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PubMed1999

Increased nicotinic receptors in brains from smokers: membrane binding and autoradiography studies.

Chronic administration of nicotine increases the density of neuronal cholinergic nicotinic receptors in cells and in rodent brain, and similar increases have been reported in brains from human smokers. To further examine this phenomenon, we measured nicotinic receptor binding sites in brain regions from matched populations of smokers and nonsmokers. We first measured binding of [3H](+/-)epibatidine ([3H]EB) and [3H]cytisine in homogenate preparations from samples of prefrontal and temporal cerebral cortex. Binding of each radioligand was significantly higher (250-300%) in both cortical regions from brains of smokers. Frozen sections from each of the cerebral cortical regions and the hippocampus were used for autoradiographic analysis of [3H]EB binding. In cerebral cortex, binding was most dense in layer VI in the prefrontal cortex and layers IV and VI in the temporal cortex. Densitometric analysis of [3H]EB binding sites revealed marked increases of 300 to 400% of control in all cortical regions examined from smokers' brains. Binding in the hippocampal formation was heterogeneously distributed, with dense areas of binding sites seen in the parasubiculum, subiculum, and molecular layer of the dentate gyrus, and the lacunosum-moleculare layer of the CA1/2. Binding of [3H]EB was significantly higher in all six regions of the hippocampus examined from brains of smokers compared with nonsmokers. These increases ranged from 160% of control in parasubiculum to 290% in the molecular layer of the dentate gyrus. The increase in nicotinic receptors in the cerebral cortex and hippocampus of smokers may modify the central nervous system effects of nicotine and contribute to an altered response of smokers to nicotine.

Adult↗
PubMed1999

kappa-Opioid receptor effects of butorphanol in rhesus monkeys.

Butorphanol and nalbuphine have substantial affinity for mu and kappa-opioid receptor sites, yet their behavioral effects in monkeys are largely consistent with a mu receptor mechanism of action. Using ethylketocyclazocine (EKC) discrimination and diuresis assays in rhesus monkeys (Macaca mulatta), the purpose of the current investigation was to characterize the in vivo kappa-opioid activity of these compounds through the use of an insurmountable mu-opioid receptor antagonist, clocinnamox. Alone, butorphanol (0.001-0.032 mg/kg i.m.) failed to generalize to EKC, and pretreatment with the competitive opioid receptor antagonist quadazocine (0.1 or 0.32 mg/kg i.m.) did not alter this generalization. At 24 h after clocinnamox (0.1 mg/kg i.m.) administration, butorphanol fully generalized to EKC, and this generalization was maintained in two of three monkeys at 72 h. Parallel results were observed in diuresis: butorphanol alone and in the presence of quadazocine (1 mg/kg i.m.) did not alter urine output, and a marked diuretic effect was demonstrated 24 h to 2 weeks after clocinnamox administration. Clocinnamox did not alter the discriminative stimulus or diuretic effects of nalbuphine or of the kappa-opioid receptor agonists EKC or U69593. These results are consistent with an in vivo agonist activity of butorphanol at kappa-opioid receptors that can only be demonstrated when an insurmountable antagonist has substantially eliminated the dominant receptor population through which it exerts its action.

Analgesics, Opioid↗
PubMed1999

Effects of systemically administered dynorphin A(1-17) in rhesus monkeys.

The effects of i.v. dynorphin A(1-17) and its main nonopioid biotransformation fragment, dynorphin A(2-17), were compared in rhesus monkeys with those of the selective kappa-opioid agonist, U69, 593, in assays of operant behavior, thermal antinociception, and neuroendocrine function (prolactin release). Dynorphin A(1-17) (0. 1-3.2 mg/kg i.v.) and U69,593 (0.001-0.032 mg/kg s.c.) decreased rates of schedule-controlled (fixed ratio 20) food-reinforced responding, whereas dynorphin A(2-17) (1-3.2 mg/kg i.v.) was ineffective. Pretreatment studies with the opioid antagonist quadazocine (0.32 mg/kg s.c.) revealed that the operant effects of dynorphin A(1-17) were not mediated by kappa- or micro-opioid receptors. A different profile was observed in the warm water tail withdrawal assay of thermal antinociception, where both dynorphin A(1-17) and A(2-17) (0.032-3.2 mg/kg i.v., n = 4) were modestly effective in 50 degrees C water, and both were ineffective in 55 degrees C water. By comparison, U69,593 (0.032-0.18 mg/kg s.c.) was maximally effective in 50 degrees C water and partially effective in 55 degrees C. kappa-opioid agonists increase serum levels of prolactin in animals and humans. Dynorphin A(1-17) (ED(50) = 0.0011 mg/kg i.v.), similar to U69,593 (ED(50) = 0.0030 mg/kg i.v.), was very potent in increasing serum prolactin levels in follicular phase female rhesus monkeys, whereas dynorphin A(2-17) (0.32 mg/kg i.v.) was ineffective. The effects of dynorphin A(1-17) and U69,593 on serum prolactin were both antagonized by quadazocine (0.32 mg/kg s.c.) in a surmountable manner, consistent with opioid receptor mediation. The present studies show that serum prolactin levels are a sensitive quantitative endpoint to study the systemic effects of the endogenous opioid peptide, dynorphin A(1-17), in primates.

Analgesics, Opioid↗
PubMed1999

Discriminative stimulus effects of the nonpeptidic delta-opioid agonist SNC80 in rhesus monkeys.

Five rhesus monkeys were trained to discriminate the nonpeptidic, delta-opioid agonist SNC80 (0.32 mg/kg i.m.) from saline by using a food-reinforced drug-discrimination procedure. Cumulative doses of SNC80 produced a dose-dependent increase in SNC80-appropriate responding and a dose-dependent decrease in response rate. In time-course studies, peak effects of the training dose of SNC80 were observed after 15 min, and these effects diminished over 240 min. In substitution studies, other piperazinyl benzamide delta agonists (SNC86, SNC162, and SNC243A) substituted for SNC80 with relative potencies similar those of SNC80. However, SNC67, the (-)-enantiomer of SNC80, did not occasion SNC80-appropriate responding up to a dose (32.0 mg/kg) that produced convulsions in one monkey. The mu agonists morphine and fentanyl and the kappa agonists U-50,488 and enadoline failed to substitute for SNC80 up to doses that eliminated responding. Two nonopioids (the N-methyl-D-aspartate antagonist ketamine and the monoamine reuptake inhibitor cocaine) also produced primarily saline-appropriate responding. Both the discriminative stimulus and rate-decreasing effects of SNC80 were antagonized by the delta-selective antagonist naltrindole (0.01-1.0 mg/kg) but not by doses of the opioid antagonist quadazocine (0.1-1.0 mg/kg) that block the effects of mu and kappa agonists. These data suggest that the discriminative stimulus effects of SNC80 are mediated by delta-opioid receptors and that the discriminative stimulus effects of delta opioids in primates can be differentiated from the effects of other opioid and nonopioid compounds.

Analgesics, Opioid↗
PubMedDate not supplied

[Cytisine pharmacokinetics when used in a transdermal therapeutic system in rabbits].

Experimental study of pharmacokinetics of transdermal system with cytisin in rabbits showed a possibility of controlled intake of the drug over a 4-day period. The two stages of attaining the stationary levels of cytisin concentrations are revealed. The first stage lasted during first 24h and the second stage during succeeding 3 days. Using the data on intravenous cytisin injection we found that the stationary concentrations and the rate of cytisin intake in the first stage is twice as large as in the second stage. Thus cytisin can be classed as a short-living drug.

Administration, Cutaneous↗
PubMed2000

[Antibacterial and antineoplastic activity of 2,4-disubstituted 6H-5,1,3-benzothiadiazocines].

Nine 2,4-disubstituted 6H-5,1,3-benzothiadiazocines have been tested for antibacterial and cytotoxic efficacy. None of the tested compounds showed any significant antibacterial activity in comparison with ampicillin. The most cytotoxic effect was manifested by those derivatives which have morpholine or phenyl in position 2 and benzimidazole, imidazole or 1,2,4-triazole in position 4. The highest concentrations of derivatives I, VII, IX induced an acute cytotoxic effect which was manifested by cell lysis after 24 h of culturing. Derivative VII, concentration 30.5 mumol/L, and derivative IX, concentration 13.3 mumol/L, exhibited a delayed cytotoxic effect on L1210 cells. While during the first 24 and 48 h a certain part of cell population proliferated, during further 24 h a total inhibition of cell division was found. The cytotoxic concentration of derivative IX induced damage to the integrity of the cytoplasmic membrane. Benzothiadiazocines I, VII and IX induced a two-phase unbalanced growth. Based on these results, benzothiodiazocines I, VII and IX could be considered new potential anticancer drugs which are appropriate for further research.

Anti-Bacterial Agents↗
PubMed2000

Phenotypic characterization of an alpha 4 neuronal nicotinic acetylcholine receptor subunit knock-out mouse.

Neuronal nicotinic acetylcholine receptors (nAChR) are present in high abundance in the nervous system (Decker et al., 1995). There are a large number of subunits expressed in the brain that combine to form multimeric functional receptors. We have generated an alpha(4) nAChR subunit knock-out line and focus on defining the behavioral role of this receptor subunit. Homozygous mutant mice (Mt) are normal in size, fertility, and home-cage behavior. Spontaneous unconditioned motor behavior revealed an ethogram characterized by significant increases in several topographies of exploratory behavior in Mt relative to wild-type mice (Wt) over the course of habituation to a novel environment. Furthermore, the behavior of Mt in the elevated plus-maze assay was consistent with increased basal levels of anxiety. In response to nicotine, Wt exhibited early reductions in a number of behavioral topographies, under both unhabituated and habituated conditions; conversely, heightened levels of behavioral topographies in Mt were reduced by nicotine in the late phase of the unhabituated condition. Ligand autoradiography confirmed the lack of high-affinity binding to radiolabeled nicotine, cytisine, and epibatidine in the thalamus, cortex, and caudate putamen, although binding to a number of discrete nuclei remained. The study confirms the pivotal role played by the alpha(4) nAChR subunit in the modulation of a number of constituents of the normal mouse ethogram and in anxiety as assessed using the plus-maze. Furthermore, the response of Mt to nicotine administration suggests that persistent nicotine binding sites in the habenulo-interpeduncular system are sufficient to modulate motor activity in actively exploring mice.

Aggression↗
PubMed2000

Measurement of alpha4beta2 nicotinic acetylcholine receptors with [123I]5-I-A-85380 SPECT.

UNLABELLED: Nicotinic acetylcholine receptors (nAChRs) play an important role in tobacco dependence and a potential therapeutic role in neuropsychiatric disorders such as Alzheimer's disease. [123I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) is a new SPECT tracer that labels alpha4beta2 nAChRs. The purpose of this study was to assess the usefulness of this tracer to measure regional nAChR binding in baboon brain using both a bolus/kinetic paradigm and also a bolus plus constant infusion/equilibrium paradigm. METHODS: A pair of bolus/kinetic and bolus plus constant infusion/equilibrium studies was performed in each of 3 isoflurane-anesthetized baboons. Bolus studies were performed by intravenous injection of 191-226 MBq [123I]5-I-A-85380 and image acquisition for 289-367 min. The data were analyzed with 1- and 2-tissue compartment models. Bolus plus constant infusion/equilibrium studies were performed by a bolus injection (74-132 MBq) followed by a 468- to 495-min infusion with a bolus/infusion ratio (B/I) of 4.8-5.0 h. The distribution volumes in the thalamus were measured in these 2 paradigms. To study whether the cerebellum was appropriate as a receptor-poor region, displacement studies were done in 2 baboons using the B/I paradigm with subcutaneous injection of (-)-cytisine (0.8 and 1.0 mg/kg). RESULTS: The kinetics of this tracer was best described by the 1-tissue compartment model. The 2-compartment model showed poor identifiability of rate constants. The total (specific plus nondisplaceable compartments) distribution volumes (V(T)') agreed between bolus and B/I paradigms (average percentage difference in V(T)', 16.8%). (-)-Cytisine (0.8 and 1.0 mg/kg) displaced 70% and 72% of the radioactivity in the thalamus and 36% and 55% in the cerebellum, respectively, indicating that the latter was not appropriate as a receptor-poor region. CONCLUSION: These results show the feasibility of quantifying alpha4beta2 nAChRs using [123I]5-I-A-85380 and support the use of V(T)' as an appropriate outcome measure.

Alkaloids↗
PubMed2000

Different effect of the Ca(2+) sensitizers EMD 57033 and CGP 48506 on cross-bridge cycling in human myocardium.

Ca(2+) sensitizers may be advantageous for treatment in human heart failure by increasing cardiac force without increasing the Ca(2+) transient or energy consumption. To study the mode of action of the Ca(2+) sensitizers EMD 57033 (EMD) and CGP 48506 (CGP), their influence on butanedione monoxime (BDM)-mediated depression of cross-bridge cycling was analyzed in human myocardium (explanted hearts, dilated cardiomyopathy, n = 19). In Triton X (1%)-skinned fiber preparations of left ventricular myocardium from patients suffering from dilated cardiomyopathy, troponin I was extracted by vanadate (10 mM) treatment, resulting in a Ca(2+)-independent contraction. In troponin I-depleted fibers BDM (5-50 mM) was applied in the absence and presence of EMD (10 microM) or CGP (10 microM). To analyze the influence on cross-bridge kinetics, tension cost (ratio of ATPase activity and tension development) was studied. BDM exerted a dose-dependent force inhibition in troponin I-depleted fibers (IC(50) = 7.22 mM), which was antagonized by EMD (IC(50) of BDM + EMD = 19.97 mM) and CGP (IC(50) of BDM + CGP = 15.30 mM). EMD increased Ca(2+) sensitivity of force and maximal force in Triton X-skinned fibers. The Ca(2+)-sensitizing effect of CGP was accompanied by an increased Ca(2+) sensitivity of myosin-ATPase activity, an increased slope of the Ca(2+) force and Ca(2+) ATPase curve, as well as a reduced maximal myosin ATPase activity. CGP and EMD reduced tension cost. In conclusion, EMD and CGP antagonize the BDM-mediated relaxation in troponin I-depleted cardiac muscle fibers. The Ca(2+)-sensitizing effect of CGP seems to be dependent on an improvement of the myofilament cooperativity, whereas EMD seems to operate by increasing the force per cross-bridge.

Adult↗
PubMed2001

Effect of nicotine on cerebellar granule neuron development.

To assess the role of nicotinic cholinergic receptors (nAChR) on neuronal maturation, nAChR expression and the direct effects of nAChR activation were examined in cerebellar external granular layer (EGL) precursors isolated in vitro. Treatment of EGL neuroblasts with nicotine elicited a concentration-dependent increase in DNA content and synthesis, implying an increase in cell numbers. Pretreatment of cultures with the nAChR antagonist dihydro-beta-erythroidine (DHBE) attenuated nicotine-induced changes in DNA abundance and synthesis. Furthermore, chronic nicotine treatment for 4-7 days promoted EGL cell survival. Epibatidine but not cytisine stimulated granule neuroblast DNA synthesis and survival. Survival effects mediated by nicotine and epibatidine were attenuated by pretreating cultures with DHBE. Immunocytochemical analysis revealed that EGL neurons possessed alpha3, but not alpha4, nAChR immunoreactivity. Quantitative autoradiography was used to determine which nAChRs are present during the period of granule cell neurogenesis in vivo. On postnatal day 5, the EGL was intensely labelled by [3H]-epibatidine but virtually devoid of [3H]-A85380 binding, suggesting that a high concentration of alpha3 AChRs is present in granule neuroblasts. The pharmacology of [3H]-epibatidine displacement from EGL neurons also suggested an interaction with the alpha3-nAChR subunits. Together these data provide novel evidence that the activation of nAChRs directly affect the development of primary cerebellar neuroblasts and further suggest that the effects are mediated through the alpha3-nAChR subtype.

Alkaloids↗
PubMed1975

Tumor induction in rats by feeding heptamethyleneimine and nitrite in water.

Groups of 15 males and 15 females Sprague-Dawley rats were given 20 ml of drinking water solution containing either 0.2% heptamethyleneimine hydrochloride or this salt together with 0.2% sodium nitrite, 5 days a week for 28 weeks. Another group of 17 male and 30 female rats was given 0.2% sodium nitrite solution for 104 weeks. Most of the animals given heptamethyleneimine hydrochloride or sodium nitrite alone survived 2 years or more after the beginning of the treatment, and no tumors attributable to the treatment were seen at death; tumors appearing were those of endocrine origin found commonly in untreated controls. In the group receiving the combined treatment, most females were dead at 50 weeks and most males were dead at 80 weeks, 27 of 30 having tumors not seen in either control group. A total of 16 had squamous carcinomas in the lung; 25 had tumors of the oropharynx, tongue, esophagus, and forestomach; and there were a few animals with tumors in the nasal cavity and trachea. The expericment showed that squamous tumors of the lung could be induced by ingestion an amine and sodium nitrite.

Animals↗
PubMed2001

Toxicity of sediment-associated nitroaromatic and cyclonitramine compounds to benthic invertebrates.

The toxicity of nitroaromatic (2,4-diaminonitrotoluene [2,4-DANT] and 1,3,5-trinitrobenzene [TNB]) and 14C-labeled cyclonitramine compounds (hexahydro-1,3,5-trinitro-1,3,5-triazine [RDX] and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine [HMX]) to the marine polychaete Neanthes arenaceodentata and the estuarine amphipod Leptocheirus plumulosus following 10- or 28-d exposures to spiked sediments was investigated. Organismal-level effects on survival, growth, and reproduction and cellular-level effects on apoptosis (programmed cell death) were evaluated. Because cyclonitramines have low affinity for sediment, overlying water was not exchanged in the RDX and HMX exposures. Nitroaromatics sorbed strongly to sediment, resulting in near complete resistance to solvent extraction. Cyclonitramines sorbed weakly to sediment, as more 14C-activity was found in the overlying water than in the sediment at exposure termination. No significant decrease in survival or growth was observed with cyclonitramines at initial sediment concentrations as high as 1,000 microg/g. Survival was significantly affected by nitroaromatics at nominal sediment concentrations as low as 200 microg/g, with L. plumulosus being more sensitive than N. arenaceodentata. Growth was significantly decreased at sublethal concentrations of 2,4-DANT for N. arenaceodentata. Reproduction, measured only with L. plumulosus, was significantly decreased only in the highest RDX treatment and also in the lower TNB treatment. However, no decrease was observed in higher concentrations of TNB. Body burden at exposure termination was below detection limit (1 microg/kg) for all compounds. Significant inhibition of apoptosis was not accompanied by significant decreases in growth or reproduction. Because of its critical function in many biological processes. alterations in this endpoint may result in adverse effects on the organism and could be used as an early indicator of toxicity.

Animals↗
PubMed2002

Distribution and pharmacology of alpha 6-containing nicotinic acetylcholine receptors analyzed with mutant mice.

The alpha6 subunit of the nicotinic acetylcholine receptor (nAChR) is expressed at very high levels in dopaminergic (DA) neurons. However, because of the lack of pharmacological tools selective for alpha6-containing nAChRs, the role of this subunit in the etiology of nicotine addiction remains unknown. To provide new tools to investigate this issue, we generated an alpha6 nAChR knock-out mouse. Homozygous null mutants (alpha6-/-) did not exhibit any gross neurological or behavioral deficits. A careful anatomic and molecular examination of alpha6-/- mouse brains demonstrated the absence of developmental alterations in these animals, especially in the visual and dopaminergic pathways, where the alpha6 subunit is normally expressed at the highest levels. On the other hand, receptor autoradiography revealed a decrease in [3H]nicotine, [3H]epibatidine, and [3H]cytisine high-affinity binding in the terminal fields of retinal ganglion cells of alpha6-/- animals, whereas high-affinity [125I]alpha-conotoxinMII (alphaCtxMII) binding completely disappeared in the brain. Moreover, inhibition of [3H]epibatidine binding on striatal membranes, using unlabeled alphaCtxMII or cytisine, revealed the absence of alphaCtxMII-sensitive and cytisine-resistant [3H]epibatidine binding sites in alpha6-/- mice, although the total amount of binding was unchanged. Because alphaCtxMII, a toxin formerly thought to be specific for alpha3beta2-containing nAChRs, is known to partially inhibit nicotine-induced dopamine release, these results support the conclusion that alpha6 rather than alpha3 is the partner of beta2 in the nicotinic modulation of DA neurons. They further show that alpha6-/- mice might be useful tools to understand the mechanisms of nicotine addiction, although some developmental compensation might occur in these mice.

Alkaloids↗
PubMed2002

Toxicity of the explosives 2,4,6-trinitrotoluene, hexahydro-1,3,5-trinitro-1,3,5-triazine, and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine in sediments to Chironomus tentans and Hyalella azteca: low-dose hormesis and high-dose mortality.

The toxicity of the explosives 2,4,6-trinitrotoluene (TNT); hexahydro-1,3,5-trinitro-1,3,5-triazine (royal demolition explosive [RDX]); and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (high-melting explosive [HMX]), was evaluated in spiked sediment with two freshwater invertebrates. The midge Chironomus tentans and the amphipod Hyalella azteca demonstrated significant toxic effects after exposure to TNT and its degradation products, 1,3,5-trinitrobenzene (TNB) and 2,4-diamino-6-nitrotoluene (2,4-DANT). Significant reductions in survival of C. tentans exposed to TNT, TNB, and 2,4-DANT were observed at nominal sediment concentrations as low as 200 mg/kg. Hyalella azteca was more sensitive to TNT, TNB, and 2,4-DANT than the midge, where significant reductions in survival were observed at nominal concentrations of 50, 100, and 200 mg/kg, respectively. Survival of the midge and the amphipod was unaffected after exposure to RDX or HMX at the highest concentrations of 1,000 and 400 mg/kg, respectively. Growth of the midge, measured as total weight, was significantly reduced by 2,4-DANT. However, significantly increased growth was observed after exposure to sublethal concentrations of RDX and HMX. Although significant reductions in amphipod survival were observed at high concentrations of TNB, growth was significantly increased at sublethal concentrations. The results of the current investigation suggest that organisms exposed to explosives at contaminated sites may be affected at concentrations less than 25 mg/kg through hormetic growth enhancement and at higher concentrations through increased mortality.

Amphipoda↗