Selection for individual recognition and the evolution of polymorphic identity signals in Polistes paper wasps.

Individual recognition (IR) requires individuals to uniquely identify their social partners based on phenotypic variation. Because IR is so specific, distinctive phenotypes that stand out from the crowd facilitate efficient recognition. Over time, the benefits of unique appearances are predicted to produce a correlation between IR and phenotypic variation. Here, we test whether there is an association between elevated phenotypic polymorphism and IR in paper wasps. Previous work has shown that Polistes fuscatus use variable colour patterns for IR. We test whether two less variable wasp species, Polistes dominulus and Polistes metricus, are capable of IR. As predicted, neither species is capable of IR, suggesting that highly variable colour patterns are confined to Polistes species with IR. This association suggests that elevated phenotypic variation in taxa with IR may be the result of selection for identity signals rather than neutral processes. Given that IR is widespread among social taxa, selection for identity signalling may be an underappreciated mechanism for the origin and maintenance of polymorphism.

A comparison of models used to predict MLH1, MSH2 and MSH6 mutation carriers.

BACKGROUND: MMRpro, prediction of mutations in MLH1 and MLH2 (PREMM(1,2)) and MMRpredict are models which were developed to predict the probability that an individual carries a Lynch syndrome-causing mutation. Each model utilizes data from personal and family histories of cancer. To date, no studies have compared these models in a cancer genetics clinic. The purpose of this study was to determine each model's ability to predict the probability of carrying a Lynch syndrome-causing mutation in individuals with a family history of colorectal cancer and to determine their clinical applicability. METHODS: We obtained family pedigrees from 81 individuals who presented for Lynch syndrome testing due to a personal and/or family history of cancer. Data from each pedigree were entered into the models and analyzed using SPSS. RESULTS: We found that MMRpredict, PREMM(1,2) and MMRpro showed similar performances with areas under the receiver-operating characteristic curve of 0.731, 0.765 and 0.732, respectively. MMRpro showed the least dispersion of mutation probability estimates with a P value of 0.205, compared with 0.034 for PREMM(1,2) and 0.001 for MMRpredict. CONCLUSION: We found all three carried out well in a cancer genetics setting, with PREMM(1,2) giving slightly better estimates. There were some significant discrepancies between the models in cases where the proband had endometrial cancer.

The discovery and synthesis of highly potent, A2a receptor agonists.

A series of N6,2-disubstituted adenosine analogues have been synthesized and their functional activity measured against A2a and A1 receptors. Examples of compounds with both a lipophilic N6-substituent and amino-functionalized 2-position were highly active at the A2a receptor on the human neutrophil.

Studies on the effects of adenosine A3 receptor stimulation on human eosinophils isolated from non-asthmatic or asthmatic donors.

OBJECTIVE: This study was designed to demonstrate the presence of adenosine A3 receptors on human peripheral blood eosinophils, and to investigate the effect of A3 receptor stimulation on eosinophil function. MATERIAL: Eosinophils from either non-asthmatic or asthmatic donors. METHODS: Eosinophils were isolated from peripheral venous blood by discontinuous gradient centrifugation and negative immunoselection. Receptor localisation was investigated by immunoblotting and by immunocytochemistry using a novel antibody specific for the human A3 receptor. Two pharmacological responses were studied: elevation of intracellular calcium in single eosinophils, measured by microfluorimetry, and hydrogen peroxide generation in cell suspensions. RESULTS: The expression of A3 receptors by eosinophils was confirmed using the selective antibody. Addition of the A3 receptor selective agonist, IB-MECA (100 nM), produced increases in intracellular calcium in less than 10% of the eosinophils isolated from non-asthmatic donors. These responses were only partially attenuated with the A3 receptor antagonist, I-ABOPX. IB-MECA (0.001-1000 nM) did not stimulate hydrogen peroxide (H2O2) generation, nor did it enhance fMLP- or C5a-stimulated generation of H2O2. In fact high concentrations of IB-MECA inhibited the generation of H2O2 (when stimulated by fMLP or C5a), an effect probably mediated by A2 receptors. Similar results were obtained using eosinophils from asthmatic donors. CONCLUSIONS: Stimulation of adenosine A3 receptors does not appear to be a prime mechanism for free radical generation by human peripheral blood eosinophils.

The effectiveness of local exhaust-ventilated (shrouded) hand power tools used for grinding/sanding composite materials.

The effectiveness of one particular shrouded tool type in capturing composite dust generated during dry machining operations was tested. The effectiveness of the shrouded tool was measured by comparing exposures during identical operations done by the same workers. The operation was conducted by dividing the time into two equal portions, one using an unshrouded tool and the other with same tool shrouded. The operations included sanding and grinding operations of fibrous glass/epoxy composite materials. Unshrouded short-term exposures ranged from 2.17 mg/m3 to 50.81 mg/m3. There was a significant reduction in exposure using the shroud (paired t-test, p = 0.005). The effect of a shroud on respirable dust exposures was inconclusive, because of the limited amount of respirable dust collected in these short-term samples.

Pharmacokinetic-pharmacodynamic modelling of the anti-lipolytic and anti-ketotic effects of the adenosine A1-receptor agonist N6-(p-sulphophenyl)adenosine in rats.

1. The purpose of this study was to develop and validate an integrated pharmacokinetic-pharmacodynamic model for the anti-lipolytic effects of the adenosine A1-receptor agonist N6-(p-sulphophenyl)adenosine (SPA). Tissue selectivity of SPA was investigated by quantification of haemodynamic and anti-lipolytic effects in individual animals. 2. After intravenous infusion of SPA to conscious normotensive Wistar rats, arterial blood samples were drawn for determination of blood SPA concentrations, plasma non-esterified fatty acid (NEFA) and beta-hydroxybutyrate levels. Blood pressure and heart rate were monitored continuously. 3. The relationship between the SPA concentrations and the NEFA lowering effect was described by the indirect suppression model. Administration of SPA at different rates and doses (60 microg kg[-1] in 5 min and 15 min, and 120 microg kg[-1] in 60 min) led to uniform pharmacodynamic parameter estimates. The averaged parameters (mean+/-s.e., n=19) were Emax: -80+/-2% (% change from baseline), EC50: 22+/-2 ng ml(-1), and Hill factor: 2.2+/-0.2. 4. In another group, given 400 microg kg(-1) SPA in 15 min, pharmacodynamic parameters for both heart rate and anti-lipolytic effect were derived within the same animal. The reduction in heart rate was directly related to blood concentration on the basis of the sigmoidal Emax model. SPA inhibited lipolysis at concentrations lower than those required for an effect on heart rate. The EC50 values (mean+/-s.e., n=6) were 131+/-31 ng ml(-1) and 20+/-3 ng ml(-1) for heart rate and NEFA lowering effect, respectively. 5. In conclusion, the relationship between blood SPA concentrations and anti-lipolytic effect was adequately described by the indirect suppression model. For SPA a 6 fold difference in potency was observed between the effects on heart rate and NEFAs, indicating some degree of tissue selectivity in vivo.

Adenosine A3 receptors promote degranulation of rat mast cells both in vitro and in vivo.

OBJECTIVE: To investigate the effects of adenosine receptor agonists and antagonists on 5-HT release from rat isolated pleural mast cells and on plasma protein extravasation in the skin of conscious rats. In vitro METHODS: Rat isolated pleural mast cells were loaded with [14C] 5-HT, sensitised with mouse monoclonal anti-DNP and then challenged with human serum albumin-DNP. DNP-stimulated 5-HT release from mast cells was determined. In vivo METHODS: Rats, loaded intravenously with [125I] human serum albumin, were injected intradermally with adenosine agonists at sites on the back. 30 min later plasma protein extravasation at each injection site was determined. RESULTS: In isolated mast cells, each adenosine agonist enhanced DNP-induced 5-HT release, N6-(3-iodobenzyl)-5-(N-methyl-carboxamidoadenosine), (IB-MECA), being the most potent agonist. The adenosine A1/A2 antagonist, 8-phenyltheophylline (8-PT), had no effect on the response to IB-MECA. In contrast, 3-(4-amino-iodobenzyl)-8-[4-[[[carboxy]methyl]oxy]phenyl]-1-propylxanthi ne, (I-ABOPX), inhibited (pA2 6.2) the IB-MECA responses. In the skin of conscious rats, intradermal IB-MECA produced a marked plasma protein extravasation (PPE) which was mimicked by N6-2-(4-aminophenyl)-ethyladenosine (APNEA). The PPE produced by IB-MECA was not affected by either 8-PT or CGS15943A, but was virtually abolished by cyproheptadine and in rats pre-treated with Compound 48/80. CONCLUSIONS: These results indicate that stimulation of adenosine A3 receptors both enhances degranulation in vitro and directly produces degranulation of rat mast cells in vivo.

Comparison of metalworking fluid mist exposures from machining with different levels of machine enclosure.

This research investigated the efficacy of machine enclosures in reducing employee exposures to metalworking fluid mist. Four hundred fifty-five personal samples from automotive machining and grinding operations collected over six years were divided into three groups based on the type and extent of enclosure and local exhaust ventilation. The sample groups were (1) machining equipment with original equipment manufacturer (OEM) total enclosures and local exhaust ventilation, (2) machining equipment with partial or retrofit enclosures and local exhaust ventilation, and (3) machining equipment with little or no enclosure. The results of the Mann Whitney U test of the three data sets indicated that the employees operating equipment with OEM enclosures had significantly lower exposures than employees operating equipment that had either of the other two control methods. There was no difference between the exposures of operators of equipment with retrofit enclosures compared to operators of equipment without enclosures. The median exposure for operators of equipment with OEM enclosures was 0.21 mg/m3, about half that found with the other two control methods. Each of the data sets was compared to exposure criteria; 100% of the exposures associated with OEM enclosures were below 1.0 mg/m3, and 90% of the exposures were below 0.5 mg/m3. The other two methods were not as effective as OEM in reducing exposure to below these criteria. These results indicate that OEM enclosures provide the most effective control of metalworking fluid mist exposure.

Further investigations into adenosine A1 receptor-mediated contraction in rat colonic muscularis mucosae and its augmentation by certain alkylxanthine antagonists.

1. The alkylxanthine antagonists, 8-phenyltheophylline (8-PT), 8-p-sulphophenyltheophylline (8-SPT) and 1,3,7-trimethylxanthine (caffeine) produced rightward displacements of contractile concentration-effect curves to 5'-N-ethylcarboxamidoadenosine (NECA) in rat isolated colonic muscularis mucosae (RCMM) with concentration-ratios consistent with adenosine receptor blockade. The non-xanthine antagonist, 9 fluro-2-(2-furyl)-5,6-dihydro [1,2,4] triazo to [1,5-c]-quinazin-imine (CGS15943A) also antagonized contractions to NECA with an affinity (pKB8.1-8.5) consistent with adenosine A1 receptor blockade. 2. In addition to producing rightward shifts of the concentration-response curves, the maximum contractions to 5'-N-ethylcarboxamidoadenosine (NECA) were also markedly increased in the presence of 8-PT (by 83 +/- 16% at 1 microM), 8-SPT (by 37 +/- 7% at 10 microM) and caffeine (by 45 +/- 5% at 100 microM) but were unaffected by CGS15943A (at 0.01 and 0.03 microM). 3. As with NECA, the maximum contractions to the adenosine A1 receptor agonists R-phenylisopropyladenosine (R-PIA) and N-[(1S, trans)-2-hydroxyclopentyl] adenosine (GR79236) were both antagonized and augmented by 8-PT. In addition, the contractions to NECA in the presence of 8-PT (1 microM) were inhibited by nanomolar concentrations of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). 4. The non-selective phosphodiesterase (PDE) inhibitor, 3-isobutyl-1-methylxanthine (1 microM) produced a marked increase in the NECA maximum without producing a rightward shift in the NECA curve, whereas a higher concentration (10 microM) virtually abolished responses. The PDE type III inhibitor,milrinone (1 microM), the type IV inhibitor, rolipram (10 microM), and the type V PDE inhibitor, zaprinast(3 microM), were all without effect on NECA responses in RCMM.5. Partial inhibitions of contractions to NECA were produced by indomethacin (at 3 or 10 micro M) or piroxicam (at 3 microM). Responses to GR79236 were also partially inhibited by indomethacin. In the presence of indomethacin, 8-PT was still able to enhance markedly the maximum contractions obtained to NECA in RCMM.6. The present study has shown that certain alkylxanthine antagonists (but not the non-xanthineCGS15943A) produced a marked augmentation of adenosine Al receptor-mediated contractions inRCMM. The mechanism of this augmentation is, as yet, not known but is unlikely to result from inhibition of PDE. This study has also shown that adenosine Al receptor-induced contractions inRCMM are mediated, in part, via products of the cyclo-oxygenase pathway.

Characterization of the adenosine receptors mediating hypothermia in the conscious mouse.

1. The effects of a range of adenosine receptor-selective ligands on body temperature were investigated following intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) injection in conscious mice. The compounds tested were the non-selective adenosine receptor agonist 5'-N-ethyl-carboxamidoadenosine (NECA), the adenosine A1 receptor-selective agonists cyclopentyl-adenosine (CPA), N6-(9R-phenyl-isopropyl)-adenosine (R-PIA) and N-(1S,trans)-[2-hydroxyclopentyl]-adenosine (GR79236), the A2a receptor selective agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxyamidoaden osine (CGS-21680), the A2b receptor agonist N-[(2-methylphenyl)methyl[adenosine (metrifudil) and the A3 receptor agonist N6-(4-aminophenylethyl)adenosine (APNEA). 2. NECA (0.01-1 microgram, i.c.v.), all of the A1-selective agonists (0.01-1 microgram, i.c.v.) and APNEA (0.1-3 micrograms i.c.v.) produced profound and dose-related hypothermia and sedation. However, CGS-21680 (0.1-10 micrograms i.c.v.) and metrifudil (0.01-1 microgram i.c.v.), produced only mild hypothermia at the highest doses tested. 3. The hypothermic response to the A1 receptor-selective agonists, GR79236 and R-PIA was dose-dependently antagonized by peripheral administration of either the non-selective adenosine receptor antagonist, 8-phenyltheophylline (8-PT, approximately 40 and 30 fold rightward shifts of the dose-response curves respectively at 10 mg kg-1, i.p.), or the adenosine A1 receptor-selective antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, approximately 20 fold shift of the GR79236 dose-response curve at 1 mg kg-1, i.p.). The hypothermic response to APNEA was similarly dose-dependently antagonized by the A1 receptor-selective antagonist, DPCPX (5 fold shift at 0.1 mg kg-1, i.p.). 4.8(p-Sulphophenyl)theophylline (8-SPT, 10 and 30 mg kg-1, i.p.), a non-selective adenosine receptorantagonist that penetrates the blood brain barrier poorly, produced only modest antagonism (approximately 2 fold shift at 30 mg kg-1, i.p.) of the hypothermic response to GR79236.5. These data suggest that hypothermia induced by adenosine analogues in the conscious mouse is mediated via adenosine A1 receptors, which are probably located in the CNS.

Characterization of the prejunctional adenosine receptors in the rat anococcygeus muscle.

Adenosine receptor agonists inhibited electrically-evoked contractions of the rat isolated anococcygeus muscle. The compounds tested were: N6-cyclopentyladenosine (CPA), N((S, trans)-2-hydroxycyclopentyl)adenosine (GR79236), the R- and S-isomers of phenylisopropyladenosine (PIA), 5'-N-ethylcarboxamidoadenosine (NECA), ((2-(4-(2-carboxyethyl)phenyl)ethyl)amino)-N-ethylcarbox-amidoa denosine (CGS 21680) and N-((2-methylphenyl)methyl)adenosine (metrifudil). The rank order of agonist potency was: CPA = R-PIA = GR79236 = NECA >> S-PIA > metrifudil > CGS 21680, which is consistent with an effect mediated by adenosine A1 receptors. A similar rank order of potency was obtained for inhibition of electrically-evoked contractions of the guinea-pig ileum. However, there may be a lower receptor reserve in rat anococcygeus compared with the guinea-pig ileum, since higher concentrations of agonists were necessary to produce effects in the anococcygeus than in the guinea-pig ileum and S-PIA behaved as a partial agonist. The effect of NECA was antagonized in rat anococcygeus and guinea-pig ileum by the mixed A1/A2 receptor antagonist, 8-phenyltheophylline (pA2 values of 6.8 and 6.9, respectively). The selective A1-receptor antagonist, 8-cyclopentyl-1,3- dipropylxanthine (DPCPX), also blocked the inhibitory response to NECA in both tissues. Here, however, the pA2 values (9.6 and 8.6, respectively) were slightly but significantly different. These values confirm that the prejunctional adenosine receptors of the rat anococcygeus are of the A1 type, and suggest that they are similar but not necessarily identical to those of the guinea-pig ileum. The differing potencies of DPCPX as an antagonist of NECA between the preparations may reflect a tissue-dependent variation in sensitivity to this antagonist.

Failure of CGS15943A to block the hypotensive action of agonists acting at the adenosine A3 receptor.

1. Adenosine receptor agonists were evaluated for their activity at the putative adenosine A3 receptor which mediates a 'xanthine-resistant' hypotensive response in the anaesthetized rat. The compounds tested were: the A1/A3 receptor agonist, N-[2-(4-aminophenyl)ethyl]adenosine (APNEA), the non-selective adenosine receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA), the adenosine A1 receptor-selective agonists, N-[(1S,trans)-2-hydroxycyclopentyl]adenosine (GR79236) and N6-cyclopentyl adenosine (CPA), the A2a receptor-selective agonists, 2-[[2-[4-(2-carboxyethyl) phenyl] ethyl] amino]-N- ethylcarboxamidoadenosine (CGS21680) and 2-phenylaminoadenosine (CV1808), and the moderately A2b selective agonist, N-[(2-methylphenyl)methyl]adenosine (metrifudil). 2. In confirmation of literature findings, APNEA (1-1000 nmol kg-1) induced hypotension and bradycardia; the hypotension was not blocked by pretreatment with the xanthine antagonist, 8-P-sulphophenyltheophylline (8-sPT; 40 mg kg-1, i.v.), whereas the bradycardia was attenuated. The non-xanthine antagonist, 9-fluoro-2-(2-furyl)-5,6-dihydro [1,2,4]triazolo[1,5-c]- quinazin-5-imine (CGS15943A; 3 mg kg-1 i.v.), also attenuated the bradycardia without affecting the hypotension. 3. The adenosine A1 receptor-selective agonists, GR79236 and CPA, both produced dose-dependent falls in blood pressure and heart rate which were antagonized by 8-sPT (40 mg kg-1) and CGS15943A (3 mg kg-1). 4. The adenosine A2a receptor-selective agonists, CGS21680 and CV1808, produced only a hypotensive response which was antagonized by 8-sPT (40 mg kg-1) and to a much greater extent by CGS15943A (3 mg kg-1), consistent with the response being mediated solely by A2a receptors. 5. The modestly A2b receptor-selective agonist, metrifudil, produced a dose-dependent fall in blood pressure and at higher doses a fall in heart rate. The hypotension induced by metrifudil was not antagonized by either 8-sPT (40 mg kg-1) or CGS15943A (3 mg kg-1) even though the bradycardia was abolished, suggesting that this agonist activates the putative A3 receptor.6. The non-selective adenosine receptor agonist, NECA, produced a hypotension and bradycardia that was attenuated by 8-sPT (40 mg kg-1), confirming previous work. The non-xanthine antagonist,CGS15943A (3 mg kg-'), also attenuated the hypotension and bradycardia. The bradycardia was blocked to a much greater extent, suggesting that NECA may therefore induce hypotension partly by activating the putative A3 receptor.7. In conclusion, we have confirmed that the putative A3 receptor mediating hypotension in the anaesthetized rat is not blocked by 8-sPT, and further shown that it is not blocked by CGS15943A. The A2a agonists CGS21680 and CV1808 showed no discernible activity at the A3 receptor, whereas APNEA,NECA, CPA and metrifudil appear to activate this receptor. The adenosine A1 receptor agonist,GR79236, shows considerable selectivity for the A1 receptor but may activate the A3 receptor at high doses.

1,3-Dipropyl-8-cyclopentyl xanthine (DPCPX): a useful tool for pharmacologists and physiologists?

There is now ample evidence in the literature to demonstrate the selectivity of action of DPCPX for adenosine A1 vs other adenosine receptor types in tissues derived from a wide range of species. However, care has to be exercised to ensure that its physiochemical properties do not result in the production of quantitatively misleading data. In experiments using canine tissues the still limited data available in the literature clearly and consistently demonstrate that DPCPX has a lower affinity than expected in preparations which would be anticipated to contain A1 receptors. A range of in vitro experiments also demonstrate that DPCPX is not always a "neutral" or "silent" antagonist. The mechanism underlying these additional effects is unclear, but may result from an ability of the compound to disrupt the normal interaction of the A1 receptor with Gi, or may be indicative of a lack of specificity of action. The limited evidence available suggests that the compound retains its selectivity and specificity of action in vivo, and early work indicates that the compound is proving to be a useful tool with which to explore the potential of activation of adenosine A1 receptors as an important mechanism in physiological and pathophysiological processes.

Characterization of the adenosine receptor mediating contraction in rat colonic muscularis mucosae.

1. The objective of this study was to characterize the adenosine receptor mediating contraction in rat isolated colonic muscularis mucosae (RCMM). 2. Sequential additions of the adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA; 0.01-10 microM) elicited reproducible, concentration-related contractions in RCMM. The effects of NECA were mimicked by the adenosine A1 receptor-selective agonists cyclopentyladenosine (CPA), R-phenylisopropyladenosine (R-PIA) and N-[1S, trans)2-hydroxycyclopentyl] adenosine (GR79236) and by S-PIA (the stereoisomer of R-PIA). The adenosine A2 agonists N-[(2-methylphenyl)methyl] adenosine (metrifudil) and 2-[p-(2-carboxyethyl)phenethylamine]-5'-N-ethylcarboxamidoadenosine (CGS21680) also produced contractions in RCMM but were 54 and 165 times less potent respectively than NECA. The rank order of agonist potency for contraction of RCMM was CPA > or = GR79236 = R-PIA > or = NECA > > S-PIA = metrifudil > CGS21680, which is identical to that reported for the inhibition of spontaneous rate in rat isolated right atria and inhibition of lipolysis in rat isolated adipocytes by these same agonists. 3. R-PIA, S-PIA and metrifudil behaved as partial agonists in RCMM. 4. The adenosine A1 receptor-selective antagonist 8-cyclopentyl-1,3- dipropylxanthine (DPCPX) inhibited the contractions produced by all the adenosine agonists tested, with pKB values between 9.2 and 9.5. The non-selective adenosine antagonist 8-phenyltheophylline (8-PT) antagonized the effects of NECA but also markedly potentiated (by 93.0 +/- 10.2% at 3 microM) the maximum contractile response to NECA in RCMM. Neither 8-PT (3 microM) nor DPCPX (0.1 microM) had any effect on the contractions produced by carbachol. 5. The contractile responses to NECA in RCMM were not affected by atropine (1 microM), tetrodotoxin(0.3 microM) or the P2 antagonist, suramin (100 microM).6. The present study confirms that contractions to adenosine agonists in the RCMM are mediated via adenosine Al receptors.

The use of treatment progress scales in client monitoring and evaluation.

This article describes a multiple-use patient monitoring and evaluation system, the Treatment Progress Scales (TPS), which has been used for the last six years on 4,600 psychiatric and chemically dependent patients in a state-operated mental health facility. The system has been used for patient monitoring, management information, and program evaluation purposes. The article summarizes these and offers a brief overview of the TPS, its psychometric properties, and its advantages and disadvantages.

Synthesis, antinociceptive activity, and opioid receptor profiles of substituted trans-3-(decahydro- and octahydro-4a-isoquinolinyl)phenols.

A series of trans-3-(6- and 7-substituted-decahydro-4a-isoquinolinyl)phenols and trans-3-(octahydro-4a-isoquinolinyl)phenols have been synthesized as potential opioid analgesics. Using a combination of in vitro and in vivo test systems, the receptor profiles of selected compounds have been assessed and in some instances distinguish between mu- and kappa-receptor agonists. In general, introduction of a 6-exocyclic methylene group into the trans-3-(decahydro-4a-isoquinolinyl)phenol system enhanced both antinociceptive activity and kappa-opioid receptor selectivity. For each series, analogues bearing an N-cyclopropylmethyl substituent exhibited greater kappa-receptor selectivity while N-methyl derivatives showed greater mu-receptor selectivity. The 7-substituted compounds (3b) were significantly less potent antinociceptive agents than their 6-substituted counterparts (3a), the octahydroisoquinoline analogues exhibiting intermediate activity. The axial 8-methyl-6-exocyclic methylene isoquinoline (20) is the most potent compound in the mouse abdominal constriction assay (ED50 = 0.05 mg/kg sc), whereas the equatorial 8-methyl isomer (16) was significantly less potent (ED50 = 3.3 mg/kg sc).

Characterization of dopamine autoreceptors in the amygdala: a fast cyclic voltammetric study in vitro.

The present study has employed the technique of fast cyclic voltammetry to measure electrically-evoked dopamine release within the central amygdaloid complex in a rat brain slice. Local electrical stimulation caused the release of an electroactive substance which was identified, biochemically and pharmacologically, as being neuronal dopamine. Dopamine release could be inhibited by the dopamine D2 receptor agonist, quinpirole, but not by the D1 receptor agonist, SKF38393. Quinpirole-induced inhibitions were antagonized by sulpiride, metoclopramide and clozapine but not by SCH23390. It is concluded that dopamine release in the amygdala can be modulated by presynaptic D2 receptors which appear to be the same type as those found in striatum and nucleus accumbens.

Presynaptic regulation of electrically evoked dopamine overflow in nucleus accumbens: a pharmacological study using fast cyclic voltammetry in vitro.

Fast cyclic voltammetry has been used to measure electrically evoked dopamine overflow from slices of rat nucleus accumbens in vitro. The substance detected was shown voltammetrically and biochemically to be dopamine of neuronal origin. Enough dopamine was released by a single electrical pulse to be easily detectable, and under these conditions there was no auto-inhibition by the endogenous transmitter (as demonstrated by the failure of dopamine antagonists to increase the amount released). There was no significant inhibition, or enhancement, of release by agonists at the following receptor types: dopamine D1, 5-hydroxytryptamine, cholinoceptors, alpha 1-, alpha 2-, beta-adrenoceptors, cholecystokinin or neurotensin receptors. However, the dopamine D2 receptor agonist, quinpirole, was capable of totally inhibiting the release; this effect was concentration-dependently antagonized by the D2 antagonists haloperidol, sulpiride, metoclopramide and clozapine, with potencies which corresponded to their affinities for D2 receptors in striatal tissue. The results show that the presynaptic receptors on dopaminergic nerve terminals are of the D2 type and apparently identical to those in the corpus striatum.