Biomedical subjects

D J Anderson

Publications and source records attributed to D J Anderson.

At least 199 records · Page 11Linked to original sources

PubMed1994

Nicotinic receptor binding of [3H]cytisine, [3H]nicotine and [3H]methylcarbamylcholine in rat brain.

Three radiolabeled nicotinic receptor agonists were examined for their binding characteristics and for inhibition by cholinergic compounds in order to distinguish possible differential affinities for subtypes of neuronal nicotinic acetylcholine receptors. KD and Bmax values for [3H]cytisine, [3H]methylcarbamylcholine and [3H]nicotine were determined from Scatchard analysis using an enriched whole-brain membrane fraction from male Sprague-Dawley rats. Respective KD values were 0.15, 1.07 and 0.89 nM while Bmax values were 99, 64 and 115 fmol/mg protein respectively. All three ligands fit a one-site model of receptor-ligand interaction. Concentration-inhibition curves were used to determine Ki values for 16 cholinergic compounds. The rank order of potencies for displacement of the three ligands was: (-)-cytisine > (-)-nicotine > (-)-lobeline = methylcarbamylcholine > 1,1-dimethyl-4-phenylpiperazinium, (+)-nicotine, dihydro-beta-erythroidine, (+/-)-nornicotine > carbachol > arecoline >> oxotremorine, tetrahydroaminoacridine, AF102B >> (-)-cotinine > RS86 = heptylphysostigmine. Correlations of the affinities of these compounds determined with the three ligands were very near to unity. In contrast, there was a negative correlation of affinities for [3H]cytisine compared to affinities for the muscarinic receptor agonist, [3H]oxotremorine-M, and the muscarinic receptor antagonist, [3H]quinuclidinyl benzoate. Using membranes from whole rat brain yields data suggesting that all three nicotinic ligands bind to the same nicotinic acetylcholine receptor subtype, and are unable to distinguish subtypes of neuronal nicotinic acetylcholine receptor at the level examined.

Alkaloids↗

PubMed1994

Practices of cardiothoracic transplant centers regarding hepatitis C-seropositive candidates and donors.

The purpose of this survey was to determine current practices of cardiothoracic transplant centers regarding transplantation of hearts and lungs into hepatitis C (HCV)-seropositive candidates and the use of organs from HCV-seropositive donors. A telephone survey of 48 cardiothoracic transplant centers was conducted in October 1992. Questions included the center's policy for listing HCV-seropositive candidates; if, and under what conditions, organs from HCV-seropositive donors would be used; and which HCV assays were used. Forty-five programs responded; 75% will list an HCV-seropositive candidate, either directly or by lack of routine screening to exclude such patients; only 16% will not accept HCV-seropositive candidates; 9% had no policy. Overall, 69% will accept organs from HCV-seropositive donors, at least for selected recipients (22% for any recipient, 45% for HCV-seropositive and/or status I recipients; 2% do not screen donors). A total of 27% will never accept organs from an HCV-seropositive donor, and 4% had no policy. Thirty centers provided information on HCV methodology. All but one use a second generation ELISA or EIA as a first-line test. A positive result will be followed by a confirmatory assay/liver biopsy in 42%. The variation in practices reflects the ambiguity in the literature. Adequate evaluation of morbidity and mortality due to HCV infection in this population has not yet been possible, although currently available reports do not show a substantial increase. Prospective controlled trials in cardiothoracic transplant patients are necessary.

Data Collection↗

PubMed1994

p75LNGFR regulates Trk signal transduction and NGF-induced neuronal differentiation in MAH cells.

We have examined NGF-induced signal transduction events and neuronal differentiation in MAH cells, a neuronal progenitor cell line, in which the expression of the two NGF receptors, p140trk (Trk) and p75LNGFR (p75), has been independently manipulated. Coexpression of a large molar excess of p75 substantially enhances the NGF-induced tyrosine autophosphorylation of Trk, compared with cells expressing Trk alone. MAH cells expressing both Trk and p75 stop dividing and acquire a mature neuronal morphology more rapidly and with greater efficiency than MAH cells expressing Trk alone. These biochemical and biological influences of p75 are not observed using a mutant form of NGF that binds Trk but not p75. These data provide evidence that p75 can modulate signal transduction through Trk in a neuronal progenitor cell context and that such modulation has functional consequences for the neuronal differentiation pathway induced by NGF.

Animals↗

PubMed1994

Neurotrophins regulate sequential changes in neurotrophin receptor expression by sympathetic neuroblasts.

We have examined the mechanisms controlling the induction of the two NGF receptors, trkA and p75, in proliferating neuroblasts immuno-isolated from thoracolumbar embryonic sympathetic ganglia. Contrary to prior studies, we find that induction of p75 follows rather than precedes that of trkA; this late induction is consistent with the fact that p75 functions at relatively late stages of sympathetic development. trkA induction is apparently not controlled by a cell-intrinsic mechanism. Rather, this receptor is induced by environmental signals including NT-3, which also acts as an interim survival factor for these neuroblasts. trkA induction by NT-3 is consequent to its promotion of mitotic arrest, as anti-mitotic drugs also efficiently induce trkA. p75 expression is induced in trkA-expressing cells by NGF. Thus, the development of sympathetic neurons involves sequential actions of different neurotrophins, which also regulate the expression of their own and each other's receptors.

Animals↗

PubMed1994

The effects of disease progression and zidovudine therapy on semen quality in human immunodeficiency virus type 1 seropositive men.

OBJECTIVE: To investigate the effects of disease progression and zidovudine antiretroviral therapy on semen parameters in human immunodeficiency virus type 1 (HIV-1) seropositive men. DESIGN: Cross-sectional analysis of semen parameters of 166 HIV-1 seropositive men in various stages of disease progression as defined by peripheral CD4+ cell count. Clinical symptoms and zidovudine therapy status were obtained from medical records and clinical interviews. PATIENTS: Human immunodeficiency virus type 1 seropositive men participating in clinical studies at the Fenway Community Health Center (Boston, MA), the University of San Francisco (San Francisco, CA), and Brown University (Providence, RI). MAIN OUTCOME MEASURES: Ejaculate volume; sperm concentration, motility, forward progression, morphology, total sperm count; seminal immature germ cell; and white blood cell (WBC) concentrations. RESULTS: Human immunodeficiency virus type 1 seropositive men that were not on zidovudine therapy and were in early disease stage (> 200 CD4+ cells/mm3) had normal semen parameters as defined by World Health Organization criteria. In contrast untreated men in advanced disease stage (< or = 200 CD4+ cells/mm3) had significant reductions in sperm concentration and total sperm count and an increased percentage of abnormal sperm forms. Men receiving zidovudine antiretroviral therapy, regardless of disease stage, had normal semen parameters similar to those of untreated early disease stage patients. Seminal WBC concentrations were not affected significantly by disease progression but were reduced in patients receiving zidovudine. CONCLUSION: Most HIV-1-infected men in this study had semen parameters consistent with fertility. Disease progression was associated with reduced semen quality, but this effect appeared to be abrogated by zidovudine therapy. Zidovudine was also associated with a significant reduction of WBC numbers in semen. As seminal WBC are principal HIV-1 host cells in ejaculates of HIV-1-infected men, this effect could explain recent laboratory and epidemiological evidence that zidovudine therapy is associated with a reduced prevalence of HIV-1 in semen and a lower rate of sexual transmission.

Acquired Immunodeficiency Syndrome↗

PubMed1994

Short-term effects of smoking marijuana on balance in patients with multiple sclerosis and normal volunteers.

A double-blind randomized placebo-controlled study of inhaled marijuana smoke on postural responses was performed in 10 adult patients with spastic multiple sclerosis (MS) and 10 normal volunteers matched as closely as possible for age, sex, and weight. A computer-controlled dynamic posturographic platform with a video line scan camera measured shoulder displacement in response to pseudorandom platform movements. Premarijuana smoking patient tracking was inferior to that of the normal volunteers as indicated by the higher noise variance of the former. Smoking one marijuana cigarette containing 1.54% delta 9-tetrahydrocannabinol increased postural tracking error in both the patients and normal control subjects with both eyes open and closed; this untoward effect was greatest for the patients. The tracking error was also accompanied by a decrease in response speed for the patients with their eyes closed. Marijuana smoking further impairs posture and balance in patients with spastic MS.

Adult↗

PubMed1994

Clinical courses of seven survivors of Clostridium septicum infection and their immunologic responses to alpha toxin.

Clostridium septicum bacteremia typically portends a fulminant disease associated with high mortality. We describe the clinical courses of seven survivors of C. septicum infection and their antibody responses to the alpha toxin produced by C. septicum. Three patients had clinical syndromes ranging from uncomplicated bacteremia to early typhlitis, and three patients had syndromes ranging from abscess to myonecrosis and septic shock. In addition, an AIDS patient who developed septic shock and who had extensive gas in the retroperitoneal musculature did not undergo surgery but survived after receiving antimicrobial therapy and intensive supportive care. Both immunocompetent patients with myonecrosis had detectable IgG to alpha toxin by immunoblot analysis. IgG to alpha toxin was not detected in the four immunocompetent patients who had C. septicum bacteremia but who did not have myonecrosis or in the AIDS patient with myonecrosis. Therefore, humoral responses to alpha toxin during C. septicum infection may be related to the host's clinical syndrome and immune status.

Adult↗

PubMed1994

Seminal white blood cells and recurrent abortion.

The incidence of leukocytospermia (> 1 million white blood cells/ml semen) and concentrations of white blood cell populations in semen from men whose partners experience unexplained recurrent spontaneous abortion by conventional testing criteria are described and compared to those of men whose partners have normal reproductive histories. Comparable seminal granulocyte and total white blood cell concentrations between groups suggest that couples with unexplained recurrent abortion do not have an abnormally high incidence of subclinical genital tract infections for which leukocytospermia could serve as a marker. However, a significantly higher prevalence of elevated CD4+ and CD8+ T lymphocyte concentrations in semen from men whose partners have cellular immunity to sperm antigens (i.e. produce embryotoxic factors in response to sperm antigen stimulation) warrants further investigation.

Abortion, Habitual↗

PubMed1994

Use of the translational mobility of a plasma membrane protein to assess fertilization of mouse oocytes and viability of mouse zygotes and two-cell embryos.

The fluorescence photobleaching recovery (FPR) technique was used to measure the translational mobility of a glycoprotein recognized by the monoclonal antibody (mAb) S75 in plasma membranes of mouse oocytes, zygotes, and two-cell embryos. Glycoprotein fractional mobility (f) was significantly decreased in membranes of unfertilized oocytes compared to zygotes or two-cell embryos (f values, 46 +/- 2 and 65 +/- 2%, respectively; p < 0.0001). Reduced apparent glycoprotein mobility was also observed in morphologically degenerated zygotes and two-cell embryos compared to viable zygotes and two-cell embryos (f values, 8 +/- 1 and 60 +/- 3%, respectively; p < 0.0001). These results indicate that the FPR technique can be used to assess oocyte fertilization and preimplantation embryonic viability. This method may be useful in the evaluation of embryonic viability following in vitro fertilization and in the detection of toxic effects of novel compounds on embryonic development.

Animals↗

PubMed1994

Characterization of T lymphocytes and antigen-presenting cells in the murine male urethra.

The male lower urogenital tract is exposed to sexually transmitted pathogens and is therefore a strategic site of immune defense. To further define the immunodynamics of this region, we studied the histology, immune cell distribution, and draining lymph nodes of the murine male lower urogenital tract. The external surface of the foreskin was covered by skin composed of keratinized stratified epithelium containing numerous hair follicles and sebaceous glands. Immunologically the penile foreskin was characterized by the presence of few T lymphocytes and macrophages. Numerous Langerhans cells, however, were detected within the epithelium. The penile urethra was composed of stratified columnar epithelium, with a meatus lined by keratinized squamous epithelium preceding the opening proper. The most abundant immune cells of the penile urethra were macrophages. In young adult, virgin males, these were found primarily underlying the urethral epithelium, but in older, mated mice, they were usually intraepithelial in location, and were more abundant. Langerhans cells could not be specifically identified in the urethral mucosa. T lymphocytes were found underlying and occasionally within the epithelium of the urethral mucosa, with CD4+ cells more abundant than CD8+ cells. The majority of lymphocytes observed around the urethra were positive for the integrin beta 7 alpha M290, which is selectively expressed by mucosal lymphocytes, providing indirect evidence that the urethra is part of the common mucosal system. Lymphocytes expressing the gamma delta T cell receptor and IgA-positive plasma cells were not detected. The primary draining nodes for the vas deferens and urethra were the lumbar nodes. Lymphatic drainage from the rectum also involved the lumbar nodes. Information obtained in this study should help to elucidate optimal genital tract vaccination strategies for defense of the male urogenital tract against sexually transmitted pathogens.

Animals↗

PubMed1994

Stem cells and transcription factors in the development of the mammalian neural crest.

The neural crest is a migratory population of multipotent embryonic cells that generates the neurons and glia of the peripheral nervous system, as well as a variety of non-neural mesectodermal and endocrine cell types. The study of neural crest cell and molecular biology provides a system to investigate how such multipotent cells choose their fates, and whether the repertoire of fates becomes progressively restricted with time. The study of mammalian neural crest development has lagged behind studies of avian crest development due to the relative inaccessibility of mammalian embryos. The development of reverse genetic methods in mice, however, has made the analysis of mammalian neural crest development both more attractive and more tractable. Rodent neural crest cells have been isolated and grown in clonogenic cultures, where they behave as multipotent stem cells. This system provides an assay for factors that influence the differentiation of these multipotent cells. Transcription factors provide valuable early markers for neural crest cells as well as molecular handles on the lineage segregation process. One such factor is Mash1, a homolog of the Drosophila proneural genes, achaete-scute. Mash1 marks autonomic progenitor cells and is essential for their development in vivo, as shown by gene knockout experiments.

Animals↗

PubMed1994

Silicon ribbon cables for chronically implantable microelectrode arrays.

This paper describes the design, fabrication, and testing of miniature ultraflexible ribbon cables for use with micromachined silicon microprobes capable of chronic recording and/or stimulation in the central nervous system (CNS). These interconnects are of critical importance in reliably linking these microelectrodes to the external world through a percutaneous connector. The silicon cables allow the realization of multilead, multistrand shielded local interconnects that are extremely flexible and yet strong enough to withstand normal handling and surgical manipulation. Cables 5 microns thick, 1-5 cm long, and from 60 to 250 microns wide have been fabricated with up to eight leads. The series lead resistance is typically 4 k omega/cm for polysilicon and 500 omega/cm for tantalum, with shunt capacitance values of 5-10 pF/cm and an interlead capacitance below 10 fF/cm. Soak tests in buffered saline performed under electrical and mechanical stress have been underway for over three years and show subpicoampere leakage levels. Silicon microprobes with built-in ribbon cables have remained functional for up to one year in the guinea pig CNS, recording driven single-unit activity and maintaining impedance levels in the 1-7 M omega range.

Animals↗

PubMed1994

Effect of dexamethasone treatment on the biotransformation of glyceryl trinitrate: cytochrome P450 3A1 mediated activation of rat aortic guanylyl cyclase by glyceryl trinitrate.

It is generally accepted that organic nitrates act via vascular biotransformation to an activator of guanylyl cyclase (presumably NO), resulting in increased cyclic GMP accumulation and vascular smooth muscle relaxation. Previously, we have shown that cytochrome P450 can mediate the biotransformation of glyceryl trinitrate (GTN) and that at least a portion of this biotransformation results in the formation of an activator of guanylyl cyclase. To assess the role of the cytochrome P450 3A subfamily in this phenomenon, we treated male and female rats with dexamethasone (DEX) (150 mg/kg, i.p., daily for 3 days). Under anerobic conditions, hepatic microsomal biotransformation of GTN was increased three-fold in DEX-treated male rats compared with all other treatment groups. Incubation of aortic 100,000 x g supernatant fraction from untreated rats (as a source of guanylyl cyclase) with GTN and hepatic microsomes from all groups resulted in concentration-dependent increases in guanylyl cyclase activation. Microsomes from DEX-treated male and female rats demonstrated a significantly greater activation of guanylyl cyclase compared with microsomes from untreated males and females. Furthermore, GTN-induced guanylyl cyclase activation mediated by microsomes from DEX-treated male and female rats was markedly inhibited by a polyclonal antibody raised to rat CYP3A1. Since CYP3A2 is absent or very low in hepatic microsomes from DEX-treated adult female rats, this identifies CYP3A1 as an isoform capable of biotransforming GTN to an activator of guanylyl cyclase. Similarly, CYP2C11 was identified as an isoform capable of biotransforming GTN to an activator of guanylyl cyclase, since monoclonal antibody to CYP2C11 inhibited GTN-induced activation of guanylyl cyclase mediated by microsomes from control male rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Cytokine regulation of trophoblast steroidogenesis.

Activated monocytes and lymphocytes secrete cytokines that act as autocrine and paracrine mediators to promote and regulate local immune processes. These cell types are abundant at the maternal-fetal interface, and cytokines may play a role in pregnancy maintenance or failure. The purpose of this study was to determine the effects of selected monocyte- and lymphocyte-derived cytokines on trophoblast progesterone and estradiol production. JEG-3 choriocarcinoma cells were cultured in supplemented medium alone or in various concentrations of selected recombinant monocyte or lymphocyte cytokines. The cytokines were evaluated both individually and in combination. After 48 h of incubation, the culture supernatant was aspirated and stored at -20 C. Samples were then analyzed for steroid concentration by specific RIAs. Specific interleukin-1 (IL-1)-and tumor necrosis factor (TNF)-neutralizing antibodies were evaluated for their ability to abrogate the cytokine's observed stimulatory effect. To evaluate the physiological relevance of the progesterone-stimulating effect observed with monocyte-derived cytokines, JEG-3 cells were incubated with activated monocyte supernatant or directly cocultured with activated monocytes, and supernatants from these cultures were analyzed for progesterone levels. The monocyte cytokines [IL-1 alpha (5 U/mL), IL-1 beta (5 U/mL), and TNF alpha (1000 U/mL) significantly stimulated trophoblast progesterone production (nanograms per mL): JEG-3 control, 4.1 +/- 0.5; IL-1 alpha, 7.8 +/- 0.9; IL-1 beta, 8.8 +/- 0.5; and TNF alpha 7.2 +/- 0.8 (P < 0.05). Neither the monocyte nor the lymphocyte cytokines altered trophoblast estradiol production. Activated monocyte supernatant and direct JEG-3-monocyte cocultures also significantly stimulated trophoblast progesterone production in vitro. The stimulatory effect of the monocyte-derived cytokines was specific, as demonstrated by neutralization assay. The increased trophoblast progesterone production was not due to enhanced cellular proliferation, but to enhance cellular steroidogenesis, as measured by quantitative DNA analysis. The lymphocyte cytokines (IL-2, interferon-gamma, and granulocyte-macrophage colony-stimulating factor had no effect on trophoblast progesterone production. We conclude that monocyte IL-1 alpha, IL-1 beta, and TNF alpha may regulate trophoblast progesterone production through paracrine effects. Monocyte-trophoblast interactions may be significant in normal pregnancy as well as pregnancy disorders.

Cell Division↗

PubMed1994

Diagnosis of pulmonary complications associated with lung transplantation in children: value of CT vs histopathologic studies.

OBJECTIVE: The purpose of this study was to compare the CT findings with those of histopathologic studies to determine if CT can be used to differentiate between the pulmonary parenchymal complications that occur in children after lung transplantation. MATERIALS AND METHODS: Seventeen children who underwent 14 bilateral and three single lung transplantations were studied. The study population included nine girls and eight boys 2-16 years old (mean, 11 years). CT scans were examined for evidence of interlobular septal thickening, air-space consolidation, ground-glass opacities, nodules, bronchial dilatation, decreased vascularity, and pleural effusions. Thirty-one histopathologic diagnoses from 25 transbronchial biopsies were available for comparison with CT findings. The final histopathologic diagnoses were acute rejection (n = 10), chronic rejection (n = 6), infection (n = 7), nonspecific findings (n = 4), and no abnormalities (n = 4). RESULTS: No significant difference was noted in the CT findings in patients with acute rejection, chronic rejection, and infection. CONCLUSION: In this limited study of children, CT findings were not helpful in differentiating between the different parenchymal pulmonary complications associated with lung transplantation. On the basis of these preliminary findings, we recommend caution in suggesting specific diagnoses based on CT scans without histologic proof.

Bronchiolitis Obliterans↗

PubMed1994

(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl) isoxazole (ABT 418): a novel cholinergic ligand with cognition-enhancing and anxiolytic activities: I. In vitro characterization.

A diversity of nicotinic acetylcholine receptor (nAChR) subtypes has been identified in mammalian brain using recombinant DNA technology. Alterations in the activity of these acetylcholinegated ion channels have been implicated in a number of central nervous system disorders including Alzheimer's disease (AD). The potential therapeutic usefulness of (-)-nicotine [(S)-3-(1-methyl-2-pyrrolidinyl) pyridine], the prototypic agonist at nAChRs, is severely limited by side effects that are the result of activation of both cholinergic and noncholinergic pathways in the central and peripheral nervous systems. This study sought to determine the in vitro selectivity of (S)-3-methyl-5-(1methyl-2-pyrrolidinyl)isoxazole (ABT 418), a novel analog of (-)-nicotine in which the pyridine ring was replaced with an isoxazole bioisotere, to activate nAChRs. ABT 418 was a potent inhibitor of [3H]-cytisine binding to nAChR in rat brain (Ki = 3 nM) but was inactive (Ki > 10,000 nM) in 37 other receptor/neurotransmitter-uptake/enzyme/transduction system binding assays, including those for alpha-bungarotoxin, muscarinic and 5-hydroxytryptamine3 receptors. In PC12 cells, patch-clamp studies indicated that ABT 418 was an agonist with an EC50 value of 209 microM, a potency to activate cholinergic channel currents some 4-fold less than that of (-)-nicotine (52 microM). Channel current responses elicited by ABT 418 were prevented by the cholinergic channel blocker, mecamylamine. ABT 418 was also approximately 10-fold less potent (EC50 value = 380 nM) than (-)-nicotine (40 nM) in increasing [3H]-dopamine release from rat striatal slices, an effect that was blocked by the nAChR antagonist, dihydro-beta-erythroidine (10 microM).2+ In contrast, ABT 418 appeared equipotent with (-)-nicotine in enhancing 86Rb+ flux from mouse thalamic synaptosomes. ABT 418 demonstrated an in vitro pharmacological profile of cholinergic channel activation that was robust at some nAChR, but not others. The reasons for this are unclear. However, a nAChR subtype selectivity may account for the in vitro potency differences of ABT 418 on various neurotransmitter systems, and the substantial separation between the cognitive enhancement/anxiolytic benefits, and the reduced central nervous system side-effect liabilities seen in vivo. ABT 418 represents the first neuronal nAChR ligand that differentiates the toxicities/liabilities and other negative aspects normally associated with liabilities and other negative aspects normally associated with (-)-nicotine from the potential pharmacological benefits of selective cholinergic channel activation.

Alkaloids↗

PubMed1994

MASH-1: a marker and a mutation for mammalian neural crest development.

The ability to generate mice containing null mutations in any cloned gene promises new insights into the molecular control of mammalian neural crest development. This approach has recently been applied to MASH-1, a transcription factor in the bHLH family that is a mammalian homologue of the Drosophila proneural genes achaete-scute. In wild-type embryos, this gene is expressed early in the development of the autonomic nervous system, in apparent precursors of sympathetic, parasympathetic, and enteric neurons (as well as in restricted regions of the central nervous system). A null mutation in the MASH-1 gene eliminates sympathetic and parasympathetic neurons and enteric neurons of the foregut (esophagus); however, enteric neurons of the stomach and hindgut are only partially affected. Analysis with other markers indicates that the mutation acts after neural crest cells have localized in the anlagen of the autonomic nervous system to prevent neuronal differentiation. The differentiation of autonomic glia appears unaffected. Thus, MASH-1 provides one of the most specific mutations affecting neural development in mammals, as well as a valuable marker to study the early segregation of neural crest cell lineages.

Adrenal Glands↗

PubMed1994

(+/-)-Epibatidine elicits a diversity of in vitro and in vivo effects mediated by nicotinic acetylcholine receptors.

(+/-)-Epibatidine, exo-2-(6-chloro-3-pyridyl)-7-azabicyclo-[2.2.1] heptane, is a novel, potent analgesic agent that acts through nicotinic acetylcholine receptor (nAChR) mechanisms. This study sought to establish whether (+/-)-epibatidine, like (-)-nicotine, also displays a wide diversity of behavioral responses that are known to be elicited by nAChR activation or whether it demonstrates subtype selectivity for its interactions with nAChRs.(+/-)-Epibatidine displaced [3H](-)-cytisine binding to the alpha 4 beta 2 nAChR subtype in rat brain membranes with high affinity (Ki, 43 pM). The compound was approximately 5000-fold less potent (Ki = 230nM) in the displacement of [125I] alpha-bungarotoxin binding from the alpha-bungarotoxin-sensitive nAChR subtype present in rat brain but was a potent inhibitor (Ki, 2.7 nM) of [125I] alpha-bungarotoxin binding to the nAChR subtype in Torpedo electroplax, which is similar to that present in the neuromuscular junction. Functionally, (+/-)-epibatidine enhanced 86Rb+ flux in IMR 32 cells with an EC50 value of 7 nM. It was some 3000-fold more potent than (-)-nicotine (EC50 value, 21,000 nM) and was approximately 150-fold more potent (EC50 value, 0.4 nM) than (-)-nicotine (EC50 value = 60 nM) in increasing [3H]dopamine release from rat striatal slices. Remarkably, (+/-)-epibatidine was 40% to 50% more efficacious than (-)-nicotine in both functional assays. Both functional effects were blocked by the nAChR channel blocker, mecamylamine (100 microM). (+/-)-Epibatidine was 300 to 1000 times more potent than (-)-nicotine in the reduction of body temperature and locomotor activity in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗