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At least 181 records · Page 10Linked to original sources
PubMed1985

Motor dysfunction after spinal cord injury is mediated by opiate receptors.

Naloxone, an opiate receptor antagonist, improves neurological outcome following traumatic cervical spinal cord injury in the cat and ischemic lumbar spinal cord injury in the rabbit. However, the doses of naloxone required have been quite high (greater than 1 mg/kg), suggesting that its beneficial actions are either not opiate receptor mediated or mediated by non-mu opiate receptors (which are less naloxone-sensitive). The kappa receptor appears to be the predominant opiate receptor in the spinal cord in a variety of species. For these reasons we evaluated the effects of a somewhat kappa selective opiate receptor antagonist WIN44,441-3 [WIN(-)] on neurological recovery following traumatic spinal injury in the cat and ischemic spinal injury in the rabbit. Animals treated with this more selective antagonist showed improved motor recovery as compared with animals treated with either physiological saline or with the dextroisomer of the WIN compound [WIN44,441-2; WIN(+)]. These findings support the hypothesis that motor dysfunction after spinal cord injury is in part mediated by opiate receptors and indicate that kappa selective opiate receptor antagonists may have particular therapeutic utility in spinal cord injury.

Animals↗
PubMed1994

Distribution of neuronal nicotinic receptor subunits in human brain.

Neuronal nicotinic acetylcholine receptors (nAchRs) are multimeric proteins constituted of two different subunits, alpha and beta, with different subtypes arrangement and different pharmacological and functional properties. nAchRs mediate neurotransmission in many central and peripheral synapses and appear to be affected in human degenerative disorders. We have studied the distribution of nAchR in human brain, particularly in the hippocampus and thalamus, by binding of 3H-nicotine and 3H-cytisine and by in situ hybridization with human alpha 3 and beta 2 nAchR subunits of mRNA. An alpha 3 probe shows a strong hybridization signal in the thalamus, while a beta 2 probe has a good signal at the level of the enthorinal cortex, hippocampus and in caudate and putamen. The alpha 3 and beta 2 mRNA localization is different from that described in other species. 3H-nicotine and 3H-cytisine binding were very similar in terms of anatomical distribution and comparable to the binding described in other animal species. The binding of the two ligands was distributed over the areas labeled by the alpha 3 and beta 2 probes and did not completely overlap with either of the subunits.

Alkaloids↗
PubMed1983

Morphine exacerbates anaphylactic shock in mice by stimulating central opiate receptors.

Intravenous (i.v.) administration of 25 mg/kg morphine significantly increased mortality following induction of systemic anaphylaxis in mice. This effect was blocked by pretreatment with the opiate antagonist naltrexone but not by the selective peripherally acting antagonist naltrexone methyl bromide. Additionally, the effect of i.v. morphine was blocked by the opiate antagonist Win 44,441-3, but not by its inactive (+)-isomer Win 44,441-2. Furthermore, intracerebroventricular (i.c.v.) administration of 25 micrograms morphine increased anaphylactic mortality. This effect was blocked by i.v. naloxone. Finally, the effect of i.v. morphine, 25 mg/kg, on anaphylactic mortality was reversed by i.c.v. naloxone. Collectively, these findings demonstrate that morphine can exacerbate anaphylactic shock reactivity by stimulating specific CNS opiate receptors. The role of endogenous opiate mechanisms in the pathogenic sequence of circulatory shock is discussed.

Anaphylaxis↗
PubMed1987

[3H]acetylcholine nicotinic recognition sites in human brain: characterization of agonist binding.

In the presence of a cholinesterase inhibitor to prevent hydrolysis and atropine to block muscarinic cholinergic receptors, [3H]acetylcholine ([3H]ACh) binding to human brain membranes showed highest levels of nicotinic binding sites in the thalamus. [3H]ACh, in the presence of atropine, binds to heterogeneous high-affinity binding sites in human thalamus. Scatchard analysis of the binding gave a Kd of 0.58 nM and a Bmax of 3.3 pmol/g protein for the 'super high-affinity' site and a Kd of 27 nM and a Bmax of 70 pmol/g protein for the 'high-affinity' site. Moreover, in competition studies nicotinic agonists such (-)-nicotine and carbachol displaceable [3H]ACh-specific binding sites consist of both a high- and a low-affinity population of sites. These results indicate that highest levels of [3H]ACh binding in human brain were found in the thalamus. Moreover, the human thalamus was found to have multiple high-affinity nicotinic agonist sites.

Acetylcholine↗
PubMed1992

Pharmacological properties of the homomeric alpha 7 receptor.

The pharmacological properties of the alpha-bungarotoxin sensitive alpha 7 neuronal nicotinic acetylcholine receptor (nAChR) were studied upon reconstitution in Xenopus oocytes. Channels formed by alpha 7 are about 10-fold more sensitive to nicotine and cytisine than to ACh but are little, if at all, activated by the ganglionic agonist 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP). Tubocurarine (TC) was found to act as a non-competitive inhibitor, whereas dihydro-beta-erythroidine (DH beta E) behaves as a pure competitive inhibitor whose blockade is fast and fully reversible. In addition, the alpha 7 receptor displays a poor sensitivity to methonium salts. The pharmacological properties of the alpha 7 channels are readily distinguishable from those of other identified neuronal nicotinic receptors.

Acetylcholine↗
PubMed1993

Identification and functional significance of nicotinic cholinergic receptors in the rat pineal gland.

The existence and subunit identification of the nicotinic cholinergic receptors in the rat pineal gland were examined by autoradiography, using [3H]cytisine and [125I]alpha-bungarotoxin as labelled ligands. The experiments performed with radioactive cytisine did not reveal specific binding, while iodinated alpha-bungarotoxin disclosed moderate specific binding density, suggesting that the nicotinic cholinergic receptor in the rat pineal is structurally organized with the alpha 7 or alpha 8 subunits present, the only ones that bind alpha-bungarotoxin with high affinity. In vitro functional experiments using pineal explants demonstrated that the binding site may represent a readily accessible nicotinic cholinergic receptor. Nicotine, though having no effect per se on the synthesis and release of melatonin, significantly diminished, in a dose-dependent manner, the norepinephrine-stimulated melatonin accumulation. This effect could be blocked by coincubation with the cholinergic antagonist d-tubocurarine, suggesting that the nicotinic cholinergic receptor in the rat pineal could be involved in the functional regulation of the gland.

Alkaloids↗
PubMed1995

The effect of cholinoceptor agonists and neurotoxins on the release of vasopressin in the rat in relation to the subunit composition of the cholinoceptor.

The effects of cholinoceptor agonists and neurotoxins on the release of vasopressin and oxytocin have been investigated in water-loaded rats under ethanol anaesthesia. Release of vasopressin was monitored by antidiuretic responses accompanied by increased urinary excretion of vasopressin. The rate of excretion of oxytocin-like radioimmunoreactivity was measured as an indicator of oxytocin release. Both nicotine and cytisine caused a preferential release of vasopressin. The release by nicotine was not inhibited by alpha- or neuronal-bungarotoxin. Neosurugatoxin blocked the release by cytisine. Comparison with the effects of these agents on combinations of alpha and beta subunits expressed in oocytes suggests that the central cholinoceptors mediating release of vasopressin are similar to those at autonomic ganglia and may contain a beta 4 subunit.

Alkaloids↗
PubMed1995

Nicotine increases intracellular calcium in rat hippocampal neurons via voltage-gated calcium channels.

The effect of nicotinic receptor activation on intracellular calcium concentrations ([Ca2+]i) was quantitated in populations of cultured hippocampal neurons loaded with Fura-2. Nicotine (50 microM) and cytisine (50 microM) increased [Ca2+]i by 100%. This response was abolished in the presence of the nicotinic antagonist methyllycaconitine (MLA) whereas KCl-evoked increases in [Ca2+]i were insensitive to MLA. Glial cultures were unaffected by nicotine, although they did respond to glutamate with increased [Ca2+]i. In hippocampal neurons, responses to nicotinic agonists and KCl were dependent on the presence of extracellular Ca2+ and were similarly sensitive (85% inhibition) to CdCl2. These results are consistent with the presence of functional nicotinic receptors on hippocampal neurons. The receptors appear to elevate [Ca2+]i by promoting the influx of extracellular Ca2+ through voltage-gated calcium channels.

Aconitine↗
PubMed1994

Effects of chronic nerve growth factor treatment on hippocampal [3H]cytisine/nicotinic binding sites and presynaptic nicotinic receptor function following fimbrial transections.

Recent studies with nerve growth factor (NGF) have identified the pharmacological actions of this neurotrophin in a variety of animal models that mimic some of the neurotransmitter deficits that occur in Alzheimer's disease (AD, for reviews see Refs 7, 15, 17, 19). Based upon extensive pharmacological studies, NGF has been characterized as a crucial maintenance factor for adult cholinergic neurons of the septo-hippocampal and basalo-cortical pathways. Among the reported actions of NGF is an attenuation of lesion-induced decrements in presynaptic and postsynaptic cholinergic markers and functions in the hippocampal formation. Thus, in studies that used partial fimbriectomies to parallel the cholinergic neurodegeneration that occurs in AD, intraventricularly administered nerve growth factor prevented the loss of choline acetyltransferase (ChAT) and acetylcholinesterase immunoreactivity in the septum and increased a variety of presynaptic cholinergic markers involved in the synthesis, storage and release of the neurotransmitter acetylcholine (for reviews see Refs 7, 17, 19). More specifically, chronic NGF treatment attenuates lesion-induced reductions in hippocampal ChAT activity and high-affinity choline uptake, the end-result of which is an enhanced capacity to synthesize acetylcholine. This increased acetylcholine synthesis, in turn, appears to translate directly into augmented vesicular storage and release of the neurotransmitter. For instance, not only does NGF treatment reverse lesion-induced reductions in maximal binding densities of the acetylcholine vesicular transport marker [3H]vesamicol, but it also enhances acetylcholine release and turnover rate. NGF treatment also appears to restore the sensitivity of postsynaptic muscarinic receptors to agonist-induced stimulation following partial fimbriectomies.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗
PubMed1994

Localization of nicotinic cholinergic receptors in rat brain: autoradiographic studies with [3H]cytisine.

There is a great deal of interest in the role of nicotinic acetylcholine receptors in the central nervous system, although their function is not well understood at present. Currently, central nicotinic receptors can be classified broadly as either alpha-bungarotoxin binding sites with low affinity for acetylcholine agonists, or as high-affinity agonist binding sites with low affinity for alpha-bungarotoxin. Neuronal nicotinic receptors with a high affinity for agonists are distributed widely in the central nervous system. Evidence from molecular biology and electrophysiology suggests that multiple nicotinic receptor types exist in the brain. In this study we have used the agonist [3H]cytisine as a ligand for autoradiography to generate a detailed quantitative map of the high-affinity agonist binding nicotinic receptor in the rat brain. Optimized binding conditions, characterization of the kinetic and equilibrium binding properties, and demonstration of the nicotinic pharmacology of this binding site in tissue sections confirm the usefulness of [3H]Cytisine as a ligand for nicotinic receptor autoradiography. [3H]Cytisine autoradiography provides excellent anatomic resolution with very low non-specific binding. This property has allowed us to describe variations in receptor density within subnuclei and gradients of receptor density in larger brain regions. Data from several studies suggest that the predominant high-affinity agonist binding nicotine receptor in the central nervous system is composed of the alpha 4 and beta 2 subunits. The data in the current study are consistent with the suggestion that [3H]cytisine labels only the alpha 4 beta 2 nicotinic receptor with high affinity, offering the possibility of localizing a specific nicotinic receptor subtype in the central nervous system. In summary, we characterize the optimum experimental conditions for the use of [3H]cytisine in tissue section autoradiography. [3H]Cytisine proves to be an excellent marker for nicotinic cholinergic receptors with a very high affinity and very low background. We provide a detailed quantitative characterization of nicotinic receptor density in the rat central nervous system and we find there are significant variations and gradients in receptor density within specific brain regions, including subregions previously thought to be homogeneous.

Alkaloids↗
PubMed1994

In vitro pharmacologic characterization of a cholinergic receptor on outer hair cells.

Acetylcholine (ACh) is the major neurotransmitter released from the efferent fibers in the cochlea onto the outer hair cells (OHCs). The type of ACh receptor on OHCs and the events subsequent to receptor activation are unclear. Therefore we studied the effect of agonists and antagonists of the ACh receptor on isolated OHCs from the guinea pig. OHCs were recorded from in whole cell voltage and current clamp configuration. ACh induced an increase in outward K+ current (IACh) which hyperpolarized the OHCs. No desensitization to ACh application was observed. Cs+ replaced K+ in carrying the IACh. The IACh is Ca(2+)-dependent, time and voltage sensitive, and different from the IKCa induced by depolarization of the membrane potential. When tested at 100 microM, several agonists also induced outward current responses (acetylcholine > suberyldicholine > or = carbachol > DMPP) whereas nicotine, cytisine and muscarine did not. The IACh response to 10 microM ACh was blocked by low concentrations of traditional and non-traditional-nicotinic antagonists (strychnine > curare > bicuculline > alpha-bungarotoxin > thimethaphan) and by higher concentrations of muscarinic antagonists (atropine > 4-DAMP > AF-DX 116 > pirenzepine). Pharmacologically, the ACh receptor on OHCs is nicotinic.

Acetylcholine↗
PubMed1995

Comparative laminar distribution of various autoradiographic cholinergic markers in adult rat main olfactory bulb.

To provide anatomical information on the complex effects of acetylcholine (ACh) in the olfactory bulb (OB), the distribution of different cholinergic muscarinic and nicotinic receptor sub-types was studied by quantitative in vitro autoradiography. The muscarinic M1-like and M2-like sub-types, as well as the nicotinic bungarotoxin-insensitive (alpha 4 beta 2-like) and bungarotoxin-sensitive (alpha 7-like) receptors were visualized using [3H]pirenzepine, [3H]AF-DX 384, [3H]cytisine and [125I] alpha-bungarotoxin (BTX), respectively. In parallel, labelling patterns of [3H]vesamicol (vesicular acetylcholine transport sites) and [3H]hemicholinium-3 (high-affinity choline uptake sites), two putative markers of cholinergic nerve terminals, were investigated. Specific labelling for each cholinergic radioligand is distributed according to a characteristic laminar and regional pattern within the OB revealing the lack of a clear overlap between cholinergic afferents and receptors. The presynaptic markers, [3H]vesamicol and [3H]hemicholinium-3, demonstrated similar laminar pattern of distribution with two strongly labelled bands corresponding to the glomerular layer and the area around the mitral cell layer. Muscarinic M1-like and M2-like receptor sub-types exhibited unique distribution with their highest levels seen in the external plexiform layer (EPL). Intermediate M1-like and M2-like binding densities were found throughout the deeper bulbar layers. In the glomerular layer, the levels of muscarinic receptor subtypes were low, the level of M2-like sites being higher than M1. Both types of nicotinic receptor sub-types displayed distinct distribution pattern. Whereas [125I] alpha-BTX binding sites were mostly concentrated in the superficial bulbar layers, [3H]cytisine binding was found in the glomerular layers, as well as the mitral cell layer and the underlying laminae. An interesting feature of the present study is the visualization of two distinct cholinoceptive glomerular subsets in the posterior OB. The first one exhibited high levels of both [3H]vesamicol and [3H]hemicholinium-3 sites. It corresponds to the previously identified atypical glomeruli and apparently failed to express any of the cholinergic receptors under study. In contrast, the second subset of glomeruli is not enriched with cholinergic nerve terminal markers but displayed high amounts of [3H]cytisine/nicotinic binding sites. Taken together, these results suggest that although muscarinic receptors have been hypothesized to be mostly involved in cholinergic olfactory processing and short-term memory in the OB, nicotinic receptors, especially of the cytisine/ alpha 4 beta 2 sub-type, may have important roles in mediating olfactory transmission of efferent neurons as well as in a subset of olfactory glomeruli.

Alkaloids↗
PubMed2005

Genetic correlation between the free-choice oral consumption of nicotine and alcohol in C57BL/6JxC3H/HeJ F2 intercross mice.

Previous studies in humans have demonstrated a high co-morbidity between alcoholism and smoking. This co-morbidity between alcohol and nicotine dependence can be attributed, in part, to common genetic factors. In rodents, behavioral and physiological responses to alcohol and nicotine also appear to share common genetic influences. In this report, the genetic correlation between free-choice oral nicotine and oral alcohol consumption was evaluated using an ascending two-bottle choice paradigm in C57BL/6xC3H/HeJ F2 intercross mice. For all concentrations of nicotine (25, 50, and 100 microg/ml) and alcohol (3, 6, and 10%) tested, nicotine consumption was significantly correlated with alcohol consumption. Nicotine consumption at the highest nicotine concentration tested (100 microg/ml) showed low, but significant, correlations with the number of [3H]-cytisine binding sites in the hippocampus (r=0.307) and the number of [125I]-alpha-bungarotoxin binding sites in the cortex (r=-0.328). No significant correlations between alcohol consumption and the number of either [3H]-cytisine or [125I]-alpha-bungarotoxin binding sites was observed. A polymorphism in the nicotinic receptor alpha4 subunit gene, Chrna4, showed a trend with nicotine consumption and a significant association with alcohol consumption in female but not male mice. These results indicate that common genetic factors influence nicotine and alcohol consumption in mice. However, neither individual differences in the expression of [3H]-cytisine or [125I]-alpha-bungarotoxin binding nicotinic receptors nor the polymorphism in Chrna4 likely contribute to the genetic overlap that influences the consumption of both of these drugs of abuse in C57BL/6xC3H/HeJ F2 mice.

Alcohol Drinking↗
PubMed2004

Chemotaxis-mediated biodegradation of cyclic nitramine explosives RDX, HMX, and CL-20 by Clostridium sp. EDB2.

Cyclic nitramine explosives, RDX, HMX, and CL-20 are hydrophobic pollutants with very little aqueous solubility. In sediment and soil environments, they are often attached to solid surfaces and/or trapped in pores and distribute heterogeneously in aqueous environments. For efficient bioremediation of these explosives, the microorganism(s) must access them by chemotaxis ability. In the present study, we isolated an obligate anaerobic bacterium Clostridium sp. strain EDB2 from a marine sediment. Strain EDB2, motile with numerous peritrichous flagella, demonstrated chemotactic response towards RDX, HMX, CL-20, and NO(2)(-). The three explosives were biotransformed by strain EDB2 via N-denitration with concomitant release of NO(2)(-). Biotransformation rates of RDX, HMX, and CL-20 by the resting cells of strain EDB2 were 1.8+/-0.2, 1.1+/-0.1, and 2.6+/-0.2nmol h(-1)mgwet biomass(-1) (mean+/-SD; n=3), respectively. We found that commonly seen RDX metabolites such as TNX, methylenedinitramine, and 4-nitro-2,4-diazabutanal neither produced NO(2)(-) during reaction with strain EDB2 nor they elicited chemotaxis response in strain EDB2. The above data suggested that NO(2)(-) released from explosives during their biotransformation might have elicited chemotaxis response in the bacterium. Biodegradation and chemotactic ability of strain EDB2 renders it useful in accelerating the bioremediation of explosives under in situ conditions.

Aza Compounds↗
PubMed2003

Synthesis of a [2-pyridinyl-18F]-labelled fluoro derivative of (-)-cytisine as a candidate radioligand for brain nicotinic alpha4beta2 receptor imaging with PET.

In recent years, there has been considerable effort to design and synthesize radiotracers suitable for use in Positron Emission Tomography (PET) imaging of the alpha4beta2 neuronal nicotinic acetylcholine receptor (nAChR) subtype. A new fluoropyridinyl derivative of (-)-cytisine (1), namely (-)-9-(2-fluoropyridinyl)cytisine (3, K(i) values of 24 and 3462 nM for the alpha4beta2 and alpha7 nAChRs subtypes, respectively) has been synthesized in four chemical steps from (-)-cytisine and labelled with fluorine-18 (T(1/2): 119.8 min) using an efficient two-step radiochemical process [(a). nucleophilic heteroaromatic ortho-radiofluorination using the corresponding N-Boc-protected nitro-derivative, (b). TFA removal of the Boc protective group]. Typically, 20-45 mCi (0.74-1.67 GBq) of (-)-9-(2-[18F]fluoropyridinyl)cytisine ([18F]-3, 2-3 Ci/micromol or 74-111 GBq/micromol) were easily obtained in 70-75 min starting from a 100 mCi (3.7 GBq) aliquot of a cyclotron-produced [18F]fluoride production batch (20-45% non decay-corrected yield based on the starting [18F]fluoride). The in vivo pharmacological profile of (-)-9-(2-[18F]fluoropyridinyl)cytisine ([18F]-3) was evaluated in rats with biodistribution studies and brain radioactivity monitoring using intracerebral radiosensitive beta-microprobes. The observed in vivo distribution of the radiotracer in brain was rather uniform, and did not match with the known regional densities of nAChRs. It was also significantly different from that of the parent compound (-)-[3H]cytisine. Moreover, competition studies with (-)-nicotine (5 mg/kg, 5 min before the radiotracer injection) did not reduce brain uptake of the radiotracer. These experiments clearly indicate that (-)-9-(2-[18F]fluoropyridinyl)cytisine ([18F]-3) does not have the required properties for imaging nAChRs using PET.

Animals↗
PubMed2006

Synthesis and cytotoxic activity of pyrazino[1,2-b]-isoquinolines, 1-(3-isoquinolyl)isoquinolines, and 6,15-iminoisoquino[3,2-b]-3-benzazocines.

A series of pyrazino[2,1-b]isoquinoline and 6,15-iminoisoquino[3,2-b]-3-benzazocine compounds related to renieramycins, cribrostatin 4, and phthalascidin was synthesized and their in vitro cytotoxic activities were evaluated against three human cancer cell lines. Pyrazino[2,1-b]isoquinolines, 6,15-iminoisoquino[3,2-b]-3-benzazocines, and other more complex octacyclic compounds have been obtained and derived to precursors of iminium ion species. Hydrogenolysis of the lactam function in pentacyclic compounds gave 1-(3-isoquinolyl)isoquinolines. The micromolar cytotoxic activity of representative structures was apparently uninfluenced by the ability to generate intermediates which would permit covalent bonding to DNA.

Azocines↗
PubMed2005

Halogenated and isosteric cytisine derivatives with increased affinity and functional activity at nicotinic acetylcholine receptors.

A series of pyridone ring-modified derivatives of (7R,9S)-(-)-cytisine were evaluated for affinity and functional activity at neuromuscular alpha1beta1gammadelta, ganglionic alpha3beta4, and central neuronal alpha4beta2 subtypes of nicotinic receptors. Halogenation at the 3-position improved affinity and functional activity, while substitution at the 5-position led to modest decreases in both, and disubstitution led to near abolition of functional activities and could be correlated with the electron-withdrawing ability of the halogen. Subtype selectivities of the halogenated derivatives were altered relative to cytisine in a substitution-dependent manner. Caulophylline methiodide was less potent than cytisine, but retained significant activity. Thiocytisine was relatively weak in potency and efficacy, but was significantly selective for the alpha4beta2 subtype.

Alkaloids↗
PubMed2005

In pursuit of alpha4beta2 nicotinic receptor partial agonists for smoking cessation: carbon analogs of (-)-cytisine.

The preparation and biological activity of analogs of (-)-cytisine, an alpha4beta2 nicotinic receptor partial agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy partial agonist profiles relative to (-)-cytisine. In vivo, selected compounds exhibit lower efficacy partial agonist profiles than that of (-)-cytisine.

Alkaloids↗