The excitatory effect of nitric oxide on carotid body chemoreception is blocked by oligomycin.
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Actions of cisplatin on the electrophysiological properties of cultured dorsal root ganglion neurones from neonatal rats.
In this study we have employed the whole cell patch clamp technique to investigate the effects of an anti-cancer drug cisplatin on basic electrophysiological properties of cultured dorsal root ganglion neurones from neonatal rats. The results show that within the clinical concentration range, cisplatin (0.1 to 10 microM) caused a decrease in input conductance, and complex changes in resting membrane potential in these cultured sensory neurones. The dominant effects of cisplatin on input conductance may be due to inhibition of leak conductances. Transplatin (5 microM) was significantly less effective than cisplatin at reducing input conductance which suggests a degree of stereoselectivity. Cisplatin (1 to 5 microM) transiently increased excitability of the cultured neurones as reflected by a reduction in the threshold for activation of action potentials by 8 mV. The rise time, peak amplitude and duration of action potentials were not changed by acute application of 5 microM cisplatin. Long term treatment of neurones with cisplatin (5 microM), for up to 1 week reduced the viability of the cultures, and attenuated neurone excitability, although input conductance of the cells was significantly increased to 322 +/- 49 M omega (n = 9) compared with controls of 210 +/- 20 M omega (n = 30; P < 0.05). Acute and chronic treatment of cultured neurones with cisplatin therefore produced contrasting actions.
Animals↗
Neuronal and non-neuronal control of the neurosecretory caudo-dorsal cells of the freshwater snail Lymnaea stagnalis (L.).
The cerebral ganglia of the freshwater snail Lymnaea stagnalis contain two clusters of neurosecretory Caudo-Dorsal Cells (CDC). These cells produce a neurohormone which stimulates ovulation. Ganglion transplantation and quantitative electron microscopy show that neuronal isolation of the cerebral ganglia complex (CCC) results in an activation of the CDC. It was, therefore, concluded that the CDC are controlled by an inhibitory neuronal input originating outside the cerebral ganglia. Ultrastructural studies on synaptic degeneration in the CCC suggest that this input reaches the CDC via a special type of synapse-like structure, the type C-SLS. Furthermore, transplantation of CCC into acceptor snails leads to a reduced release and an increased intracellular brekdown of neurohormone in the CDC of the nervous system of the acceptors. It is supposed that these phenomena are caused by the release of an (unknown) factor from the transplanted CCC. Special attention was given to the formation and degradation of a peculiar type of neurohormone granule, the large electron dense granule. The physiological significance of the neuronal and non-neuronal control mechanisms which regulate CDC activity is discussed.
Animals↗
The origin of the S (slow) potential in the mammalian lateral geniculate nucleus.
While recording extracellularly from single neurons in the Lateral Geniculate Nucleus (LGN) of cats and monkeys, one often observes, in addition to action potentials, smaller and slower potentials which have been called 'S Potentials' (Bishop et al. 1962). Injection of the sodium channel blocker tetrodotoxin (TTX) into the eye of the cat causes spontaneous and light evoked S potentials to disappear. However, electrical stimulation of ganglion cells axons at the optic chiasm still elicits S potentials. Previous studies have shown that retinal ganglion cell impulses elicit S potentials. Our results prove that ganglion cell impulses are the ONLY source of these potentials; therefore, one can use them as a measure of ganglion cell input to the LGN.
Animals↗
Autoradiographic localization of binding sites for muscarinic and nicotinic agonists and antagonists on cultured astrocytes.
The cellular localization of cholinergic binding sites was studied in organotypic cultures of rat spinal cord and brain stem by means of autoradiography with radiolabelled muscarinic and nicotinic agonists and antagonists. Many astrocytes in both types of cultures showed intense labelling by 3H-acetylcholine in the presence of nicotine and the muscarinic antagonists 3H-pirenzepine, 3H-quinuclidinyl benzilate and 3H-propylbenzilcholine mustard. Incubation of the cultures with 3H-nicotine or 3H-acetylcholine in the presence of atropine also caused labelling of astrocytes. In addition to glial cells, many neurones showed binding of muscarinic and nicotinic agonists and antagonists. From our results it is suggested that astrocytes, besides neurones, possess both muscarinic and nicotinic receptors.
Animals↗
The cholinergic system and nociception in the primate: interactions with morphine.
In Experiment 1 the shock titration task was used to evaluate the antinoceptive properties of 5 different classes of cholinergic compounds in the rhesus monkey. Only scopolamine and high doses of physostigmine were effective in elevating the shock threshold. The apparent antinociceptive effect of physostigmine, however, was difficult to separate from its nonspecific behavioral depressant effect and was probably not related to an increase in cholinergic tone. Experiment 2 examined the interaction of morphine with arecoline, scopolamine and physostigmine. Only scopolamine (0.05 and 0.1 mg/kg) and high doses of physostigmine (0.1 mg/kg) interacted with morphine in the shock titration paradigm. The multiplicative interaction of morphine with scopolamine was confirmed in Experiment 3 over a wider range of doses. It was concluded that morphine and the cholinergic compounds produce antinociceptive effects through different mechanisms of the pain system.
Analgesia↗
A comparison of the effects of muscarinic and nicotinic anticholinergic drugs on habituation and fear conditioning in rats.
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Animals↗
Radial-arm maze performance in rats is impaired by a combination of nicotinic-cholinergic and D2 dopaminergic antagonist drugs.
Performance on the radial-arm maze depends on the integrity of both cholinergic and dopaminergic systems. We have previously found that administration of either the nicotinic-cholinergic antagonist, mecamylamine, or the muscarinic-cholinergic antagonist, scopolamine, impairs choice accuracy in the radial-arm maze. Co-administration of the dopaminergic antagonist, haloperidol, ameliorated the performance deficit caused by scopolamine but exacerbated the deficit caused by mecamylamine. Furthermore, antagonism of the effect of scopolamine is due specifically to blockade of D1 receptors. In the present experiment behaviorally subthreshold doses of mecamylamine and the D2 antagonist raclopride impaired maze performance when administered together. No interactive effects were observed between mecamylamine and the D1 antagonist SCH 23390. Although several of the drug treatments studied significantly increased choice latency, an index of motor behavior, there was no perfect relationship between choice accuracy and choice latency. These data indicate that nicotinic-cholinergic and muscarinic-cholinergic systems interact selectively and differentially with D1 and D2 dopaminergic systems.
Animals↗
The use of the De Deckere-Ten Hoor preparation for study of nicotinic and potassium-evoked dopamine beta-hydroxylase release from the rabbit heart.
1. Dopamine beta-hydroxylase (DBH) and noradrenaline were determined both in the venous effluent (perfusate) and in the transmyocardial fluid (TMF) collected from the apex of the rabbit isolated heart which was prepared according to De Deckere and Ten Hoor (1977) and perfused with Tyrode's solution at 20 ml/min. 2. Perfusion for 2 min with the nicotinic drug, p-aminophenethyl-trimethylammonium (PAPETA), both in the absence of presence of atropine evoked noradrenaline overflow into the perfusate and TMF that was maximal in the 0-2 min sample and declined from maximum with a t 1/2 of 0.6 min. DBH was released into TMF with the maximum from 2-4 min and a t 1/2 of decline of 5.6 min. 3. High K-low Na solution containing 54 mM KCl was perfused for 4 min. The maximum outputs of noradrenaline into the perfusate and TMF occurred between 2 and 4 min and that of DBH into TMF 2 min later. The t 1/2 of decline from the maxima were similar to those after PAPETA but the output ratio DBH/noradrenaline was 5 times that after PAPETA. 4. Both chemical stimuli were not observed to increase the DBH content of the perfusates. The noradrenaline concentration in the TMF was 3 times that in the perfusates. 5. It is concluded that TMF reflects concentration changes in the synaptic region more truly than the venous effluent does. TMF is particularly suitable for determination of DBH output of the heart; the DBH concentration is higher than in the perfusate and its washout faster than from the conventional Langendorff preparation.
Animals↗
Subclassification of muscarinic receptors in the heart, urinary bladder and sympathetic ganglia in the pithed rat. Selectivity of some classical agonists.
In pithed normotensive rats muscarinic receptors were characterized in heart, urinary bladder and sympathetic ganglia; the selectivity of some classical muscarinic agents for these subtypes was investigated. The potencies in decreasing heart rate, increasing bladder pressure and increasing diastolic blood pressure were measured for the following, intraarterially administered cholinergic agonists: McN-A-343 ([4-m-chlorophenylcarbamoyloxy]-2-butynyltrimethylammonium), pilocarpine, carbachol, oxotremorine, arecoline, acetyl-beta-methylcholine and acetylcholine. The selective M1-antagonist pirenzepine, the mixed M1/M2-antagonist dexetimide and the cardioselective M2-antagonist gallamine were used as tools for identification of the receptors. All data were obtained after intravenous pretreatment with a high dose of atenolol to eliminate tachycardia induced by stimulating sympathetic ganglionic muscarinic receptors. Dexetimide strongly antagonized the bradycardia as well as the increase in bladder pressure induced by pilocarpine, carbachol, oxotremorine, arecoline, acetyl-beta-methylcholine and acetylcholine, whereas pirenzepine was much less effective. Gallamine antagonized the bradycardia, whereas no influence was found on the bladder contraction. Pilocarpine acted as a partial agonist in reducing heart rate as well as in increasing bladder pressure, whereas McN-A-343 was almost ineffective in doses up to 1 mg/kg. The hypertensive response to pilocarpine and carbachol was less pronounced than that produced by McN-A-343. Pirenzepine and dexetimide significantly antagonized the hypertensive response to McN-A-343 and pilocarpine, whereas gallamine was much less effective. The hypertensive response induced by carbachol was totally blocked by hexamethonium. The other agonists used in this study did not produce a significant increase in diastolic blood pressure in doses that produced a maximal effect on heart rate and urinary bladder pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Role of training dose in discrimination of nicotine and related compounds by rats.
Rats were trained to discriminate nicotine from saline in a two-bar operant conditioning procedure with food reinforcement. There was partial generalization to the nicotine analogues anabasine and cytisine in rats trained to discriminate either 0.2 or 0.4 mg/kg nicotine from saline. However, generalization was complete in rats trained to discriminate 0.1 mg/kg nicotine and, in a novel procedure, any one of three doses of nicotine (0.1, 0.2, or 0.4 mg/kg). There was no generalization to the muscarinic-cholinergic agonist oxotremorine (0.0025-0.04 mg/kg). Additional experiments were carried to further characterize the response of rats trained with nicotine (0.1 mg/kg). These animals failed to generalize to compounds from a range of pharmacological classes (i.e., apomorphine, cocaine, chlordiazepoxide, picrotoxin, and quipazine), but there was partial generalization to amphetamine. Mecamylamine (0.5 mg/kg) but not hexamethonium (5.0 mg/kg) blocked the discrimination of nicotine and the generalization to cytisine. Anabasine (1.0-4.0 mg/kg) did not block the response to nicotine. The results support the view that the nicotine cue is mediated mainly through central cholinergic mechanisms. The dose of nicotine used for training has a very significant influence on the characteristics of the cue and 0.1 mg/kg of nicotine may be more suitable than 0.4 mg/kg as a training dose in future work.
Alkaloids↗
Muscarinic acetylcholine receptor in chick limb bud during morphogeneis.
In the chick embryo a cholinesterase activity appears in various organ anlagen which has been correlated with morphogenetic movements (Drews 1975). The cholinesterase activity is present in the mesenchyme of the limb bud during aggregation of the central chondrogenic core. In the present study binding of tritium labelled quinuclidinyl benzilate ((3H)QNB), a muscarinic antagonist, to homogenates of chicken limb buds was investigated by a filtration assay. In the homogenate of limb buds at Stage 24 specific binding of (3H)QNB was demonstrated. Determination of binding constants and inhibition of binding by agonists and antagonists was studied at Stage 25/26. Specific binding was defined by the difference in binding in the absence and presence of atropine (1 microM). Specific binding of (3H)QNB reflected a muscarinic receptor. The Kd in two experiments was 0.11 nM and 0.16 nM, the binding capacity was 15.7 fmol (3H)QNB/mg protein and 12.0 fmol (3H)QNB/mg protein, respectively. Data on displacement of specific bound (3H)QNB by various nicotinic and muscarinic ligands confirmed the muscarinic nature of the receptor. Muscarinic ligands inhibited the (3H) QNB binding, whereas nicotinic ligands caused no inhibition at pharmacological concentrations. I conclude that a specific muscarinic acetylcholine receptor is part of the cholinergic system whose presence is indicated by cholinesterase activity in the chondrogenic core of the limb bud during morphogenesis.
Animals↗
Alkaline ribonuclease activity is increased in rat sympathetic ganglia after nerve injury.
Ribonuclease activity at pH 7.1 ("alkaline" ribonuclease) was determined in homogenates of rat superior cervical ganglion up to 5 days after postganglionic nerve injury under optimal conditions of assay. Measurements were performed in the presence and absence of the sulfhydryl blocking agent, N-ethylmaleimide, to assess the proportion of "alkaline" ribonuclease apparently bound to endogenous inhibitor. Total ribonuclease activity per ganglion was stimulated 1.3 fold by 1 day after injury and remained elevated over the 5 day period. Free ribonuclease activity accounted for about 60% of the observed increase in total activity at day 1, but had returned to control level by day 3. At day 3 the entire 90% increase in total activity was attributable to ribonuclease bound to endogenous inhibitor (i.e. latent activity). These changes are occurring at times after nerve injury when marked alterations in RNA turnover have been observed, implicating "alkaline" ribonucleases in the control of RNA metabolism during nerve regeneration.
Animals↗
Ablation of the area postrema and emesis.
The emetic action of dopamine, norepinephrine, epinephrine, nicotine, dimethylphenyl-piperazinium (DMPP), and 4-m-chlorophenylcarbamoyloxy-2-butynyltrimethylammonium (McN-A-343) injected intracerebroventricularly (i.c.v.) to the unanesthetized cat was investigated and compared. ED50 values (mg) were as follows: nicotine, 0.011; epinephrine, 0.047; norepinephrine, 0.57; DMPP, 0.9; dopamine, 1.66; and McN-A-343, 4.42. The most potent was nicotine, whereas the least active McN-A-343. On the other hand, DMPP produced the longest emetic response, about 30 min, while McN-A-343-induced emesis lasted up to 1 min. The ablation of the area postrema abolished the emetic response to i.c.v. dopamine, norepinephrine, epinephrine, nicotine, and DMPP. However, the emetic response to i.c.v. McN-A-343 was significantly reduced in cats with an ablated area postrema. Taken together, the results obtained show that the area postrema is almost always involved in the central regulation of emesis and that the area postrema represents, in most cats, a common site of confluence of different inputs subserving the emesis.
Animals↗
Effect of chemical sympathectomy on coronary flow and cardiovascular adjustment to exercise in dogs.
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Adrenal Medulla↗
Participation of cholinergic mechanisms in the origination of the dendritic potential of the cerebral cortex.
The influence of a series of muscarinic (M) and nicotinic (N) substances on the dendritic potentials of the cerebral cortex was studied in acute experiments on adult cats under deep nembutal anesthesia. M-Antagonists in large doses and M-agonists, N-agonists and acetylcholine elicited a decrease in the amplitude of dendritic potentials. M-Antagonists in small doses and N-antagonists elicited an increase in the amplitude of the dendritic potentials. The application of an anticholinesterase substance, proserine, to the cortex elicited an increase in the amplitude and duration of the dendritic potentials. It is hypothesized that there are postsynaptic M-cholinoreceptors of the M1 type, presynaptic M-cholinoreceptors of the M2 type, and presynaptic N-cholinoreceptors in the neuropil of layer I of the cortex.
Acetylcholine↗
[Experimental research on the peripheral action of the autonomic nervous system; research on the periodontium of the domestic cat after stimulation of the superior cervical ganglion].
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Animals↗
Designing novel nicotinic agonists by searching a database of molecular shapes.
We introduce an approach by which novel ligands can be designed for a receptor if a pharmacophore geometry has been established and the receptor-bound conformations of other ligands are known. We use the shape-matching method of Kuntz et al. [J. Mol. Biol., 161 (1982) 269-288] to search a database of molecular shapes for those molecules which can fit inside the combined volume of the known ligands and which have interatomic distances compatible with the pharmacophore geometry. Some of these molecules are then modified by interactive modeling techniques to better match the chemical properties of the known ligands. Our shape database (about 5000 candidate molecules) is derived from a subset of the Cambridge Crystallographic Database [Allen et al., Acta Crystallogr., Sect. B,35 (1979) 2331-2339]. We show, as an example, how several novel designs for nicotinic agonists can be derived by this approach, given a pharmacophore model derived from known agonists [Sheridan et al., J. Med. Chem., 29 (1986) 889-906]. This report complements our previous report [DesJarlais et al., J. Med. Chem., in press], which introduced a similar method for designing ligands when the structure of the receptor is known.
Algorithms↗