Clozapine-induced gastrointestinal hypomotility: presenting features and outcomes, UK pharmacovigilance reports, 1992-2017.

BACKGROUND: Clozapine-induced gastrointestinal hypomotility (CIGH) affects some 75% of patients treated with clozapine. AIMS: To document the incidence of potentially harmful CIGH in the UK. METHOD: We studied spontaneous UK pharmacovigilance reports recorded as clozapine-related gastrointestinal adverse drug reactions, 1992-2017. RESULTS: There were 527 patients reported with potentially harmful CIGH; 33% (n = 172) died. Deaths averaged 1 per year 1992-1999, 5 per year 2000-2009 and 15 per year 2010-2017. Those who died were older (median 52 years v. 49 years) and had been prescribed clozapine for longer than those who recovered (median 11.3 years v. 4.8 years), but there was no difference in prescribed dose. Within the first 4 years of clozapine treatment, there were 169 reports of CIGH, of which 3% (n = 5) were fatal. At 10-14 years there were 63 reports of CIGH, of which 25% (n = 16) were fatal. Among the deaths, males were younger (median 51, range 22-89 v. median 57, range 24-89 years) with higher clozapine doses (median 450, range 100-900 v. median 300, range 12.5-800 mg/d) than females. In non-fatal CIGH, surgery was the most frequent outcome (n = 92). The procedures included appendectomy, ileostomy, total/partial colectomy, colostomy/stoma and proctosigmoidectomy. Clozapine dosage was reduced in 6 patients, stopped and restarted in 23, 'continued' in 6 and discontinued permanently in at least 76 patients. CONCLUSIONS: The risk of serious morbidity/mortality from CIGH is substantial. The need to actively monitor bowel function and give laxatives to patients treated with clozapine is clear.

Simple methodology for the therapeutic drug monitoring of the tyrosine kinase inhibitors dasatinib and imatinib.

A simple HPLC method has been developed to measure imatinib and N-desmethylimatinib (norimatinib) in plasma or serum at concentrations attained during therapy. Adaptation of this method to LC-MS/MS also allows dasatinib assay. A small sample volume (100 µL HPLC-UV, 50 µL LC-MS/MS) is required and analysis time is <5 min in each case. Detection was by UV (270 nm) or selective reaction monitoring (two transitions per analyte) tandem mass spectrometry. Assay calibration was linear (0.05-10 mg/L imatinib, 0.01-2.0 mg/L norimatinib and 1-200 µg/L dasatinib), with acceptable accuracy (86-114%) and precision (<14% RSD) for both methods. A comparison between whole blood and plasma confirmed that plasma is the preferred sample for imatinib and norimatinib assay. For dasatinib, although whole blood concentrations were slightly higher, plasma is still the preferred sample. Despite considerable variation in the (median, range) plasma imatinib and norimatinib concentrations in patient samples [1.66 (0.02-4.96) and 0.32 (0.01-0.99) mg/L, respectively, N = 104], plasma imatinib was >1 mg/L (suggested target for response) in all but one sample from patients achieving complete molecular response. As to dasatinib, the median (range) plasma dasatinib concentration was 13 (2-143) µg/L (N = 33). More observations are needed to properly assess the potential role of therapeutic drug monitoring in guiding treatment with dasatinib.

Verification of the Bühlmann fCAL turbo faecal calprotectin assay on the Binding Site Optilite benchtop analyser.

Objectives: Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are increasingly prevalent disorders. Faecal calprotectin is useful in the differential diagnosis of IBD from IBS and monitoring IBD activity. We verified the Bühlmann fCAL turbo faecal calprotectin assay on the Binding Site, Optilite benchtop analyser. Design: Accuracy, precision, lower limit of quantitation (LLoQ), and linearity of the Bühlmann fCAL turbo faecal calprotectin assay on the Binding Site, Optilite benchtop analyser were ascertained. Comparison with the Bühlmann Quantum Blue fCAL extended and DiaSorin, Liaison calprotectin assays were also undertaken. Difference between assays was evaluated using the Wilcoxon signed-rank test and method comparison was undertaken using Spearman's rank correlation (rs), difference plots and Passing-Bablok regression analyses. Results: The fCAL turbo assay was linear between 25 and 10,000 µg/g, and the LLoQ was 25 µg/g. Intra-, and inter-assay imprecision was <5%. There was a good agreement (rs = 0.96) and no significant bias (3%, p = 0.10) present between the fCAL turbo and Quantum Blue extended assays. Between the fCAL turbo and DiaSorin, liaison assays there was a good agreement (rs = 0.97), but a significant bias (53%, p = <0.01) was present. Conclusions: The fCAL turbo assay performs well on the Binding Site, Optilite benchtop analyser. Calprotectin results are commutable between with Bühlmann fCAL turbo and Quantum Blue fCAL extended assays, but not between Bühlmann and DiaSorin calprotectin assays.

8†Unexpected retinopathy in a patient presenting with bilateral optic disc swelling.

A 12-year-old boy presented with 5 day history of blurry vision, 'wobbly eyes', tinnitus and difficulty seeing at night. Local ophthalmology noted bilateral optic disc swelling and referred him urgently for neurological investigations.Clinical Findings: At presentation VA was RE 0.00 and LE 0.2 with normal Ishihara colour vision. His extraocular movements were full without manifest strabismus. Fundoscopy showed bilateral optic disc swelling. Electrophysiology unexpectedly revealed a functionally cone isolated retina with markedly abnormal rod function. Pattern VEPs indicated bilateral macular pathway dysfunction affecting left eye more than right eye. Wide field imaging showed bilateral diffusely scattered yellow-white flecks in the midperiphery of each eye. His kinetic visual fields were moderately restricted bilaterally. MRI showed a Chiari 1 malformation with cerebellar tonsil herniation, but LP opening pressure was normal.Differential diagnosis included RDH5 retinopathy or vitamin A deficiency. On questioning he reported a diet restricted to only meat and biscuits. His vitamin A levels were subnormal at 0.14 umol/L (reference range 0.9-2.5umol/l) and he was started on high-dose Vitamin A supplements.Four months after supplementation retinal appearances had normalised, the rod ERGs recovered, nyctalopia and visual field restriction resolved. PVEPs had improved but an element of LE macular pathway dysfunction remained. Optic disc swelling settled leaving mild temporal pallor, particularly of the LE with some RNFL loss.It is important to recognise nutritional Vitamin A deficiency in children as prompt recognition and treatment can improve symptoms, reverse retinal pathology which we have demonstrated with electrophysiological findings.

7†Scoping review of homonymous hemianopia in childhood.

Cerebral visual impairment (CVI) encompasses a heterogeneous group of disorders and a spectrum of types of visual impairments. Research is needed to characterise the different forms of CVI and identify the specific needs of these groups to inform individualised patient care. Homonymous hemianopia (HH) is a definable visual field defect that affect some children with CVI. As part of a new research programme, we conducted a scoping review of the literature on HH in children and young people to map current knowledge and identify evidence gaps.We used the PRISMA extension for Scoping Reviews methodology. Multiple online databases were searched using terms associated with 'homonymous hemianopia' and 'children'. This yielded 1588 papers which were screened by two reviewers. Of these 1001 were excluded at abstract screen and a further 415 excluded after full text review, with full text unavailable for 15. Data were extracted and charted from 157 studies and additional grey literature.Interim analysis shows reported studies are predominantly from high income countries with a paucity of higher-level evidence, and a preponderance of case reports. Most papers reported causative pathology and diagnosis of HH. There was minimal attention to or evidence relating to intervention. Child-specific grey literature on HH was limited.This review collates the current evidence-base for HH in children. It demonstrates the important evidence-gap relating to intervention in these cases that would help inform more individualised care. Similar scoping reviews may be prove useful in assessing the evidence relating to other definable groups within the CVI umbrella.

Visual outcomes and predictors in optic pathway glioma: a single centre study.

BACKGROUND/AIMS: Optic pathway gliomas (OPGs) may cause progressive visual loss despite chemotherapy. Newer, less toxic treatments might be given earlier, depending on visual prognosis. We aimed to investigate the prognostic value of visual evoked potentials (VEP) and optical coherence tomography (OCT). METHODS: A retrospective study of OPG patients (treated 2003-2017) was conducted. Primary outcome was PEDIG category visual acuity in better and worse eyes (good < = 0.2, moderate 0.3-0.6 and poor > = 0.7 logMAR). Binary logistic regression analysis was used to identify predictors of these outcomes. RESULTS: 60 patients (32 Neurofibromatosis type 1 [NF1] and 28 sporadic) had median presentation age 49 months (range 17-183) (NF1) and 27 months (range 4-92) (sporadic). Median follow up was 82 months (range 12-189 months). At follow up 24/32 (75%) of NF1 children and 14/28 (50%) of sporadic children had good better eye visual acuity and 11/32 (34%) of NF1 children and 15/28 (54%) of sporadics had poor worse eye acuity. Mean peripapillary retinal nerve fibre layer (RNFL) thickness predicted good better eye final acuity (OR 0.799, 95%CI 0.646-0.987, p = 0.038). Presenting with visual symptoms (OR 0.22 95% CI 0.001-0.508, p = 0.017) and poorer VEP scores (OR 2.35 95% CI 1.1-5.03, p = 0.027) predicted poor worse eye final acuity. 16 children had homonymous hemianopias at follow up, predicted by poor presenting binocular VEP score (OR 1.449 95%CI 1.052-1.995, p = 0.02). CONCLUSIONS: We found that both RNFL thickness on OCT and VEP were useful in predicting future visual acuity and vision and potentially in planning treatment. We had a high prevalence of homonymous hemianopia.

Atomic structure of the DNA repair [4Fe-4S] enzyme endonuclease III.

The crystal structure of the DNA repair enzyme endonuclease III, which recognizes and cleaves DNA at damaged bases, has been solved to 2.0 angstrom resolution with an R factor of 0.185. This iron-sulfur [4Fe-4S] enzyme is elongated and bilobal with a deep cleft separating two similarly sized domains: a novel, sequence-continuous, six-helix domain (residues 22 to 132) and a Greek-key, four-helix domain formed by the amino-terminal and three carboxyl-terminal helices (residues 1 to 21 and 133 to 211) together with the [4Fe-4S] cluster. The cluster is bound entirely within the carboxyl-terminal loop with a ligation pattern (Cys-X6-Cys-X2-Cys-X5-Cys) distinct from all other known [4Fe-4S] proteins. Sequence conservation and the positive electrostatic potential of conserved regions identify a surface suitable for binding duplex B-DNA across the long axis of the enzyme, matching a 46 angstrom length of protected DNA. The primary role of the [4Fe-4S] cluster appears to involve positioning conserved basic residues for interaction with the DNA phosphate backbone. The crystallographically identified inhibitor binding region, which recognizes the damaged base thymine glycol, is a seven-residue beta-hairpin (residues 113 to 119). Location and side chain orientation at the base of the inhibitor binding site implicate Glu112 in the N-glycosylase mechanism and Lys120 in the beta-elimination mechanism. Overall, the structure reveals an unusual fold and a new biological function for [4Fe-4S] clusters and provides a structural basis for studying recognition of damaged DNA and the N-glycosylase and apurinic/apyrimidinic-lyase mechanisms.

Plasma and Urine Levamisole in Clinical Samples Containing Benzoylecgonine: Absence of Aminorex.

Aminorex has been reported as a metabolite of levamisole in man, but data on the aminorex concentrations in clinical samples are scant. We thus measured levamisole, aminorex and benzoylecgonine in urine, and levamisole and aminorex in plasma using achiral liquid chromatography-high resolution mass spectrometry. Centrifuged urine (50 µL) was diluted with LC eluent containing internal standard (benzoylecgonine-D3, 25 µg/L) (450 µL). For plasma, sample (200 µL) and Tris solution (2 mol/L, pH 10.6, 100 µL) were added to a 60.5 × 7.5 mm i.d. glass test tube. Internal standard solution (ketamine-D4, 200 µg/L) (10 µL) was added and the tube contents vortex-mixed (5 s). Butyl acetate:butanol (9 + 1, v/v; 200 µL) was added and after vortex-mixing (30 s) and centrifugation (13,680 × g, 4 min), the extract was evaporated to dryness and reconstituted in 10 mmol/L aqueous ammonium formate containing 0.1% (v/v) formic acid (150 µL). Prepared samples and extracts (100 µL) were analyzed using an AccucoreTM Phenyl-Hexyl column (2.6 mm a.p.s., 100 × 2.1 mm i.d.) maintained at 40°C. MS detection was in positive mode using heated electrospray ionization (ThermoFisher Q-ExactiveTM). Intra- and inter-assay accuracy and precision were ±20%, and ≤11%, respectively, for all analytes in both matrices. Lower limits of quantitation were 0.1 and 1 µg/L (all analytes) in plasma and urine, respectively. Of 100 consecutive urine samples submitted for drugs of abuse screening containing benzoylecgonine, levamisole was detected in 72 (median 565, range 4-72,970 µg/L). Levamisole was also measured in eight plasma samples (median 10.6, range 0.9-64.1 µg/L). A number of metabolites of levamisole (4-hydroxylevamisole, levamisole sulfoxide, levamisole glucuronide, and hydroxylevamisole glucuronide) were tentatively identified in urine. Neither aminorex, nor any of its reported metabolites were detected in any sample.

Antipsychotic-related fatal poisoning, England and Wales, 1993-2013: impact of the withdrawal of thioridazine.

CONTEXT: Use of second generation antipsychotics in England and Wales has increased in recent years whilst prescription of first generation antipsychotics has decreased. METHODS: To evaluate the impact of this change and of the withdrawal of thioridazine in 2000 on antipsychotic-related fatal poisoning, we reviewed all such deaths in England and Wales 1993-2013 recorded on the Office for National Statistics drug poisoning deaths database. We also reviewed antipsychotic prescribing in the community, England and Wales, 2001-2013. Use of routine mortality data: When an antipsychotic was recorded with other drug(s), the death certificate does not normally say if the antipsychotic caused the death rather than the other substance(s). A second consideration concerns intent. A record of "undetermined intent" is likely to have been intentional self-poisoning, the evidence being insufficient to be certain that the individual intended to kill. A record of drug abuse/dependence, on the other hand, is likely to have been associated with an unintentional death. Accuracy of the diagnosis of poisoning: When investigating a death in someone prescribed antipsychotics, toxicological analysis of biological samples collected post-mortem is usually performed. However, prolonged attempts at resuscitation, or diffusion from tissues into blood as autolysis proceeds, may serve to alter the composition of blood sampled after death from that circulating at death. With chlorpromazine and with olanzapine a further factor is that these compounds are notoriously unstable in post-mortem blood. Deaths from antipsychotics: There were 1544 antipsychotic-related poisoning deaths. Deaths in males (N = 948) were almost twice those in females. For most antipsychotics, the proportion of deaths in which a specific antipsychotic featured either alone, or only with alcohol was 30-40%, but for clozapine (193 deaths) such mentions totalled 66%. For clozapine, the proportion of deaths attributed to either intentional self-harm, or undetermined intent was 44%, but for all other drugs except haloperidol (20 deaths) the proportion was 56% or more. The annual number of antipsychotic-related deaths increased from some 55 per year (1.0 per million population) between 1993 and 1998 to 74 (1.5 per million population) in 2000, and then after falling slightly in 2002 increased steadily to reach 109 (1.9 per million population) in 2013. Intent: The annual number of intentional and unascertained intent poisoning deaths remained relatively constant throughout the study period (1993: 35 deaths, 2013: 38 deaths) hence the increase in antipsychotic-related deaths since 2002 was almost entirely in unintentional poisoning involving second generation antipsychotics. Clozapine, olanzapine, and quetiapine were the second generation antipsychotics mentioned most frequently in unintentional poisonings (99, 136, and 99 deaths, respectively). Mentions of diamorphine/morphine and methadone (67 and 99 deaths, respectively) together with an antipsychotic were mainly (84 and 90%, respectively) in either unintentional or drug abuse-related deaths. Deaths and community prescriptions: Deaths involving antipsychotics (10 or more deaths) were in the range 11.3-17.1 deaths per million community prescriptions in England and Wales, 2001-2013. Almost all (96%) such deaths now involve second generation antipsychotics. This is keeping with the increase in annual numbers of prescriptions of these drugs overall (<1 million in 2000, 7 million in 2013), largely driven by increases in prescriptions for olanzapine and quetiapine. In contrast, deaths involving thioridazine declined markedly (from 40 in 2000 to 10 in 2003-2013) in line with the fall in prescriptions for thioridazine from 2001. CONCLUSIONS: The removal of thioridazine has had no apparent effect on the incidence of antipsychotic-related fatal poisoning in England and Wales. That such deaths have increased steadily since 2001 is in large part attributable to an increase in unintentional deaths related to (i) clozapine, and (ii) co-exposure to opioids, principally diamorphine and methadone.

Inhaled nitric oxide use in preterm infants in California neonatal intensive care units.

OBJECTIVE: To describe inhaled nitric oxide (iNO) exposure in preterm infants and variation in neonatal intensive care unit (NICU) use. STUDY DESIGN: This was a retrospective cohort study of infants, 22 to 33+6/7 weeks of gestational age (GA), during 2005 to 2013. Analyses were stratified by GA and included population characteristics, iNO use over time and hospital variation. RESULTS: Of the 65 824 infants, 1718 (2.61%) received iNO. Infants, 22 to 24+6/7 weeks of GA, had the highest incidence of iNO exposure (6.54%). Community NICUs (n=77, median hospital use rate 0.7%) used less iNO than regional NICUs (n=23, median hospital use rate 5.8%). In 22 to 24+6/7 weeks of GA infants, the median rate in regional centers was 10.6% (hospital interquartile range 3.8% to 22.6%). CONCLUSION: iNO exposure varied with GA and hospital level, with the most use in extremely premature infants and regional centers. Variation reflects a lack of consensus regarding the appropriate use of iNO for preterm infants.

5-Hydroxytryptamine pathways in anxiety and its treatment.

The effects of manipulating 5-hydroxytryptamine (5HT) neuronal function in humans and in animals are reviewed. 5HT pathways do not have a unitary function in modulating anxiety. It is proposed that, rather than acting as input or output channels for brain aversive systems, these pathways provide information concerning waking/motor status, which is crucial to the organisation of appropriate responses to threat. Each terminal region can make use of this information in different ways. Globally, the influence of 5HT neurones on higher centres appears predominantly to facilitate information processing relevant to threat, while their major influence on brainstem centres may be a restraining one.

Outcomes of extremely preterm infants after delivery room cardiopulmonary resuscitation in a population-based cohort.

OBJECTIVE: To describe the relationship of delivery room cardiopulmonary resuscitation (DR-CPR) to short-term outcomes of extremely preterm infants. STUDY DESIGN: This was a cohort study of 22 to 27+6/7 weeks gestational age (GA) infants during 2005 to 2011. DR-CPR was defined as chest compressions and/or epinephrine administration. Multivariable logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) associated with DR-CPR; analysis was stratified by GA. RESULT: Of the 13 758 infants, 856 (6.2%) received DR-CPR. Infants 22 to 23+6/7 weeks receiving DR-CPR had similar outcomes to non-recipients. Infants 24 to 25+6/7 weeks receiving DR-CPR had more severe intraventricular hemorrhage (OR 1.36, 95% CI 1.07, 1.72). Infants 26 to 27+6/7 weeks receiving DR-CPR were more likely to die (OR 1.81, 95% CI 1.30, 2.51) and have intraventricular hemorrhage (OR 2.10, 95% CI 1.56, 2.82). Adjusted hospital DR-CPR rates varied widely (median 5.7%). CONCLUSION: Premature infants receiving DR-CPR had worse outcomes. Mortality and morbidity varied by GA.

Involvement of the locus coeruleus in the potentiation of the quipazine-induced head-twitch response by diazepam and beta-adrenoceptor agonists.

Head-twitching in rats induced by quipazine was reduced by bilateral lesions of the locus coeruleus (LC) produced by 6-hydroxydopamine. Both beta 1-and beta 2-adrenoceptor agonists potentiated the head-twitch induced by quipazine in sham-operated controls. Lesions of the locus coeruleus increased the responses to the beta 1-adrenoceptor agonists, prenalterol and dobutamine, but reduced the response to the beta 2-adrenoceptor agonists, salbutamol and procaterol. Diazepam (0.25 mg/kg) also potentiated the response to quipazine and this was reversed to inhibition by lesions of the locus coeruleus. These results suggest that the beta 1-adrenoceptors involved are postsynaptic and the beta 2-adrenoceptors are presynaptic to neurones of the locus coeruleus and indicate a dual action of diazepam on the head-twitch induced by quipazine. Possible mechanisms for these effects are discussed.

Effects on the 5-hydroxytryptamine-induced head-twitch of drugs with selective actions on alpha1 and alpha2-adrenoceptors.

Effects of agents with selectivity for the alpha1- or alpha2-adrenoceptor have been investigated on the head twitches induced by 5-HT injected into the cerebral ventricles in the mouse. Alpha-adrenoceptor agonists inhibited head-twitching with a rank order of potency: guanabenz, clonidine, phenylephrine, methoxamine. The antagonists yohimbine and piperoxane, potentiated the head-twitch frequency. These results suggest that there may be an involvement of an alpha2-adrenoceptor. Small doses of phenylephrine (s.c.) potentiated the head-twitch. Methoxamine, injected intracerebroventricularly potentiated the head-twitch only when alpha2-adrenoceptors were blocked by a small dose of yohimbine. Prazosin and thymoxamine inhibited the head-twitch, suggesting that alpha1-adrenoceptors also modulate this phenomenon. Yohimbine and phenylephrine increased the incidence of spontaneous head-twitches. A tonic noradrenergic input may be necessary for the occurrence of the head-twitch induced by 5-HT.

The effects of alpha 2-adrenoceptor antagonists on the inhibition of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head shakes by 5-HT1A receptor agonists in the mouse.

1. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), gepirone, buspirone and ipsapirone dose-dependently antagonized the head-shakes induced by 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane hydrochloride (DOI) (1.0 mg kg-1) in mice, when these agents were given i.p. 10 min beforehand. 2. para-Chlorophenylalanine (pCPA) abolished the effect of 8-OH-DPAT (0.1 mg kg-1) and of buspirone (1.0 mg kg-1). (+/-)-Pindolol (5.0 mg kg-1) also antagonized the effect of 8-OH-DPAT (0.1 mg kg-1). 3. The alpha 2-adrenoceptor antagonists, RX811059 (1.0 mg kg-1), idazoxan (0.5 mg kg-1), yohimbine (1.0 mg kg-1) and 1-(2-pyrimidinyl)-piperazine (1-PP) (2.0 mg kg-1) i.p. prevented the antagonistic effect of 8-OH-DPAT (0.1 mg kg-1) on DOI-head-shakes. 4. Orally-administered buspirone, given 60 min beforehand, only reduced DOI-head-shakes at doses of 60 mg kg-1 and above. However, when buspirone (1.0 mg kg-1) was administered orally twice daily for 21 days, DOI-head-shakes were significantly reduced when tested 60 min after the first daily dose on days 5, 12 and 21 and 48 h after withdrawal. 5. A single oral dose of buspirone (1.0 mg kg-1) strongly antagonized DOI-head-shakes when given 24 h after the last of 4 daily doses of 1-PP (2.0 mg kg-1, p.o.) but had no effect on DOI-head-shakes 24 h after the last of 4 daily doses of water (p.o.). 6. A single oral dose of 1-PP (2.0 mg kg-1) abolished the inhibitory effect of i.p. buspirone(1.0 mg kg-1) on DOI-head-shakes in mice which had received water (p.o.) daily on the 4 previous days but not in mice which had received 1-PP (2.0mg kg-1, p.o.) on these days.7. The ability of 5-HT1A receptor agonists to antagonize DOI-head-shakes may be due to an effect at presynaptic 5-HT receptors. It is suggested that 1-PP, formed from buspirone, may act at a2-adrenoceptors to prevent acutely administered oral buspirone from antagonizing DOI-head shakes, but that tolerance occurs to this effect of I-PP, thus revealing the inhibitory effect of buspirone when the latter is given repeatedly.

Effects of 5-HT uptake inhibitors, agonists and antagonists on the burying of harmless objects by mice; a putative test for anxiolytic agents.

1. The effects of 5-hydroxytryptamine (5-HT) uptake inhibitors, agonists and antagonists have been evaluated on mouse marble-burying behaviour, a putative test for anxiolytic agents. The high levels of locomotor activity occurring on first exposure to a circular runway (runway were used as a separate test of non-specific drug effects. 2. Fluvoxamine, zimeldine, indalpine and citalopram dose-dependently inhibited burying without affecting runway activity. 5-Hydroxytryptophan (5-HTP, with carbidopa), 5-methoxy-N,N-dimethyltryptamine, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), buspirione, gepirone and ipsapirone reduced burying only at doses reducing runway activity. RU 24969 increased runway activity at all effective doses. 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI), 1,-(3-trifluoromethylphenyl) piperazine (TFMPP) and 1-(3-chlorophenyl)-piperazine (mCPP) potently and differentially reduced burying at doses below those affecting runway activity. 3. 5-HT antagonists only reduced burying at high doses which also reduced runway activity. Burying inhibition by DOI was antagonized by ritanserin, ICI 169,369 and cyproheptadine but not by pindolol or a low (0.25 mg kg-1) dose of metergoline. Burying inhibition by mCPP was not altered by any of these agents except that it was potentiated by pindolol 5 mg kg-1. 4. Zimeldine burying inhibition was potentiated by ritanserine, ICI 169,369, ICS 205-930, cyproheptadine and pindolol. Runway activity was not affected by these drug combinations. 5. Zimeldine was administered in drinking water at a dose of 10 mg kg-1 daily for 21 days. Burying inhibition had disappeared by day 14 and did not recur 24 or 48h after withdrawal at which times responses to DOI were at control levels.6. Selective inhibition of marble burying was not found to be a property of 5-HT-related putative and actual anxiolytics such as buspirone, gepirone, ipsapirone, ritanserin and ondansetron. Nevertheless it was a general property of both 5-HT uptake inhibitors and 5-HT releasing agents; this generality suggests that elevated synaptic 5-HT could be responsible for the effects of these latter agents. The action of DOI may be attributable to effects at the 5-HT2 receptor but those of the 5-HT agonist and releasing agent mCPP, and the uptake inhibitor zimeldine, could not be attributed to effects at any one 5-HT receptor subtype. This, together with the potentiating effect of several 5-HT antagonists on the response to zimeldine, raises the possibility of multiple interactions between 5-HT receptor subtypes.

Modulation of 5-hydroxytryptamine-induced head-twitch response by drugs acting at GABA and related receptors.

The effects of drugs acting at the gamma-aminobutyric acid (GABA) receptors and other chloride ionophore-related sites have been studied for their ability to modulate the head-twitch induced by 1-5-hydroxytryptophan (5-HTP) in the mouse. The GABAa receptor agonists, muscimol, imidazoleacetic acid and 3-aminopropanesulphonic acid, produced a dose-related potentiation, while bicuculline inhibited the head-twitch. The GABAb receptor agonist, baclofen, produced dose-related inhibition. Diazepam potentiated the head-twitch while the 'inverse' benzodiazepine receptor agonist ethyl-beta-carboline-3-carboxylate inhibited the head-twitch. The antagonist Ro15-1788 also produced inhibition. Ro05-4864, a ligand for the benzodiazepine 'acceptor' site, potentiated the head-twitch. Pentobarbitone and pentylenetetrazol potentiated the 5-HTP-induced head-twitch at low doses, changing to inhibition as the dose was increased. Picrotoxin in subconvulsant doses, produced only potentiation. More than one site may be involved in the action of these substances. GABA, amino-oxyacetic acid and 1-2-4-diaminobutyric acid inhibited the head-twitch, while the GABA-depletor, 3-mercaptopropionic acid potentiated it. Of all the agents tested, only muscimol produced head-twitching when given alone. It was concluded that both GABAa and GABAb receptors modulate the head-twitch response to 5-HTP.

Effects of long-term treatment with contraceptive steroids on plasma and brain tryptophan, brain 5-hydroxytryptamine, and locomotor activity in female mice [proceedings].

PIP: The effects of prolonged daily injections of norethistrone acetate (200 mcg/kg) alone and in combination with ethinyl estradiol (100 mcg/kg) were compared with daily vehicle injection. Locomotor activity was determined continuously for 2 estrus cycles prior to injection, the every 7th day throughout 42 days of treatment. Free and total plasma tryptophan and brain tryptophan and 5-HT (serotonin) were determined on the 43rd day and compared with diestrous values. Locomotor activity declined after both treatments. The norethistrone group had 47% of activity. The combination group was 54% of initial diestrus values. Vehicle controls resumed cyclic changes in locomotor activity within 8 days, while the hormone treatments abolished these cyclic changes. Norethistrone was ineffective in changing brain tryptophan values. The combined treatment caused the reduction of plasma total and free tryptophan, probably due to acceleration of protein synthesis.^ieng

Reasoning strategies for suppositional deductions.

Deductive reasoning shares with other forms of thinking a reliance on strategies, as shown by the results of three experiments on the nature and development of control strategies to solve suppositional deductions. These puzzles are based on assertors who may or may not be telling the truth, and their assertions about their status as truthtellers and liars. The first experiment shows that reasoners make backward inferences as well as forward inferences, to short-cut their way through the alternatives, and the generation of suppositions is a source of difficulty. The second experiment establishes that the elimination of the suppositional status of an individual does not render problems easier. The third experiment shows that reasoners can improve their reasoning accuracy and speed spontaneously, without feedback, and it clarifies the transfer of strategies and their development. We discuss the implications of these data for alternative theories of suppositional deduction and for the relationship between reasoning and other forms of thinking such as problem solving.