N1 strain has resulted in the culling of millions of birds and continues to pose a threat to poultry industries worldwide. The recent outbreak of H5N1 in the UK highlights the need for detailed assessment of the consequences of an incursion and of the efficacy of control strategies. Here, we present results from a model of H5N1 propagation within the British poultry industry. We find that although the majority of randomly seeded incursions do not spread beyond the initial infected premises, there is significant potential for widespread infection. The efficacy of the European Union strategy for disease control is evaluated and our simulations emphasize the pivotal role of duck farms in spreading H5N1.

Longitudinal study of the molecular epidemiology of Campylobacter jejuni in cattle on dairy farms.

Multilocus sequence typing (MLST), an accurate and phylogenetically robust characterization method for population studies of Campylobacter, was applied to Campylobacter jejuni isolates (n = 297) from the fecal samples of cattle from five dairy farms in Cheshire, United Kingdom, collected throughout 2003. The population dynamics of the C. jejuni strains, as identified by the occurrence of sequence types and clonal complexes, demonstrated variations within and between cattle populations over time. Three clonal lineages have emerged to predominate among the cattle isolates, namely, the ST-61 complex (24.2%), ST-21 complex (23.6%), and ST-42 complex (20.5%). This provided further evidence that the ST-61 clonal complex may present a cattle-adapted C. jejuni genotype. In addition, the ST-42 clonal complex may also represent an important cattle-associated genotype. Strong geographical associations for these genotypes were also found among the farms. This is the first longitudinal study and the largest study to date for C. jejuni involving cattle populations using MLST for accurate strain characterization. This study shows the important associations between cattle and C. jejuni clonal complexes ST-61, ST-21, and ST-42, and it suggests that cattle and/or dairy products are likely to be a source of the human Campylobacter gastroenteritis caused by such genotypes. The reported findings have significant implications for the design of effective intervention strategies for disease control and prevention.

The effects of acute and repeated nicotine doses on spontaneous activity in male and female Sprague Dawley rats: analysis of brain area epibatidine binding and cotinine levels.

Previous research in this laboratory has shown that nicotine's effects on spontaneous activity are contingent on individual differences, attenuating activity in high active rats and increasing it in low active rats. This study was designed to further evaluate this phenomenon, and to compare it with nicotine's effects on nicotinic acetylcholine receptor (nAChR) expression in several brain regions. Male and female Sprague-Dawley rats selected for differences in baseline activity were administered nicotine twice daily for 14 days, and its effects on spontaneous activity were evaluated following 1, 13 and 27 doses. Furthermore, [(3)H] epibatidine binding and plasma cotinine levels were evaluated 24 h after the 28th dose. Contrary to previous findings, the effects of repeated nicotine on spontaneous activity were minimally contingent on baseline activity levels. Following an initial attenuation, males, but not females, exhibited sensitization to nicotine's effects on spontaneous activity. [(3)H] epibatidine was significantly increased in several brain regions in both male and female nicotine-treated animals, and in females selected for high activity at baseline. However, a clear relationship between these effects and spontaneous activity was not found, due to the lack of consistent effects of nicotine administration and baseline activity on spontaneous activity. Interestingly, significant correlations suggest that rats exhibiting higher spontaneous activity on the final test day were differentially marked by higher [(3)H] epibatidine. Cotinine levels were higher in low activity males than in high activity males, but no differences were observed between high and low activity females. Thus, no clear relationship between this variable and spontaneous activity could be discerned. Based on these data, no simple relationships between the effects of nicotine administration or baseline activity on [(3)H] epibatidine binding, nicotine metabolism, or spontaneous activity were observed. However, a relationship between [(3)H] epibatidine and spontaneous activity on the final test day is suggested.

Acute nicotine reduces and repeated nicotine increases spontaneous activity in male and female Lewis rats.

The Lewis (LEW) strain of rat appears more sensitive to nicotine than other strains in self-administration, conditioned place preference, and drug discrimination behavioral studies. The present study sought to further evaluate the behavioral effects of chronic nicotine treatment in the LEW strain by assessing spontaneous activity, which has consistently revealed sensitization to chronic nicotine administration in Sprague Dawley (SD) rats. High active and low active male and female LEW rats (N=8 per group) were treated twice daily with either nicotine (0.4 mg/kg, sc) or vehicle for 14 consecutive days. Regardless of baseline activity level or sex, spontaneous activity was significantly decreased, compared to saline-treated rats, after a single nicotine injection. However, spontaneous activity increased in both low- and high-activity rats (both sexes) over the two weeks of nicotine administration to levels that were significantly higher than saline-treated rats. Based on these findings, acute and chronic nicotine administration had greater suppressive and enhancing effects on spontaneous activity in LEW rats compared to other strains of rats previously studied. These results further clarify the behavioral sensitivity of the LEW strain of rat to nicotine exposure and lend credence to the role of genetics in the individual susceptibility to nicotine dependence.

Cellular nicotinic receptor desensitization correlates with nicotine-induced acute behavioral tolerance in rats.

RATIONALE: Individuals vary in their susceptibility to nicotine addiction. However, there is little evidence that behavioral sensitivity to nicotine is dependent upon the functional state of nicotinic cholinergic receptors (nAChRs). OBJECTIVE: This study aims to determine the relationship between in vivo behavioral desensitization and in vitro desensitization of nAChR function. METHODS: Male Sprague-Dawley rats trained to discriminate nicotine were tested for development of acute behavioral tolerance. The rats were injected with nicotine (0.4 mg/kg free base, s.c.), tested for nicotine discrimination for 2 min, then injected with the same dose of nicotine 90, 180, and 270 min after the first injection and tested for nicotine discrimination after each injection. Susceptibility of nAChRs of individual rats to desensitization was assessed by use of the (86)Rb(+) efflux assay using synaptosomes prepared from the "thalamus," which included the hypothalamus and midbrain as well as the thalamic nuclei. To desensitize nAChRs, synaptsosomes were superfused with low concentrations of nicotine (5, 10, 20, and 30 nM) before stimulation of (86)Rb(+) efflux with nicotine (10 muM). RESULTS: The slopes of the behavioral desensitization were plotted as a function of the decline of nicotine-stimulated (86)Rb(+) efflux after in vitro desensitization. A significant correlation was observed between the in vitro desensitization of thalamic (86)Rb(+) efflux and the extent of behavioral desensitization of individual rats. CONCLUSIONS: These findings are consistent with the idea that production of acute behavioral tolerance by nicotine is related to its ability to induce nAChR desensitization at the cellular level.

Evidence of cellular nicotinic receptor desensitization in rats exhibiting nicotine-induced acute tolerance.

RATIONALE: Individuals vary in their susceptibility to nicotine addiction. However, there is little evidence that behavioral sensitivity to nicotine is dependent upon the functional state of nicotinic cholinergic receptors (nAChRs). OBJECTIVE: To determine the relationship between in vivo pharmacological desensitization (in other words, acute tolerance) and brain regional nAChR function. METHODS: Male Sprague-Dawley rats, trained to discriminate nicotine (0.4 mg/kg free base) from saline in a two-lever drug discrimination task, were tested for the development of acute tolerance. Rats were injected with 0.4 mg/kg nicotine, tested for nicotine discrimination for 2 min, then injected with the same dose of nicotine 90 min, 180 min, and 270 min after the first injection and tested for nicotine discrimination after each injection. These subjects were separated into two groups, desensitizers (DZ) and nondesensitizers (NDZ), based upon performance in the repetitive dosing drug discrimination paradigm. The sensitivity of nAChRs in specific brain regions of these two groups was assessed by the use of an 86Rb+ efflux assay using synaptosomes prepared from the frontal cortex, hippocampus, striatum, and "thalamus," which included the midbrain and hypothalamus as well as the thalamus. RESULTS: The nicotine-induced increase in 86Rb+ efflux was significantly greater in NDZ as compared to DZ in the "thalamus." There was no statistically significant difference in the effects of nicotine in the frontal cortex, hippocampus, and striatum of these two groups. A significant correlation was observed between thalamic 86Rb+ efflux and the rate of behavioral desensitization of individual rats. CONCLUSION: These findings are consistent with the concept that the production of acute tolerance by nicotine in vivo correlates directly with its ability to induce nAChR desensitization at the cellular level.

Buprenorphine-containing treatments: place in the management of opioid addiction.

Although the synthetic opioid buprenorphine has been available clinically for almost 30 years, its use has only recently become much more widespread for the treatment of opioid addiction. The pharmacodynamic and pharmacokinetic profiles of buprenorphine make it unique in the armamentarium of drugs for the treatment of opioid addiction. Buprenorphine has partial mu-opioid receptor agonist activity and is a kappa-opioid receptor antagonist; hence, it can substitute for other micro-opioid receptor agonists, yet is less apt to produce overdose reactions or dysphoria. On the other hand, buprenorphine can block the effects of opioids such as heroin (diamorphine) and morphine, and can even precipitate withdrawal in individuals physically dependent upon these drugs. Buprenorphine has significant sublingual bioavailability and a long half-life, making administration on a less than daily basis possible. Furthermore, its discontinuation is associated with only a mild withdrawal syndrome. Clinical trials have demonstrated that sublingual buprenorphine is effective in both maintenance therapy and detoxification of individuals addicted to opioids. The introduction of a sublingual formulation combining naloxone with buprenorphine further reduces the risk of diversion to illicit intravenous use. Because of its relative safety and lower risk of illegal diversion, buprenorphine has been made available in several countries for treating opioid addiction in the private office setting, greatly enhancing treatment options for this condition.

Nicotinic receptor inactivation after acute and repeated in vivo nicotine exposures in rats.

Nicotine tolerance is often accompanied by an upregulation of brain area nicotinic acetylcholine receptors (nAChRs) in both animal and human subjects. This upregulation has been hypothesized to result from repeated or prolonged exposures of these receptors to nicotine. To explore this further, this study examined the level of nAChR desensitization following acute and repeated nicotine administration in the male Lewis rat. Nicotine-stimulated (86)Rb(+) efflux was measured in synaptosomes prepared from the frontal cortex, hippocampus, striatum, and thalamus. Analysis of receptor functionality was achieved by calculating area-under-the-curve (AUC) for nicotine-induced fractional (86)Rb(+) efflux. Nicotine-stimulated (86)Rb(+) efflux from all brain regions was significantly less in rats that received an acute injection of 0.4 mg/kg nicotine (s.c.) 15 min prior to dissection compared to control rats. This decrease in nAChR functional status was also observed in rats treated with 1 day or 14 days of twice-daily nicotine administration. These results are consistent with the concept that acute exposure to nicotine induces rapid desensitization of nAChRs. In addition, following repeated exposure to nicotine, nAChRs did not become tolerant to the loss in receptor function that occurs after an initial nicotine administration. Overall, these data suggest that neuronal adaptations underlying nicotine tolerance may begin upon initial exposure then persist following repeated exposures.

Neurochemical and behavioral effects of bupropion and mecamylamine in the presence of nicotine.

The primary mechanism of action of bupropion, a smoking cessation drug, is commonly believed to involve the dopaminergic system although evidence exists that bupropion also has effects at nicotinic acetylcholine receptors (nAChRs). This study evaluated the disruptive effects of nicotine on response rates in the presence of bupropion and the nAChR antagonist, mecamylamine, as well as the ability of these drugs to alter nicotine-stimulated nAChR function in various brain areas. Rats were trained to respond on a single lever under a variable interval 15 (VI15) schedule for food reinforcement. Initially, dose effect curves were generated for nicotine, bupropion and mecamylamine. Upon determining the dose of nicotine (1.2 mg/kg) effective in completely disrupting rates of responding, it was established that both mecamylamine and bupropion block nicotine's rate-reducing effects. This result suggests that bupropion shares behavioral effects with mecamylamine when administered in the presence of nicotine. To explore this relationship further, the effect of in vivo administration of bupropion or mecamylamine on nicotine-stimulated (86)Rb(+) efflux was studied in synaptosomes prepared from the frontal cortex, hippocampus, striatum and thalamus. Nicotine-stimulated (86)Rb(+) efflux from all brain regions was significantly reduced in rats administered 3.0 mg/kg mecamylamine (s.c.) 15 min prior to dissection compared to control rats. In contrast, a significant increase in nicotine-stimulated (86)Rb(+) efflux was observed in all brain regions from rats administered 30.0 mg/kg bupropion (s.c.) 15 min prior to dissection compared to control rats. Taken together these results demonstrate that when administered in the presence of nicotine, bupropion elicits unique pharmacological differences such that it exhibits both nAChR agonist- and antagonistic-like effects.