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At least 163 records · Page 9Linked to original sources
PubMed1991

In vitro depressant effects of U-54494A, an anticonvulsant related to kappa opioids, in the hippocampus.

The effects of cis-3,4 dichloro-N-2-(1-pyrrolidinyl)cyclo-hexyl-benzamide (U-54494A), an anticonvulsant related to kappa opioids, were studied in vitro on the extracellular electrical activity of the CA1 region of slices of hippocampus in the rat. The effects of U-54494A were compared to those of the kappa opioid agonist trans-3,4 dichloro-N-2-(1-pyrrolidinyl)cyclo-hexyl benzeneacetamide methane sulphonate (U-50488H). Both U-54494A and U-50488H, in concentrations of 50 and 100 microM, respectively, reduced the magnitude of the orthodromically evoked CA1 population spikes after electrical stimulation of the stratum radiatum (100-200 microA, 70 microseconds, 0.1 Hz). Naltrexone (25 microM), or the selective kappa opiate receptor antagonist, 1-cyclopenthyl-5-(1,2,3,4,5,6-hexahydroxy-3,6,11-trimethyl-2 -6-methano-3- benzazocin)-3-pentatone methane sulphonate (WIN 44441-3) (25 microM), prevented the depressant activity of U-54494A (200 microM) on the CA1 population spikes. High calcium (+3mM) solutions prevented the depressant activity of increasing concentrations of both U-54494A and U-50488H on the amplitude of CA1 population spikes. Up to 200 microM, both drugs were ineffective in depressing the epileptiform bursting in CA1, due to 1 mM penicillin or to perfusion of the slice in absence of magnesium ions. The results demonstrate: (1) the inability of U-54494A to show antagonistic activity in two in vitro models of interictal epilepsy; (2) a depressant effect of U-54494A on basal synaptic transmission in the CA1 region of the hippocampus, which may be related to an influence on transneuronal calcium currents and which may be involved in the reported antagonism of ictal epileptic seizures by drugs.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

Effects of ethanol in an open field apparatus: modification by U50488H and WIN 44441-3.

The effects of U50488H, a kappa agonist, and WIN 44441-3, a kappa antagonist, and their modification of the effects of ethanol, on the behavior of rats in a modified open field apparatus, was examined. Crossover activity was increased by U50488H. Headpoke activity was decreased by WIN 44441-3 and increased by U50488H. Rearing activity was increased by WIN 44441-3 but was not affected by U50488H. The effect of both drugs was dose related, with the largest doses having no effect. Ethanol (0.5 g/kg) stimulated crossover activity while it depressed rearing, headpoke and corner activities; except for crossover activity the 2.0 g/kg dose of ethanol depressed these activities. Pretreatment with WIN 44441-3 (0.5 mg/kg) potentiated the stimulant effect of ethanol on crossover activity and partially reversed the depressant effect of ethanol on rearing and headpoke activities. U50488H potentiated the ethanol-induced depression of headpoke and reversed the depression of corner activity. Pretreatment with U50488H had no effect on ethanol's action on crossover and rearing behaviors. Our results indicate that kappa opiate receptors may mediate some behaviors exhibited by rats in a modified open field apparatus. Activation of these receptors increases locomotor and headpoke activity but had no effect on rearing activity. Furthermore, the 0.5 g/kg dose of ethanol has differential effects on different measures of open field behavior, while the 2.0 g/kg dose was largely depressant. Our data suggest that some of these effects of ethanol may be mediated via kappa opioid receptors.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1983

Addictive agents and intracranial stimulation (ICS): novel antagonists and agonists of morphine and pressing for ICS.

Rats fixed with chronically indwelling bipolar electrodes pressed for intracranial stimulation (ICS) of the lateral hypothalamus during daily sessions. The effects of two antagonists of morphine (Win 44,441 and naloxone) were then assessed. Naloxone (10 mg/kg) produced its characteristic reduction in pressing. Win 44, 441 produced a reliable increase in pressing at doses as small as 1 mg/kg. Large doses of morphine (10 mg/kg) produced its characteristic effects: depression in pressing when given 1 hr before the test session and facilitation when given 3 hr before the test session. Win 44,441 antagonized morphine's depressive effects. Other compounds (Win 44,156, Win 42,156), having similar structure to Win 44,441 but having agonist and mixed agonist-antagonist activity with respect to analgesia, also facilitated pressing for ICS. All three compounds' effects on pressing for ICS were antagonized by naloxone. It is inferred that opioids' facilitatory effects on pressing for ICS are separable from opioids' other capabilities such as production of analgesia.

Animals↗
PubMed1986

Fourth ventricle effects of nicotine, 2-methylpiperidine and cytisine in dogs.

Four distinguishable nicotinic binding sites have been identified as well as four nicotinic ligands with different specificities: (+/-)-2-methylpiperidine which binds to a very high affinity site (Site 1) and produces up-regulation of the high affinity site (Site 2); (-)-nicotine which binds to Site 1 and Site 2 as well as to a low affinity site (Site 4); (+)-nicotine which binds to Site 1, Site 4 and Site 3 which is also a high affinity site; and (-)-cytisine which binds to Sites 1 and 2. These drugs were injected into the 4th ventricle of 5 dogs in graded concentrations (12.5 to 400 micrograms) and their effects on the EEG, skin twitch reflex latency, heart rate, rectal temperature, pupillary diameter, blood pressure and the amplitude of the flexor reflex were measured. Drugs which act predominantly on Site 1 [(+/-)-2-methylpiperidine and (+)-nicotine] produced EEG synchronization and hyperalgesia while drugs which interact with Sites 2 and 4 produce EEG desynchronization, analgesia and tachycardia. These data indicate that nicotinic ligands which have different binding specificities have different actions in medullary function and support the hypothesis that the different binding sites have different pharmacologic significance.

Alkaloids↗
PubMed1988

The comparative binding characteristics of nicotinic ligands and their pharmacology.

Five drugs [(-)- and (+)-nicotine, (-)-lobeline, (-)-anabasine and (-)-cytisine] were infused IV into the urethane-pentobarbital anesthetized rat. Changes in heart rate, blood pressure, respiratory rate, minute and tidal volume, which appeared to be largely centrally mediated, were studied. Each of these compounds produced different pharmacologic profiles. The nature of these dissimilarities is not readily explained on the basis of pharmacokinetic considerations suggesting that the drugs have different mechanisms of action. Binding data obtained with these compounds using the rat brain P2 preparation also show differences. (-)-Lobeline and (-)-anabasine, like the nicotinic antagonists mecamylamine and hexamethonium, bind predominantly to low affinity sites with KDs in the micromolar range whereas (-)-cytisine binds only to a single high affinity site with a KD in the nanomolar range. Further, the binding patterns of these drugs are different from (-)- and (+)-nicotine which bind to both high and low affinity sites but differ from each other in binding characteristics. Thus the binding data are consistent with the pharmacologic data in suggesting that the drugs have different modes of action and support the concept that the low affinity site has an important role in the central nervous system action of these compounds.

Alkaloids↗
PubMed1990

Microinjections of a nicotinic agonist into dopamine terminal fields: effects on locomotion.

Nicotine induces locomotion, a behavior associated with the mesocorticolimbic dopamine system. The present study determined the effects on locomotion of direct microinjections of the nicotinic agonist cytisine into four DA terminal fields were nicotinic receptors have been localized: nucleus accumbens (NAS, n = 20), caudate putamen (CPU, n = 9), olfactory tubercle (OT, n = 8), and medial prefrontal cortex (MPC, n = 12). Male Long-Evans rats were injected with cytisine (0.1, 1, 10 and 100 nanomoles per 0.5 microliters per side) or vehicle through indwelling cannulae, and locomotor activity was recorded during a 60-minute test session; each animal was tested with each dose in counterbalanced order. NAS injections of the three highest doses of cytisine increased locomotion relative to vehicle injections; injections in the CPU, dorsal to the NAS, were ineffective, as were MPC and OT injections. The data support the notion that systemic nicotine may interact with dopaminergic projections to the NAS to produce increases in locomotor activity.

Alkaloids↗
PubMed1990

Locomotion induced by ventral tegmental microinjections of a nicotinic agonist.

Bilateral microinjections of the nicotinic agonist cytisine (0.1, 1 or 10 nanomoles per side) into the ventral tegmental area increased locomotor activity. This increase in locomotion was antagonized by mecamylamine (2 mg/kg, IP), a nicotinic antagonist that readily crosses the blood-brain barrier, and by pimozide (0.3 mg/kg, IP), a central dopaminergic antagonist. Hexamethonium (2 mg/kg, IP), a nicotinic antagonist that, unlike mecamylamine, does not cross the blood-brain barrier, had no effect; this suggests that mecamylamine's attenuation of cytisine-induced locomotor activity resulted from a blockade of central and not peripheral nicotinic receptors. The data support the notion that nicotinic and dopaminergic substrates interact at the level of the VTA to produce increases in locomotor activity.

Alkaloids↗
PubMed1994

Sensitization of locomotion following repeated ventral tegmental injections of cytisine.

Systemic injections of nicotine increase locomotion, and repeating these injections brings about a sensitization of the locomotor response. Ventral tegmental injections of the nicotinic agonist cytisine also increase locomotion. In the present study cytisine was administered repeatedly into the ventral tegmentum to determine whether sensitization of its locomotor-activating effects would develop. Four groups of animals were tested; each group received a total of six injections at a rate of one injection every 48 h. Two of these groups received injections of cytisine (10 nmol/side): one group received injections into the ventral tegmentum, and, to insure the anatomical specificity of the locomotor effect, a second group received injections dorsal to the ventral tegmentum. The remaining two groups received vehicle injections: one group received injections into the ventral tegmentum, and the other received injections into more dorsal sites. The group of animals that received injections of cytisine into the ventral tegmentum locomoted more than any other group. In addition, only with this group was a progressive increase in the locomotor response evident across test days. These findings raise the possibility that a neural substrate in the ventral tegmentum mediates the locomotor-activating and sensitizing effects associated with the systemic administration of nicotine.

Alkaloids↗
PubMed1985

Effect of Win 44441-3 and naloxone on endotoxin-induced hypotensive shock in anesthetized hypertensive rats.

A model of endotoxin-induced shock was developed in anesthetized spontaneously hypertensive rats. E. coli lipopolysaccharide (13 mg/kg i.v.) reduced systolic and diastolic blood pressure by at least 51 mm Hg in 80-90% of rats. Naloxone (1.25-10.0 mg/kg i.v.) partially restored blood pressure of hypotensive rats for 6-15 minutes after injection. Win 44441-3 (0.25-2.0 mg/kg i.v.) raised blood pressure for 3-12 minutes after injection. Ten minute pretreatment with naloxone (10 mg/kg i.v.) or Win 44441-3 (0.5 mg/kg i.v.) did not appreciably reduce the hypotensive effect of E. coli lipopolysaccharide. This model is a rapid and convenient bioassay for evaluating the effects of opioid antagonists in endotoxin shock. In this model naloxone and Win 44441-3 exhibited beneficial effects but a prolonged duration of action of the Win compound over naloxone was not observed.

Animals↗
PubMed1985

Evidence for opiate receptor involvement in the consumption of a high palatability diet in nondeprived rats.

Nondeprived adult rats were familiarized with a highly palatable diet (powdered small animal diet mixed with sweetened condensed milk and water). The palatability of food was such that it induced vigorous feeding responses, 15-20 g food consumed within the first 30 min of access. In partially-satiated male rats, the kappa receptor agonists EKC and U-50,488 (subcutaneously administered) produced large increases in food consumption in the first 30 min of access, post-injection. In experiments with naloxone and WIN 44,441-3, we found that the effects of naloxone (0.01-10 mg/kg; S.C.) were crucially dependent on the sex and dietary history of the animals. Male, obese rats were most sensitive to naloxone's anorectic effect. Lean females were completely insensitive. WIN 44,441-3 (0.01-10 mg/kg, S.C.) had no effect on food intake in any group of animals.

Animals↗
PubMed1985

Selective attenuation of sweetened milk consumption by opiate receptor antagonists in male and female rats of the Roman strains.

Male and female rats of the three Roman strains (Roman High-, Roman Low-, and Roman Control Avoidance; RHA, RLA and RCA, respectively) were familiarized with a highly palatable sweetened milk in a daily 30 min test. The animals were never food- or water-deprived prior to the test. Daily milk intake stabilised at a high level before drug tests were initiated. Effects of naloxone, diprenorphine, WIN 44,441-3, MR2266, MR2267, and ICI 154129 on milk consumption were investigated. Naloxone, diprenorphine and MR2266 each had comparable anorectic effects across strains and sexes. WIN 44,441-3 was relatively ineffective; MR2267 and ICI 154129 were without effect on milk consumption.

Animals↗
PubMed1985

Pharmacological profiles of tonazocine (Win 42156) and zenazocine (Win 42964).

The effects of tonazocine and zenazocine, two mixed agonist/antagonist analgesics, have been evaluated in a range of antinociceptive assays and in isolated tissue preparations in vitro. Both tonazocine and zenazocine were antinociceptive in writhing tests and in the i.a. bradykinin test, and were antagonists in the rat tail flick test. Additionally, zenazocine demonstrated some antinociceptive activity in the rat tail flick test. In vitro, both tonazocine and zenazocine demonstrated agonist and antagonist properties at mu receptors in the GPI and agonist properties at delta receptors in the MVD. In general, the agonist properties of zenazocine were more marked than those of tonazocine, and the antagonist properties of tonazocine were more marked than those of zenazocine.

Analgesics, Opioid↗
PubMed1993

Nicotinic receptor agonists facilitate retention of avoidance training: participation of dopaminergic mechanisms.

The effect of nicotinic receptor agonists on retention of the inhibitory avoidance (IA) response were investigated in mice. Animals received intraperitoneal drug injections before training, and retention was evaluated 24 h later. Nicotine and cytisine, but not lobeline, significantly increased retention of the IA training. Cotinine, the main metabolite of nicotine, was inactive in the same test. Retention was not affected by the injection of the D1-D2 receptor antagonist cis-flupentixol, but the preadministration of cis-flupentixol significantly blocked the facilitatory effect of nicotine and cytisine on memory. These results demonstrate that the nicotinic receptor agonists nicotine and cytisine facilitate the retention of avoidance responses and suggest that this effect is mediated through central dopaminergic pathways.

Alkaloids↗
PubMed1995

A rapid microtechnique for the estimation of muscarinic and nicotinic receptor binding parameters using 96-well filtration plates.

A microtechnique for the assay of muscarinic and nicotinic receptor binding parameters employing a 96-well filtration multiscreen system has been developed. Utilizing rat cerebral cortex as the receptor source, saturation analysis of [3H]NMS binding revealed a mean Bmax and Kd value of 1.95 pmol/mg protein and 0.71 nM, respectively. In competition studies with atropine a Ki value of 1.67 nM was determined. Nicotinic receptor binding studies were also performed with this technique with [3H]Cytisine. The binding constants for both ligands correlated well with established literature values; however, in the nicotinic assays concentrations of ligand at 20 times the Kd were required to develop adequate number of counts. Compared to presently available receptor binding techniques, this newly developed system for muscarinic and nicotinic binding is very simple and convenient to use and offers the advantages of speed, accuracy and reproducibility. In addition, a large number of samples can be assayed. This report also present the first use of the 96-well filtration multiscreen system for the estimation of muscarinic and nicotinic receptor binding constants. This methodology should prove to be useful for determining the binding characteristics of potential cholinergic ligands.

Alkaloids↗
PubMed1991

The protective effects of SA3443, a novel cyclic disulfide, on chronic liver injuries in rats.

The effects of (4R)-hexahydro-7,7-dimethyl-6-oxo-1,2,5-dithiazocine-4- carboxylic acid (SA3443), a novel cyclic disulfide compound, on the development of chronic liver injury were studied in rats, using two types of models, carbon tetrachloride (CCl4)-induced chronic liver injury and heterologous serum (swine serum)-induced liver fibrosis. SA3443 (30-100 mg/kg, p.o.) significantly suppressed increases in serum transaminase and alkaline phosphatase activity induced by CCl4-treatment for 10 weeks. This compound also inhibited increases in hepatic lipids and hydroxyproline content in CCl4-treated rats. In the histopathological studies, treatment with SA3443 resulted in a decrease in the degree of hepatic necrosis, fibrosis and steatosis. On the other hand, 8-weeks treatment with swine serum revealed hepatic fibrosis without appearance of necrosis or fatty accumulation. In this model, SA3443 (30 mg/kg, p.o.) reduced the hepatic hydroxyproline level, and diminished the formation of connective tissue in the liver. These findings indicate that SA3443 protects the liver against chronic liver injuries induced by CCl4 and heterogeneous serum.

Animals↗
PubMed1995

Pharmacological and physiological properties of a putative ganglionic nicotinic receptor, alpha 3 beta 4, expressed in transfected eucaryotic cells.

Neuronal nicotinic acetylcholine receptor subunits alpha 3 (PCA48E) and beta 4S (ZPC13) were expressed in human embryonic kidney (HEK)-293 cells by calcium phosphate transfection. In the presence of atropine, acetylcholine (ACh) induced fast activating currents which exhibited desensitization and inward rectification. The EC50 for ACh was 202 +/- 32 microM with a Hill coefficient of 1.9 +/- 0.4. The rank order of nicotinic agonist potency was 1,1-dimethyl-4-phenylpiperozinium (DMPP) > cytisine = nicotine approximately equal to ACh. The maximal response elicited by DMPP was substantially less than that elicited by other agonists, suggesting that DMPP is a partial agonist. ACh (500 microM) responses were very effectively blocked by equimolar concentrations (100 microM) of the ganglionic antagonists d-tubocurarine, mecamylamine and hexamethonium. Equal concentrations of the potent muscle receptor antagonist decamethonium and the competitive antagonist dihydro-beta-erythroidine were much less effective. alpha bungaro-toxin (1 microM) had little effect on ACh-induced responses. This physiological and pharmacological profile is consistent with a ganglionic nicotinic response.

Acetylcholine↗
PubMed1995

Characterization of nicotinic acetylcholine receptors expressed in primary cultures of cerebellar granule cells.

Nicotinic acetylcholine receptors (nAChRs), like other calcium permeable channel receptors, may play a crucial role during neuronal development. We have characterized nAChRs in developing mouse cerebellar granule cells in primary culture. L-[3H]Nicotine, [3H]cytisine and [125I]alpha-bungarotoxin binding experiments revealed the presence of a single class of saturable and specific high affinity binding sites for each ligand. The expression of these nicotinic binding sites followed a developmental pattern reaching a maximum during the establishment of excitatory amino acid synaptic contacts. Immunolabeling with monoclonal antibodies to nAChR subunits revealed the presence of alpha 4 and beta 2 subunits in most neurons. Moreover, some neuronal cells displayed a somatic as well as a neuritic localization for the alpha 7 subunit as shown by [125I]alpha-bungarotoxin autoradiography. The reverse transcription-polymerase chain reaction (RT-PCR) detected the presence of mRNAs for alpha 3, alpha 4, alpha 5, alpha 7, beta 2 and beta 4 nAChR subunits. Non-neuronal cells did not express nAChRs, as shown by [3H]nicotine and [125I]alpha-bungarotoxin binding, immunocytochemistry and PCR. Maximum Ca2+ influx elicited by nicotine, and partly sensitive to alpha-bungarotoxin, was observed around 10-14 days after plating. This correlated with the time period at which the highest number of nicotine binding sites was detected. Sensitivity to several NMDA receptor antagonists as well as to removal of endogenous glutamate by pyruvate transaminase treatment revealed a glutamatergic component in the nicotine stimulated calcium influx. The time-dependent specific nAChR expression and the potential association between nAChRs and NMDA receptor activation suggest that nAChRs may regulate glutamatergic activity during synaptogenesis in cerebellar granule cells.

Alkaloids↗