Naltrexone and β-funaltrexamine antagonism of the antinociceptive and response rate-decreasing effects of morphine, dezocine, and d-propoxyphene

  Rationale: Patterns of competitive and insurmountable antagonism provide important data to guide the classification and characterization of different types of opioid agonists as well as infer the mechanism of action for agonists. Objective: Experiments with the competitive antagonist, naltrexone, and the insurmountable antagonist, β-funaltrexamine (β-FNA), were conducted to determine whether the antinociceptive and rate-decreasing effects of the opioid agonists dezocine and d-propoxyphene are 1) mediated through μ opioid receptors in rats, and 2) differ from morphine with respect to relative efficacy. Methods: The rat tail-withdrawal assay was used to measure antinociception and a fixed ratio 20 (FR20) schedule of food delivery was used to measure rate suppression. Results: Naltrexone (0.01–1.0 mg/kg) was approximately equipotent as an antagonist of the antinociceptive and rate-decreasing effects of both morphine and dezocine and as an antagonist of the antinociceptive effects of d-propoxyphene. Naltrexone failed to block the rate-decreasing effects of d-propoxyphene. β-FNA (5 and 10 mg/kg) also antagonized the antinociceptive and rate-decreasing effects of morphine and dezocine as well as the antinociceptive effects of d-propoxyphene. β-FNA failed to produce a dose-dependent antagonism of the rate-decreasing effects of d-propoxyphene. Conclusions: These data suggest that the antinociceptive effects of morphine, dezocine, and d-propoxyphene and the rate-decreasing effects of morphine and dezocine are mediated through μ opioid receptors. Overall, high doses of β-FNA produced a greater degree of antagonism of the behavioral effects of dezocine than morphine or d-propoxyphene, confirming other reports that dezocine is a lower efficacy agonist than morphine. Additionally, the degree of antagonism produced by β-FNA was greater for the antinociceptive effects of all three compounds than for the rate-decreasing effects. Received: 14 August 1998 / Final version: 4 December 1998     

Combinatorial investigation of the effects of the incorporation of Ti, Si, and Al on the performance of α-Fe2O3 photoanodes

The effect of adding small amounts of Ti, Si, and Al on the photoelectrochemical activity of α-Fe(2)O(3) is investigated using a high-throughput combinatorial method. Quantitative ink jet printing is used to pattern iron oxide and dopant precursors onto conductive glass substrates. Subsequent pyrolysis yields a library of doped iron oxide electrodes that are screened for photoelectrolysis activity by immersing in an electrolyte and scanning a laser over the electrodes to map the photocurrent response. When Si and Al are individually added to iron oxide at the levels we studied, the photoelectrolysis activity decreased whereas low levels of Ti addition enhanced the photocurrents. Synergistic effects were observed resulting in enhanced photocurrents when multiple impurities were added to α-Fe(2)O(3).     

Pharmacological Research of Tetrandrine and Fangchinoline, the Major Components of Stephania Tetrandrae

Purpose: The root of the Chinese herbal remedy Han Fang Ji ( Radix of Stephania Tetrandrae) has been used since antiquity by Chinese physicians as an ahtihypertenion, antirheumatic, analgesic and antipyretic agent. Tetrandrine (TET) and fangchinoline (FAN), the bisbenzylisoquinolide alkaloids, are the major components of Han Fang Ji. TET has been well known as a natural occurred non - specific calcium channel blocker. However, the effects of TET on the cardiovascular system are not fully understood, and that a few of researches about FAN, an another major constituent of Han Fang Ji, are reported. Thus, we have done these studies to investigate and compare the effects of TET and FAN on cardiovascular system,CNS and multi - drug resistance to anticancer drugs for several years.     

A systematic review of the effects of oleoylethanolamide,a high-affinity endogenous ligand of PPAR-α, on the management and prevention of obesity

Along with an increase in overweight and obesity among all age groups, the development of efficacious and safe anti-obesity strategies for patients, as well as health systems, is critical. Oleoylethanolamide (OEA), a high-affinity endogenous ligand of nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-α), plays important physiological and metabolic actions. OEA is derived from oleic acid, a monounsaturated fatty acid, which has beneficial effects on body composition and regional fat distribution. The role of OEA in the modulation of food consumption and weight management makes it an attractive molecule requiring further exploration in obesogenic environments. This systematic review was conducted to assess the effects of OEA on the obesity management, with emphasizing on its physiological roles and possible mechanisms of action in energy homeostasis. We searched PubMed/Medline, Google Scholar, ScienceDirect, Scopus, ProQuest, and EMBASE up until September 2019. Out of 712 records screened, 30 articles met the study criteria. The evidence reviewed here indicates that OEA, an endocannabinoid-like compound, leads to satiation or meal termination through PPAR-α activation and fatty acid translocase (FAT)/CD36. Additionally, the lipid-amide OEA stimulates fatty acid uptake, lipolysis, and beta-oxidation, and also promotes food intake control. OEA also exerts satiety-inducing effects by activating the hedonic dopamine pathways and increasing homeostatic oxytocin and brain histamine. In conclusion, OEA may be a key component of the physiological system involved in the regulation of dietary fat consumption and energy homeostasis; therefore, it is suggested as a possible therapeutic agent for the management of obesity.     

Patient‐perceived problems, compliance, and the outcome of hypertension treatment

Objective: To study the associations between the outcome of antihypertensive therapy with both patient-perceived problems and patient initiated modification of dosage instructions. Design and methods: In this cross-sectional survey, all chronic hypertensives aged less than 75 years (n = 971) visiting nine Finnish pharmacies between May and September of 1996 were asked to participate. Of the 866 agreeing to participate, 482 returned the questionnaire (56%). After excluding persons with missing data, the final study population consisted of 428 hypertensive patients. Information on problems with treatment, the modification of dosage instructions, and blood pressure levels was based on patient self-reports.Results: Two-thirds (68%) of the study population reported suffering from one or more problems. The most common problems were symptoms of high blood pressure and adverse drug effects. Thirty-one percent of the male respondents and 21% of the female respondents reported having modified their dosage instructions. Only 36% of the patients had reached the goal blood pressure (<160/90 mmHg). Patients having problems with hypertension treatment were significantly more likely to have modified their dosage instructions than those without problems (3+ problems, adjusted OR=4.8). Not reaching goal blood pressure levels was sigfinicantly associated with both high number of patient-perceived problems (3+ problems, adjusted OR=2.1) and modification of dosage instructions (adjusted OR=1.9).Conclusion: The poor outcome in antihypertensive therapy is associated with both patient-perceived problems and patient initiated modification of dosage instructions.     

A comparison of the content-, construct- and predictive validity of the cigarette dependence scale and the Fagerström test for nicotine dependence

BACKGROUND: Research showed that the widely used Fagerstrom test for nicotine dependence (FTND) does not cover important aspects of dependence. A new test, the cigarette dependence scale (CDS-12), covers the main elements in DSM-IV and ICD-10 definitions of dependence. We compared the psychometrics of CDS-12, FTND, and CDS-5 and the heaviness of smoking index (HSI), which are short versions of CDS-12 and FTND, respectively. METHODS: Internet survey in 2002-2003. Participants were invited one month after answering the first survey to answer a second survey on smoking status and withdrawal symptoms. RESULTS: Eight hundred two smokers answered both surveys. Cronbach's alpha coefficients were higher for CDS-12 (0.91) and CDS-5 (0.77) than for FTND (0.68) and HSI (0.63). Among 231 smokers who quit smoking at follow-up, higher baseline CDS-12 scores predicted higher withdrawal ratings at follow-up, for all withdrawal symptoms except appetite. FTND and HSI predicted higher craving in quitters, but did not predict the intensity of other withdrawal symptoms. Neither CDS-5, FTND or HSI predicted smoking cessation, but higher CDS-12 scores marginally predicted smoking cessation at follow-up (area under the receiver operating characteristic (ROC) curve = 0.55, 95% confidence interval = 0.51-0.59). CONCLUSIONS: CDS-12 had better content validity and internal consistency than FTND and was a slightly better predictor of withdrawal symptoms. Unexpectedly, higher (not lower) CDS-12 scores predicted subsequent smoking cessation, perhaps because endorsement of some CDS-12 items implies accepting that one is dependent, which in turn could reflect motivation to quit. CDS-12 may represent an alternative to FTND for measuring cigarette dependence.     

Contamination and Biomarkers in the Great Blue Heron, an Indicator of the State of the St. Lawrence River

In 1996–1997, nine breeding colonies of the great blue heron on the St. Lawrence River and its estuary (Québec, Canada) were investigated in the framework of a biomonitoring program. Fledglings from colonies in freshwater were more contaminated with mercury, PCBs and many organic contaminants than those from estuarine colonies. The level of contamination in the St. Lawrence River is generally below the levels of toxicological effects for the great blue heron. The molar ratio of retinol: retinyl palmitate in heron eggs was correlated with total PCBs (r=0.79) and Mirex (r=0.90). In plasma, all biochemical parameters were significantly different between freshwater and marine colonies. Plasma retinol concentrations at the Dickerson and Hérons colonies were significantly lower compared with those at Grande Ile (p<0.05) and Steamboat (p<0.001). Based on retinoid and β-carotene concentrations in eggs, low plasma retinol was not associated with possible dietary deficiency. Plasma retinol was negatively correlated with many PCB congeners, total PCBs (r=−0.78), p,p′-DDE, trans-nonachlor and α-HCH. Similarly, the hormone T3 was correlated with many PCB congeners, total PCBs (r=−0.69) and the same organochlorine chemicals. Plasma LDH concentrations were different among freshwater colonies, Grande Ile and Hérons colonies having LDH values significantly greater than those of Steamboat (respectively, p<0.05 and p<0.01). Globally, the health status of the St. Lawrence great blue heron population was judged to be acceptable, however, several biomarkers indicated positive responses to contaminants.     

Exposure and recovery response of isomers of HCH, metabolites of DDT and estradiol-17β in the female catfish, Heteropneustes fossilis

Effects of 40 days of exposure and 20 days of recovery response at sublethal concentration of technical grades of gamma isomer of hexachlorocyclohexane (γ-HCH, 0.025 ppm, 99.8%) and dichlorodiphenyltrichloroethane (DDT, 5.0 ppm) in tissue (liver, brain and ovary) bioconcentrations, gonadosomatic index (GSI) and plasma levels of estradiol-17β (E2) have been estimated during prespawning phase in the catfish Heteropneustes fossilis (Bloch). The results indicated that the tissue bioconcentrations of both HCHs (HCH isomers) and DDTs (metabolites of DDT) in liver, brain and ovary were in preferential order (liver > brain > ovary). The GSI and plasma levels of E2 were declined in response to exposure of γ-HCH and DDT. On withdrawal of exposure of pesticide there was recovery of HCHs in exposed fish for all tissues studied, whereas DDTs exposed fish showed recovery only in liver. Recovery of E2 production was also recorded in γ-HCH exposed fish whereas very little recorded in DDT exposed fish. It is suggested that HCHs and DDTs have preferential order (liver > brain > ovary) of their tissue bioconcentrations and HCH/DDT-withdrawal-dependent recovery during studied phase.     

Differential Effects of Anionic,Cationic, Nonionic,and Physiologic Surfactants on the Dissociation, α-Chymotryptic Degradation,and Enteral Absorption of Insulin Hexamers

Various surfactants were investigated to compare their effects on insulin dissociation, -chymotryptic degradation, and rat enteral absorption. With a circular dichroism technique, sodium dodecyl sulfate (SDS) at a 5 mM concentration was found to completely dissociate procine-zinc insulin hexamers (0.5 mg/ml) into monomers. The catalytic activity of -chymotrypsin (0.5 µM) was also abolished by 5 mM SDS. When insulin was injected into the distal jejunum/ proximal ileum segment of the rat, 5 mM SDS greatly enhanced its pharmacological availability, from a negligible value to 2.8%. Being a cationic surfactant, hexadecyl trimethylammonium bromide (CTAB) also efficiently dissociated insulin hexamers at concentrations of 1–5 mM. However, extensive charge–charge interaction was observed below a CTAB concentration of 0.6 mM, leading to insulin precipitation at a molar CTAB:insulin ratio of 1:1 to 2:1. An -chymotryptic degradation study also revealed near-complete dissociation of insulin hexamers at 1 mM CTAB. Above 1 mM, however, CTAB acted as an enzyme inhibitor, most likely by means of charge repulsion. Enteral absorption studies showed a much lower pharmacological availability, only 0.29%. Nonionic surfactants such as Tween 80 and polyoxyethylene 9 lauryl ether were ineffective in dissociating insulin hexamers. Tween 80, at 5 mM, neither significantly altered the -chymotryptic degradation pattern nor enhanced the enteral absorption of insulin. The relative effectiveness of different species of bile salts on insulin hexamer dissociation appeared to be similar. Sodium glycocholate at a 30 mM concentration also significantly increased insulin pharmacological availability, to 2.3%. A morphological study did not reveal any significant alteration of the rat intestinal mucosal integrity after exposure to 5 mM SDS for 30 min. The results further emphasize the importance of the degree of insulin aggregation on its enteral transport.     

Effect of hypophysectomy on the stimulation of liver growth by α-hexachlorocyclohexane,phenobarbital, and partial hepatectomy in the rat

Summary -Hexachlorocyclohexane (-HCH) or phenobarbital (PB) elicit growth and cell multiplication in rat liver.In hypophysectomized rats, -HCH and PB induce an increase in liver mass, but no increase in liver DNA. Hypophysectomy without additional treatment results in a decrease of liver size and RNA, while the DNA content remains unchanged, thereby leading to a relative DNA surplus. 1/3-hepatectomy in hypophysectomized animals leads to a small increase of hepatic DNA only; after 2/3-hepatectomy 75–80% of the original liver DNA are restored. In rats with intact hypophysis losses of liver DNA are known to be restored completely.The findings suggest that the relative DNA surplus in hypophysectomized rats prevents the stimulation of DNA synthesis by weak growth stimuli such as -HCH, PB, and 1/3-hepatectomy. If the relative DNA surplus is eliminated by partial hepatectomy, the inducers do produce DNA multiplication. It is concluded that the induction of liver growth and cell multiplication by -HCH and PB does not require the presence of the hypophysis or one of its hormones.Abbreviations HCH 1,2,3,4,5,6-hexachlorocyclohexane=benzene hexachloride - PB phenobarbital - b.w. body weight - BHT butylhydroxytoluene - STH somatotrophic hormone - ACTH adrenocorticotrophic hormone     

Recent progress in understanding of structure, ligand interactions and the mechanism of activation of the β₂-adrenergic receptor

The understanding of β?-adrenergic receptor (β?AR) interactions with ligands as well as the mechanism of receptor activation changed radically from 2007, when the first crystallographic structure of the receptor was reported. Since then numerous crystallographic studies described interactions with all main classes of β?AR ligands and with G proteins, which provided a great insight into the molecular structure of the receptor. However, molecular mechanisms of receptor activations remain to be determined. Functional research supported the concept of ligand-directed signaling at β-adrenoceptors. Agonist can activate alternative signaling pathways with different capacities and trigger cellular effects. It indicates that agonists nominally belonging to the same class may bind to and/or stabilize different active conformations of the receptor which are selectively recognized by signaling proteins in the allosteric manner.     

Study of the genotoxic and cytotoxic effects of the α-, β-, and γ- Hexachlorocyclohexane isomers in human lymphocyte cells using the cytokinesis-block micronucleus assay

The genotoxic potential of hexachlorocyclohexane (HCH) isomers (α-, β-, and γ-) which are organochlorine pesticides was tested in peripheral blood lymphocyte cultures from two donors by using the cytokinesis-block micronucleus assay. Micronucleus (MN) frequency, binucleated cells with micronucleus (BNMN), and cytokinesis-blocked proliferation index (CBPI) were determined as genotoxic and cytotoxic endpoints. At the concentration ranges tested (12.5–100?μg.L?^?1), all HCH isomers induced dose-dependent cytotoxic effects, γ-HCH being the most toxic. This isomer was also able to induce significant increase in MN frequency and BNMN cells indicating a genotoxic potential at 50 and 100?μg.L?^?1. The genotoxic test of β-HCH showed a positive induction of MN and BNMN cells at the highest concentration of 100?μg.L?^?1 and a significant cytotoxicity at 50?μg.L?^?1. Under the experimental condition used, α-HCH was unable to induce any significant increase in MN frequency confirming that α-HCH is a non-genotoxic agent.     

The contribution of α 1-acid glycoprotein,lipoproteins, and albumin to the plasma binding of perazine,amitriptyline, and nortriptyline in healthy man

Summary Parameters for the binding of perazine (PER), amitriptyline (AT) and nortriptyline (NT) to plasma and to single plasma proteins were determined by equilibrium dialysis. The highest affinity (K at least 10⁵ M^–1) and lowest capacity (first site 1 mol/mol) towards all three drugs was exhibited by ₁-acid glycoprotein (₁-AGP). From the parameters, ₁-AGP was estimated to contribute 43% to total binding of PER and 49 and 31%, respectively, to AT and NT binding in samples with normal protein concentrations. Fractions bound to total lipoproteins would amount to 32% (PER), 40% (AT) and 52% (NT), respectively, while the contribution of albumin would range from 11% (AT) to 25% (PER). The extent of the binding to plasma was compared with that to single proteins and their mixtures. Binding to combinations of ₁-AGP, lipoproteins and albumin exceeded that to plasma with PER, but not with AT and NT. This leads to the assumption that additional plasma constitutents interfere with PER binding.     

Thiol reactivity and its impact on the ciliate toxicity of α,β-unsaturated aldehydes, ketones, and esters

A recently introduced chemoassay has been used to determine second-order rate constants of the electrophile-nucleophile reaction of 15 α,β-unsaturated aldehydes with glutathione. The respective kGSH values vary for more than 3 orders of magnitude, and are within the range determined previously for 31 α,β-unsaturated ketones and esters. Structure-reactivity analyses yield distinct relationships between kGSH and structural features of the compounds. Moreover, increasing kGSH increases the aldehyde toxicity toward ciliates in terms of 48 h-EC50 values (effective concentration yielding 50% growth inhibition of Tetrahymena pyriformis within 48 h). A respective log-log regression equation including both kGSH and the octanol/water partition coefficient, Kow, yields a squared correlation coefficient of 0.96. Comparative analysis with corresponding data for 15 ketones and 16 esters reveals systematic differences between the three compound classes with regard to the individual contributions of hydrophobicity and electrophilic reactivity to aquatic toxicity. The former is particularly pronounced for aldehydes, while the ester toxicity is largely governed by reactivity, with ketones showing an intermediate pattern that is more similar to the one of esters than of aldehydes. It follows that within the Michael acceptor domain of α,β-unsaturated carbonyls, a distinction between aldehydes and nonaldehydic derivatives appears necessary when employing electrophilic reactivity as a component for the quantitative prediction of their reactive toxicity toward aquatic organisms.     

Estradiol and testosterone modulate the anesthetic action of the GABA-A agonist THIP,but not of the neurosteroid 3α,5β-pregnanolone in the rat

Rationale As sex steroids modify the number and distribution of brain -aminobutyric acid (GABA)_A receptor subunits, we investigated the potential modulation of anesthesia, induced by agents acting on the GABA_A receptor, by estrogen and androgen.Objectives To assess possible effects of sex and hormonal condition (i.e., intact vs castrate; estradiol vs testosterone treatment) on the anesthetic effect of a GABA_A agonist, THIP (4,5,6,7-tetrahydroisoxazolo[5,4,-c]pyridin-3-ol hydrochloride), and an allosteric modulator of the GABA_A receptor: 3-hydroxy-5-pregnan-20-one (epipregnanolone).Methods The potencies of THIP and epipregnanolone for inducing loss of the righting response were compared between: (a) female and male rats; (b) intact and castrated animals of each sex; (c) untreated castrates and castrates given estradiol or testosterone.Results Sex and endocrine condition influenced sensitivity to i.v. THIP for the induction of anesthesia. ED₅₀ values were: gonadectomized females, 80 mg/kg > intact males, 50 mg/kg > proestrous females, 35 mg/kg > gonadectomized males, 28 mg/kg. Estradiol benzoate (EB; 3 g/day for 5 days) significantly increased THIP sensitivity in gonadectomized females: THIP + EB: ED₅₀=26 mg/kg vs THIP + sesame oil: ED₅₀=94 mg/kg, while testosterone propionate (TP; 10 mg injected 24 h before THIP) decreased THIP sensitivity in orchidectomized males when compared with vehicle-injected animals (ED₅₀=72 mg/kg vs 22 mg/kg, respectively).Conclusions Results suggest that estrogen increases the density or availability of GABA_A receptor subtypes on which THIP acts, while testosterone exerts the opposite effect. Neither sex nor gonadal condition influenced the anesthetic action of epipregnanolone as a similar potency was found in intact and in gonadectomized males and females.     

Comparison of the Rates of Disintegration,Gastric Emptying,and Drug Absorption Following Administration of a New and a Conventional Paracetamol Formulation,Using γ Scintigraphy

Purpose. To investigate the hypothesis that faster drug absorption from a new paracetamol formulation containing sodium bicarbonate compared to that from a conventional formulation results from a combination of enhanced gastric emptying and disintegration/dissolution. Methods. Each formulation was administered in both fasted and fed states to 12 healthy volunteers. Gastric emptying and disintegration times were assessed by scintigraphy, and serum paracetamol concentrations were determined by HPLC. Results. The mean time to complete disintegration of the new tablets was faster than that for conventional tablets in both fasted (10.2 min vs. 22.5 min) and fed (14.3 min vs. 46.4 min) states, although this difference was statistically significant in the fed state only (p = 0.0053). Mean gastric emptying times for the new tablets, as measured by t₅₀ and t₉₀, were also faster than those for conventional tablets in both fasted (t₅₀ = 22.4 min vs. 47.5 min, t₉₀ = 30.9 min vs. 64.1 min) and fed (t₅₀ = 76.9 min vs. 106.4 min, t₉₀ = 152.7 min vs. 155.5 min) states, although these differences were not statistically significant. Two subjects showed dramatically retarded gastric emptying of the new tablets in the fasted state: if these atypical data are excluded, the differences in both t₅₀ and t₉₀ in the fasted state are significant (p = 0.0110 and 0.0035, respectively). Rate of paracetamol absorption reflected the gastric emptying profiles as shown by significant correlation of emptying times with partial AUC. Conclusions. It would seem that a combination of faster disintegration and gastric emptying of the new tablets is responsible for the faster rate of absorption of paracetamol from PA compared to P observed in both this study and in previous studies. The differences in gastric emptying are more pronounced in the fasted state, and the differences in disintegration are more pronounced in the fed state.     

The release of3H-noradrenaline by p- and m-tyramines and -octopamines,and the effect of deuterium substitution in α-position

Summary The³H-noradrenaline-releasing effects of p- and m-tyramines and -octopamines, either deuterated or not, were studied in isolated vasa deferentia of the rat (COMT inhibited and calcium-free solution in all experiments). K _m, for uptake₁ was higher for octopamines than for tyramines, but not increased by the introduction of deuterium in -position, except for (probably contaminated) deuterated p-octopamine. Other tissues were preloaded with³H-noradrenaline. After inhibition of vesicular uptake and MAO equi-releasing concentrations of the eight amines were strictly correlated withK _m, they were 6 to 7 times higher for unsubstituted octopamines than for corresponding tyramines. When only MAO (but not vesicular uptake) was inhibited, this difference decreased to about 4-fold, but the releasing potency of the deuterated amines (relative to their parent amines) remained unchanged (except for p-octopamine). When vesicular uptake and MAO were intact, unsubstituted octopamines were only 1.5 to 2.2 times less potent than the corresponding tyramines. Analysis of the efflux of³H-DOPEG confirmed that this gain in the relative potencies of octopamines is due to their increased ability to mobilize vesicular 3H-noradrenaline; moreover, deuterated amines as well were then better mobilizers than were their parent amines.It is concluded that, provided vesicular uptake is intact, the introduction of a \-OH-group enhances the ability of indirectly acting sympathomimetic amines to mobilize vesicular noradrenaline; the introduction of deuterium in -position, on the other hand, enhances this mobilizing effect exclusively when MAO is intact.Abbreviations used here COMT catechol-O-methyl transferase - DOMA dihydroxymandelic acid - DOPEG dihydroxyphenylglycol - MAO monoamine oxidase - OM-fraction column chromatographic fraction containingall O-methylated metabolites Supported by the Deutsche Forschungsgemeinschaft (SFB 176)     

Comparison of the effects of haloperidol,remoxipride and raclopride on “pre”- and postsynaptic dopamine receptors in the rat brain

Summary The ability of the dopamine receptor antagonists haloperidol, raclopride and remoxipride to prevent the B-HT 920-induced decrease in striatal and limbic L-DOPA accumulation in gamma-butyrolactone (GBL)- and NSD 1015-treated rats (termed GBL-reversal) was used to define the effects of these compounds on presynaptic dopamine receptors. The doses of the dopamine antagonists producing antagonism of GBL-reversal were in each case roughly similar to the doses required to increase dopamine turnover in striatal and limbic areas. The potencies of haloperidol, raclopride and remoxipride in the GBL model were compared with their potencies in behavioural models for postsynaptic dopamine receptors. Haloperidol produced antagonism of GBL-reversal over a similar dose range to that required for antagonism of apomorphine-induced hyperactivity and stereotypy syndromes. Raclopride was effective in the order of potency: antagonism of apomorphine-induced hyperactivity > antagonism of GBL-reversal > antagonism of apomorphine-induced stereotypy. For remoxipride, the dose-response curve for antagonism of GBL-reversal was superimposable over that for antagonism of apomorphine-induced stereotypies, with an ED₅₀ value about 12 times higher than that for antagonism of apomorphine-induced hyperactivity. Thus, the relative potencies of dopamine receptor antagonists at pre- and postsynaptic dopamine receptors vary considerably from compound to compound. Send offprint requests to O. Magnusson     

Effects of Sr2+ and Mg2+ on the phospholipase A and the presynaptic neuromuscular blocking actions of β-bungarotoxin,crotoxin and taipoxin

1.beta-Bungarotoxin, crotoxin and taipoxin, presynaptic neurotoxins of snake venom origin, have about the same phospholipid-splitting activities as a much less toxic cobra phospholipase A2 in the presence of Ca2+ and deoxycholate. 2. Sr2+ was a much less effective activator of the enzymes than is Ca2+, the activation by Sr2+ being only 3-6% for beta-bungarotoxin and crotoxin and 12% for taipoxin. 3. Sr2+ also inhibited the Ca2+ -activated enzymes by 80% in the cases of beta-bungarotoxin and crotoxin, but only 16% in the case of taipoxin. 4. Mg2" had no significant effect on beta-bungarotoxin or crotoxin, but activated taipoxin in the presence or absence of Ca2". 5. In Sr2+ -Tyrode lacking Ca2+ all three toxins exhibited the same immediate depression followed by facilitation in the rat and mouse diaphragms, but the final blocking activity was only 3-10% with beta-bungarotoxin and crotoxin and was 30% with taipoxin. 6. In Sr2+ -Tyrode, increasing in the rate of nerve stimulation had less accelerating effect on the development of neuromuscular block than in Ca2+ -Tyrode for any of the toxins. 7. Removal of Mg2+ from Sr2+ -Tyrode did not diminish the potency of taipoxin in blocking neuromuscular transmission, suggesting that enzyme activity at the outer surface of the axolemma does not contribute to the neuromuscular blocking action. 8. All of the results indicate that there are close correlations between the presynaptic activities of these toxins and their phospholipid-splitting activities in the cationic environment prevailing in the axoplasm. Apparently the final blocking effect of these toxins is due to phospholipase A action within the nerve terminal.