One-stop microvascular screening service: an effective model for the early detection of diabetic peripheral neuropathy and the high-risk foot.

AIMS: To evaluate the feasibility of a one-stop microvascular screening service for the early diagnosis of diabetic distal symmetrical polyneuropathy, painful distal symmetrical polyneuropathy and the at-risk diabetic foot. METHODS: People with diabetes attending retinal screening in hospital and community settings had their feet examined by a podiatrist. Assessment included: Toronto Clinical Neuropathy Score evaluation; a 10-g monofilament test; and two validated, objective and quick measures of neuropathy obtained using the point-of-care devices 'DPN-Check', a hand-held device that measures sural nerve conduction velocity and amplitude, and 'Sudoscan', a device that measures sudomotor function. The diagnostic utility of these devices was assessed against the Toronto Clinical Neuropathy Score as the 'gold standard'. RESULTS: A total of 236 consecutive people attending the retinal screening service, 18.9% of whom had never previously had their feet examined, were evaluated. The prevalence of distal symmetrical polyneuropathy, assessed using the Toronto Clinical Neuropathy Score, was 30.9%, and was underestimated by 10-g monofilament test (14.4%). The prevalence of distal symmetrical polyneuropathy using DPN-check was 51.5% (84.3% sensitivity, 68.3% specificity), 38.2% using Sudoscan foot electrochemical skin conductance (77.4% sensitivity, 68.3% specificity), and 61.9% using abnormality in either of the results (93.2% sensitivity, 52.8% specificity). The results of both devices correlated with Toronto Clinical Neuropathy Score (P<0.001). A new diagnosis of painful distal symmetrical polyneuropathy was made in 59 participants (25%), and 56.6% had moderate- or high-risk foot. Participants rated the service very highly. CONCLUSIONS: Combined, eye, foot and renal screening is feasible, has a high uptake, reduces clinic visits, and identifies painful distal symmetrical polyneuropathy and the at-risk foot. Combined large- and small-nerve-fibre assessment using non-invasive, quantitative and quick point-of-care devices may be an effective model for the early diagnosis of distal symmetrical polyneuropathy.

Impacts of Coastal Development on the Ecology of Tidal Creek Ecosystems of the US Southeast including Consequences to Humans.

Upland areas of southeastern U.S. tidal creek watersheds are popular locations for development, and they form part of the estuarine ecosystem characterized by high economic and ecological value. The primary objective of this work was to define the relationships between coastal development, with its concomitant land use changes and associated increases in nonpoint source pollution loading, and the ecological condition of tidal creek ecosystems including related consequences to human populations and coastal communities. Nineteen tidal creek systems, located along the southeastern United States coast from southern North Carolina to southern Georgia, were sampled during summer, 2005 and 2006. Within each system, creeks were divided into two primary segments based upon tidal zoning: intertidal (i.e., shallow, narrow headwater sections) and subtidal (i.e., deeper and wider sections) and then watersheds were delineated for each segment. Relationships between coastal development, concomitant land use changes, nonpoint source pollution loading, the ecological condition of tidal creek ecosystems, and the potential impacts to human populations and coastal communities were evaluated. In particular, relationships were identified between the amount of impervious cover (indicator of coastal development) and a range of exposure and response measures including increased chemical contamination of the sediments, increased pathogens in the water, increased nitrate/nitrite levels, increased salinity range, decreased biological productivity of the macrobenthos, alterations to the food web, increased flooding potential, and increased human risk of exposure to pathogens and harmful chemicals. The integrity of tidal creeks, particularly the headwaters or intertidally-dominated sections, were impaired by increases in nonpoint source pollution associated with sprawling urbanization (i.e., increases in impervious cover). This finding suggests these habitats are valuable early warning sentinels of ensuing ecological impacts and potential public health and flooding risk from sprawling coastal development. Results also validate the use of a conceptual model with impervious cover thresholds for tidal creek systems in the southeast region.

New perspectives for the treatment of disorders of sleep and arousal.

A variety of molecules with novel mechanisms of action are currently being evaluated for their potential as treatments for sleep disorders. The GABA-A receptor complex remains an important target for hypnotic drugs (eg gaboxadol, indiplon). However, drugs acting through histamine, calcium channels and serotonin receptors may also be of interest for the treatment of insomnia. In the case of the 5HT2A subtype of serotonin receptors, several molecules which improve sleep maintenance and modify sleep architecture by increasing slow wave sleep are currently being tested (eg eplivanserin). Two new drugs with efficacy in excessive sleepiness (modafinil, sodium oxybate) have improved the treatment of this condition. However, the mechanisms of action of these agents are poorly understood. The recent discovery of the hypocretin arousal system in the hypothalamus may aid the identification of additional new drugs. An agonist at receptors for the pineal hormone melatonin is available in some countries (ramelteon) but is currently used only for the treatment of insomnia associated with difficulties of sleep onset. Additional melatonin receptor agonists are being developed and may have potential for treating several conditions including circadian rhythm disorders and depression.

Dietary transfer of fluoranthene from an estuarine oligochaete (Monopylephorus rubroniveus) to grass shrimp (Palaemonetes pugio): Influence of piperonyl butoxide.

The objective of this study was to determine the potential for dietary transfer of sediment-associated fluoranthene from tubificid oligochaetes (Monopylephorus rubroniveus) to grass shrimp (Palaemonetes pugio). Grass shrimp, either in the presence or absence of sublethal waterborne concentrations of the metabolic inhibitor, piperonyl butoxide (PBO), were fed fluoranthene-dosed oligochaetes for 5-days. All grass shrimp bioaccumulated fluoranthene; however, bioaccumulation was 3X higher in the presence of PBO. Trophic transfer coefficients (TTCs) were 0.02 and 0.01 in the presence and absence of PBO, respectively. Following the 5-day accumulation period, shrimp in both treatments were allowed to depurate for 3 days. Depuration rates were significantly higher in PBO-exposed shrimp. These results demonstrated that sediment-associated fluoranthene can be transferred through the diet from oligochaetes to grass shrimp, and the presence of PBO enhanced fluoranthene bioaccumulation. However, the comparatively low TTCs suggest that biomagnification of fluoranthene in estuarine food webs is low.

An evaluation of polycyclic aromatic hydrocarbon (PAH) runoff from highways into estuarine wetlands of South Carolina.

This study investigated the concentrations and potential toxicity of polycyclic aromatic hydrocarbons (PAHs) associated with highway runoff into adjacent estuarine wetlands from road segments representing three levels of average daily traffic (ADT): low (<5,000 ADT), moderate (10,000-15,000 ADT), and high use (>25,000 ADT) based on SC Department of Transportation data. Sediments from three estuarine wetland habitats (tidal creeks, Spartina marsh, and mud flats) adjacent to these road segments were sampled to represent nine highway use class/habitat type combinations. Surficial sediments were collected at 3, 25, and 50 meters from the upland/wetland interface along transects established perpendicular to the road at each site, with additional samples taken from the road berm. Average PAH concentrations, representing 25 compounds, ranged from 3.9 to 11,000 ng/g dry weight. Berm samples had significantly greater total PAH concentrations than samples taken in any of the wetland habitats. Average total PAH concentrations decreased with increasing distance from the road berm within the wetland habitats sampled, but the differences were not statistically significant. Average total PAH concentrations also were not significantly different among the wetland habitats compared. Analysis of PAH profiles indicated that the PAH source was dominated by pyrogenic combustion products rather than from petrogenic sources. This, combined with the presence of dibenzothio-phene, which is a tire oxidation product, indicated that the primary source of PAHs was related to vehicles. Two sites with total PAH concentrations exceeding published bioeffects levels were resampled for bioassay tests using the amphipod Ampelisca verrilli, the polychaete Streblospio benedicti, and the clam, Mercenaria mercenaria, with the first two assays conducted under UV lighting since previous studies had demonstrated enhanced UV toxicity of PAHs for these species. No toxicity was observed in the amphipod or polychaete assays. Toxicity was observed in the juvenile clam assay at one site, possibly due to the combined effects of PAHs and other contaminants present.

The preclinical pharmacologic profile of tiapride.

Tiapride is a benzamide derivative that has been used successfully in the clinic for a number of years for the treatment of agitation and aggressiveness in elderly patients. Like many substituted benzamides, tiapride specifically blocks dopamine receptors in the brain. It has affinity for dopamine D(2) (IC(50) = 110-320 nM) and D(3) (IC(50) = 180 nM) receptors in vitro but lacks affinity for dopamine D(1) and D(4) receptors and for non-dopaminergic receptors including H(1), alpha(1), alpha(2)-adrenergic and serotonergic receptors. Tiapride also shows dose-related inhibition of [3H]-raclopride binding in limbic areas and in the striatum of the rat in vivo (ED(50) approximately 20 mg/kg, ip). In microdialysis experiments, tiapride (over the range 10-30 mg/kg, ip) increased extracellular levels of dopamine in the nucleus accumbens and striatum, a reflection of its blockade of postsynaptic dopamine receptors in these brain areas. In behavioral experiments in rats, lower doses of tiapride (ED(50) = 10 mg/kg, ip) antagonised dopamine agonist-induced hyperactivity while higher doses (ED(50) = 60 mg/kg, ip) were required to block stereotyped movements. In addition, doses of tiapride up to 200 mg/kg, ip failed to induce catalepsy, an effect observed with many other drugs which block dopamine receptors. In tests of conditioned behavior in rats, tiapride was found to give rise to an interoceptive stimulus associated with dopamine receptor blockade at doses (ED(50) = 2.2 mg/kg, ip) much lower than those producing motor disturbances or sedation (ED(50) = 40 mg/kg, ip), in striking contrast to a range of conventional or atypical neuroleptics that produced interoceptive stimulus and sedation at similar doses. Furthermore, the acquisition by rats of a place-learning task in a water maze was not affected by tiapride (over the range 3-30 mg/kg, ip), whereas haloperidol (MED = 0.25 mg/kg, ip) and risperidone (MED = 0.03 mg/kg, ip) impaired performance. The preclinical pharmacologic and behavioral profile of tiapride suggests that its clinical activity may be due to a selective blockade of dopamine D(2) and D(3) receptors in limbic brain regions. The results are also consistent with a lack of motor or cognitive side effects.

Magnifying prismatic lenses for vitrectomy.

PURPOSE: Viewing the fundus at higher magnification during vitrectomy makes surgical procedures much safer; however, the scope of magnification of the peripheral fundus has been limited. For better visualization of the periphery of the fundus, we have developed two new contact lenses called magnifying prismatic lenses. METHODS: The magnifying 15 degrees and 30 degrees prismatic lenses are made of a glass with a high index of refraction (n = 1.883). The lenses have a convex upper surface to provide a magnified view of the peripheral fundus. RESULTS: These magnifying 15 degrees and 30 degrees prismatic lenses provide an approximately 2x magnified view of the peripheral fundus. They also provide a more extensive view of the peripheral fundus than a regular (plano-concave) prismatic lens when the eye is tilted. CONCLUSION: The magnifying prismatic lenses are useful for viewing into the peripheral fundus with higher magnification.

Pharmacological and molecular targets in the search for novel antipsychotics.

The recent enthusiasm among clinicians for the so-called 'atypical antipsychotics' has both improved treatment for schizophrenic patients and provided a welcome stimulus for basic research on antipsychotic mechanisms. Even the newer drugs have shortcomings, and research is underway aimed at identifying novel agents with greater efficacy and safety. Much of this effort is directed towards compounds which, in addition to blocking dopamine receptors, also act on other neurotransmitter receptors such as 5-HT2, 5-HT1A and alpha2-adrenergic receptors. However, there is also a large amount of scientific activity seeking to discover and develop selective dopamine receptor subtype antagonists (including compounds which specifically block D3 or D4 receptors) or drugs that specifically target the dopamine autoreceptor. Finally, a number of drug development programmes are searching for non-dopaminergic antipsychotics. Drugs that do not have affinity for dopamine receptors but act through neurotensin, sigma or cannabinoid CB1 receptors or glutamatergic mechanisms are currently being evaluated. If any of these agents prove to have clinical efficacy this may lead to a third generation of antipsychotics. It is likely, however, that the mechanisms of action of such drugs will nevertheless imply the intimate involvement of dopaminergic pathways.

The effects of compounds varying in selectivity as 5-HT(1A) receptor antagonists in three rat models of anxiety.

Compounds varying in selectivity as 5-HT(1A) receptor antagonists have recently been reported to produce benzodiazepine-like antianxiety effects in mice. To assess the cross-species generality of these findings, the present experiments compared the effects of diazepam (0.625-5 mg/kg) with those of several non-selective (MM-77, 0.03-1 mg/kg and pindobind-5-HT(1A), 0.1-5 mg/kg) and selective (WAY100635, 0.01-10 mg/kg, p-MPPI, 0.01-3 mg/kg and SL88.0338, 0.3-10 mg/kg) 5-HT(1A) receptor antagonists in three well-validated anxiolytic screening tests in rats: punished lever-pressing, punished drinking, and the elevated plus-maze. In the punished lever-pressing conflict test, none of the 5-HT(1A) receptor antagonists modified rates of punished responding, whereas in the punished drinking test, WAY100635 (0.3-1 mg/kg), SL88.0338 (3-10 mg/kg), p-MPPI (1 mg/kg), MM-77 (0.03-0.3 mg/kg), but not pindobind-5-HT(1A), produced clear anticonflict activity. However, the increase in punished responding with the 5-HT(1A) compounds was smaller than that produced by diazepam, indicating weaker anxiolytic-like activity. In the elevated plus-maze test, WAY100635 (0.1-0.3 mg/kg), SL88.0338 (0.3-10 mg/kg), MM-77 (0.01-3 mg/kg), pindobind-5-HT(1A) (0.1-3 mg/kg), but not p-MPPI, showed anxiolytic-like activity on traditional behavioral indices, increasing the percentage of time spent in open arms and the percentage of open arm entries. As was the case in the punished drinking test, the magnitude of the positive effects of the 5-HT(1A) compounds was generally smaller than that of diazepam. Of the ethological measures recorded in the plus-maze, all compounds markedly decreased risk assessment (i.e. attempts) over the entire dose-range, but only diazepam clearly increased directed exploration (i.e. head-dipping). Although the present results demonstrate that 5-HT(1A) receptor antagonists elicit anxiolytic-like effects in rats, this action appears to be test-specific and, unlike previous findings in mice, smaller than that observed with benzodiazepines. The data are discussed in relation to the possible relevance of species differences in 5-HT(1A) receptor function and the nature of the anxiety response studied.

Characterisation of the effects of nicotine in the five-choice serial reaction time task in rats: antagonist studies.

RATIONALE: Nicotine has been shown to decrease reaction time and increase anticipatory responses in a five-choice serial reaction time task (5-CSRTT) in rats, but the receptor mechanisms mediating this effect remain unknown. OBJECTIVES: To evaluate further the effects of nicotine in this task and to characterise the receptors mediating these effects. METHODS: Using a standard 5-CSRTT protocol, rats were trained to respond to a 0.5-s visual stimulus, which was reduced to 0.25 s for experimental sessions to induce a performance decrement. The effects of acute (0.03-0.3 mg/kg IP) and repeated (0.1 and 0.3 mg/kg IP for 5 days) nicotine were studied, as was the ability of mecamylamine (1 mg/kg IP), hexamethonium (5 mg/kg IP), dihydro-beta-erythroidine (6 mg/kg IP) and methyllycaconitine (10 mg/kg IP) to antagonise the effects of acute nicotine. RESULTS: Nicotine had no effect on accuracy, but decreased response latencies, improved performance in the less-well attended stimulus locations and increased inappropriate responding after both acute and repeated treatment. The data suggest that nicotine improves readiness to respond and improves target scanning, and decreases the ability to withhold premature responses (i.e. increased impulsivity). Except for the reduction in error latency, all of the effects of nicotine were antagonised by the non-selective, centrally acting antagonist mecamylamine, whereas the peripheral antagonist hexamethonium had no effect, demonstrating that nicotine's actions are central in origin. Dihydro-beta-erythroidine, a competitive nicotinic antagonist, antagonised all of the effects of nicotine. In contrast, the alpha7 antagonist methyllycaconitine had no significant effects against nicotine. CONCLUSIONS: These results demonstrate that the alpha7 receptor subtype is not involved in the effects of nicotine in the 5-CSRTT and that its effects are more likely to be mediated by a receptor(s) such as alpha4beta2, alpha4beta4 and/or alpha3beta2 which is sensitive to antagonism by dihydro-beta-erythroidine.

Haloperidol-induced catalepsy is absent in dopamine D(2), but maintained in dopamine D(3) receptor knock-out mice.

We have previously found that mice homozygous for the deletion of the dopamine D(2) receptor gene (D(2)(-/-) mice) do not present spontaneous catalepsy when tested in a "bar test". In the present study, we sought to analyse the reactivity of D(2) receptor mutant mice to the cataleptogenic effects of dopamine D(2)-like or D(1)-like receptor antagonists. In parallel, we assessed the cataleptogenic effects of these antagonists in dopamine D(3) receptor mutant mice. D(2)(-/-) mice were totally unresponsive to the cataleptogenic effects of the dopamine D(2)-like receptor antagonist haloperidol (0.125-2 mg/kg i.p.), while D(2)(+/-) mice, at the highest haloperidol doses tested, showed a level of catalepsy about half that of wild-type controls. The degree of haloperidol-induced catalepsy was thus proportional to the level of striatal dopamine D(2) receptor expression (0.50, 0.30 and 0.08 pmol/mg protein as measured at 0.25 nM [3H]spiperone for D(2)(+/+), D(2)(+/-) and D(2)(-/-) mice, respectively). However, D(2)(-/-) and D(2)(+/-) mice were as sensitive as their wild-type counterparts to the cataleptogenic effects of the dopamine D(1)-like receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390: 0.03-0.6 mg/kg s.c.). Striatal dopamine D(1) receptor expression (as measured using [3H]SCH 23390 binding) was not significantly affected by the genotype. The ability of SCH 23390 to induce catalepsy in D(2)(-/-) mice suggests that their resistance to haloperidol-induced catalepsy is due to the absence of dopamine D(2) receptors, and not to the abnormal striatal synaptic plasticity that has been shown by others to occur in these mice. In agreement with the observation that dopamine D(2) and dopamine D(1) receptor expression was essentially identical in D(3)(+/+), D(3)(+/-) and D(3)(-/-) mice, dopamine D(3) receptor homozygous and heterozygous mutant mice, on the whole, did not differ from their controls in the time spent in a cataleptic position following administration of either haloperidol (0.5-2 mg/kg i.p.) or SCH 23390 (0.03-0.6 mg/kg s.c.). Also, dopamine D(3) receptor mutant mice were no more responsive than wild-type controls when co-administered subthreshold doses of haloperidol (0.125 mg/kg) and SCH 23390 (0.03 mg/kg), suggesting that dopamine D(3) receptor knock-out mice are not more sensitive than wild-types to the synergistic effects of concurrent blockade of dopamine D(2) and dopamine D(1) receptors in this model. These results suggest that the dopamine D(2) receptor subtype is necessary for haloperidol to produce catalepsy, and that the dopamine D(3) receptor subtype appears to exert no observable control over the catalepsy produced by dopamine D(2)-like, D(1)-like and the combination of D(1)-like and D(2)-like receptor antagonists.

Cultural analysis of communication behaviors among juveniles in a correctional facility.

This study addressed communication behaviors of female juvenile delinquents in a correctional facility. Qualitative methodology was used to study 78 participants ranging in age from 13.1 to 18.9 (years; months), over a five-month period. Data collection consisted of observations, participant observation, interviews, and a review of documents. Additionally, participants were tested on the Clinical Evaluation of Language Fundamentals-3. Listening and following rules, utterance types, topics of conversion, politeness, and conversational management emerged as themes. Findings indicated that as many as 22% of participants were potential candidates for language services. Implications for speech-language pathologists (SLPs) providing communication services will be provided.

Differences in anxiety-related behaviours and in sensitivity to diazepam in inbred and outbred strains of mice.

RATIONALE: Natural strain differences exist in mice for behavioural traits such as emotional reactivity. OBJECTIVE: The present experiments compared the behavioural profiles of nine strains of mice (BALB/c, C57BL/6, C3H, CBA, DBA/2, NMRI, NZB, SJL, Swiss) in two models of anxiety after the administration of the benzodiazepine diazepam. METHODS: The tests used were the light/dark choice task and the elevated plus-maze, two well-validated anxiolytic screening tests. RESULTS: In vehicle-treated animals, differences on variables designed to measure anxiety-related behaviours were observed in both tests. In the light/dark test, the strains could be divided into three distinct groups: two non-reactive strains (NZB and SJL), an intermediate-reactive group (C3H, CBA, DBA/2, NMRI, C57BL/6 and Swiss), and one highly reactive strain (BALB/c). In the elevated plus-maze, SJL, NMRI, CBA and, to a lesser extent, C3H strains of mice, consistently showed low levels of anxiety-related behaviours. Intermediate levels were seen in the Swiss and BALB/c strains, and high levels of emotional reactivity were seen in C57BL/6, DBA/2 and NZB. The strain distribution between the light/dark and the elevated plus-maze tests shows similarities and differences, suggesting that each of these experimental procedures represents a different set of behaviours. Marked differences between a number of strains of mice in their sensitivity to the anxiolytic-like action of diazepam were observed in both the light/dark and the elevated plus-maze tests. Mice of the BALB/c, Swiss and, to a lesser extent, CBA and C3H strains were responsive to diazepam in both tests, although in the case of CBA mice, effects may have been contaminated by behavioural suppression. SJL mice were largely unresponsive to the action of the benzodiazepine in both tests, whereas in C57, DBA/2, NMRI and NZB mice, diazepam produced positive effects only in the elevated plus-maze. CONCLUSION: The finding of differential strain distributions both with and without diazepam treatment in the light/dark and the elevated plus-maze tests, indicates that not all strains of mice are suitable for investigating the effects of GABA/BZ receptor ligands. This study may thus provide a useful guide for choosing the best strain of mice for studying the pharmacology of fear-related behaviours.

Decreased locomotor activity after microinjection of dopamine D2/D3 receptor agonists and antagonists into lobule 9/10 of the cerebellum: a D3 receptor mediated effect?

The restricted localization of dopamine (DA) D3 receptors in the rat cerebellum lobule 9/10 appears to provide a method for investigating the in vivo selectivity of dopaminergic compounds for the D3 receptor subtype. Sprague-Dawley rats implanted with a cannula aimed at lobule 9/10 were microinjected with DA receptor ligands and immediately placed into activity chambers to record their spontaneous locomotor activity for short term (0 to 20 min) and delayed (20 to 40 min) effects. The DA D2/D3 receptor agonists quinelorane (0.1 to 2.5 microg) and 7-OH-DPAT (0.1 to 10 microg) decreased locomotor activity in the first 20 min post-microinjection. In contrast, the DAD1, receptor agonist 6-Br-APB (0.1 to 10 microg) did not affect locomotor activity during this time period, but markedly increased locomotion between 20 and 40 min at the highest dose tested. The DA receptor antagonists haloperidol and raclopride (1 to 10 microg) were also found to reduce locomotor activity. Furthermore, quinelorane and 7-OH-DPAT, but not haloperidol, when microinjected into lobules 1/2 or 6/7 (where no DA D3 receptors have been detected) decreased locomotor scores. These results show that both DA receptor agonists and antagonists decrease locomotor activity when microinjected into lobule 9/10 of the cerebellum. Additionally, DA receptor agonists can reduce spontaneous locomotion when microinjected outside of lobule 9/10. This would suggest that, at least for quinelorane and 7-OH-DPAT, the locomotor decreasing effects following microinjection into cerebellar lobule 9/10 may not be mediated by activity at DA D3 receptors, and that this behavioural assay is unlikely to provide a means for studying the in vivo pharmacology of the DA D3 receptor.

The D3 antagonist PNU-99194A potentiates the discriminative cue produced by the D3 agonist 7-OH-DPAT.

Based on correlations between potencies of various dopamine D2/D3 agonists to substitute for the 7-OH-DPAT discriminative cue and their in vitro (mitogenesis test) potencies, it has been suggested that the 7-OH-DPAT cue is mediated by activity at the D3 subtype. We sought to verify that the 7-OH-DPAT cue could be blocked by PNU-99194A, a commercially available preferential D3 antagonist. Rats were trained (FR10 two-lever, food-reinforced schedule) to press one lever following 7-OH-DPAT (0.1 mg/kg i.p.) and the other lever following saline. Rats were then tested with various doses of 7-OH-DPAT alone or in combination with PNU-99194A. 7-OH-DPAT (0.003 to 0.3 mg/kg) engendered dose-dependent substitution; PNU-99194A (1 to 10 mg/kg) failed to antagonize the cue induced by 0.1 mg/kg of 7-OH-DPAT and, at 10 mg/kg, given in combination with 0.003 to 0.1 mg/kg of 7-OH-DPAT, PNU-99194A markedly shifted the 7-OH-DPAT dose-effect curve to the left, i.e., potentiated the 7-OH-DPAT cue. If PNU-99194A is a preferential D3 antagonist, the present data do not confirm the previous hypothesis that the 7-OH-DPAT cue is mediated by the D3 subtype.

Reduction of oral ethanol self-administration in rats by monoamine oxidase inhibitors.

Evidence for a role of dopamine and serotonin in the control of ethanol intake in animals suggests that monoamine oxidase (MAO) inhibitors, which increase the synaptic availability of serotonin and dopamine by blocking their metabolism, might have efficacy in the treatment of alcohol dependence. The aim of the present study was, therefore, to evaluate several MAO inhibitors for their capacity to affect ethanol self-administration in rats trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task. The nonselective and irreversible MAO inhibitors, phenelzine (3-10 mg/kg), tranylcypromine (1-3 mg/kg), and nialamide (30 mg/kg), decreased rates of responding maintained by ethanol reinforcement. The reversible MAO-A inhibitor, befloxatone (0.3-3 mg/kg), and the irreversible MAO-A inhibitor, clorgyline (10-30 mg/kg), also reduced ethanol self-administration. However, befloxatone-induced effects leveled off at a 50% decrease. The irreversible MAO-B inhibitors, pargyline (30 mg/kg) and l-deprenyl (3-10 mg/kg) also decreased responding maintained by ethanol reinforcement; these results are consistent with previous findings that both drugs decreased ethanol intake in mice. In conclusion, the present results showing that several MAO inhibitors decreased ethanol self-administration in rats are consistent with previous findings that synaptic levels of serotonin and dopamine play a critical role in the control of ethanol self-administration.

New evidence that the pharmacological effects of benzodiazepine receptor ligands can be associated with activities at different BZ (omega) receptor subtypes.

RATIONALE: It has been suggested that different BZ (omega) receptor subtypes may mediate distinct behavioural effects of BZ receptor ligands. OBJECTIVE: The present study examined this hypothesis further. METHODS: The antagonism exerted by the selective BZ(1) (omega(1)) receptor antagonist beta-CCT on the pharmacological effects of the selective BZ(1) (omega(1)) receptor agonist zolpidem and the non-selective BZ (omega) receptor agonist diazepam in behavioural, biochemical and electrophysiological experiments was assessed. RESULTS: beta-CCT which was devoid of activity per se, antagonized the effects of the non-selective BZ (omega) receptor full agonist diazepam and the selective BZ(1) (omega(1)) receptor full agonist zolpidem against seizures produced by isoniazid, but beta-CCT failed to affect their action on seizures produced by pentylenetetrazole (PTZ), suggesting that BZ(2) (omega(2)) receptors may be primarily involved in the convulsant action of PTZ. In the light/dark test, beta-CCT abolished the anxiolytic-like action of diazepam. In tests designed to investigate the central depressant activity of drugs, beta-CCT antagonized the sedative effects of diazepam and zolpidem, but failed to modify clearly the myorelaxant effects of diazepam. These differences may be related to the selectivity of beta-CCT for BZ(1) (omega(1)) sites as indicated by the preferential displacement of [(3)H]flumazenil in BZ(1) (omega(1))-enriched structures as compared to BZ(2) (omega(2))-enriched structures in the mouse. In in vitro experiments, beta-CCT antagonized the potentiation of the GABA-induced Cl(-) current produced by zolpidem in HEK cells expressing the alpha(1)beta(2)gamma(2) receptor or in cerebellar Purkinje neurones, while it failed to modify the diazepam potentiation at either alpha(3)beta(2)gamma(2) or alpha(5)beta(3)gamma(2) receptor subtypes. CONCLUSION: These results are consistent with the hypothesis that BZ(1) (omega(1)) receptors play an important role in the anxiolytic and sedative/hypnotic effects of BZ (omega) receptor ligands, whereas activity at BZ(2) (omega(2)) sites might be associated primarily with muscle relaxation.

Tidal creek and salt marsh sediments in South Carolina coastal estuaries: I. Distribution of trace metals.

Twenty-eight tidal creeks were sampled along the South Carolina coast in the summer of 1995 to determine the levels of sediment trace metal contamination associated with different types and varying levels of human development in their watersheds. The particle size and total organic carbon (TOC) content of creek sediments in developed watersheds (i.e., industrial, urban, and suburban) were similar to that in watersheds with little or no development (i.e., forested or reference). Those trace metals commonly associated with urban and industrial sources, including Cu, Cr, Pb, Zn, Cd, and Hg, were in significantly higher concentrations in tidal creeks located in industrial/urban watersheds compared to the suburban and forested watersheds. Sediment trace metal concentrations were similar for creeks located in suburban and forested watersheds and 2 to 10 times lower than the creeks located in industrial/urban watersheds. Concentrations of trace metals primarily associated with the natural weathering of basement rock, including Al, Fe, As, Ni, and Mn, were not significantly different among watershed types. Four of the tidal creek-salt marsh systems were extensively sampled from the creek channel to the marsh-upland interface to characterize sediment trace metal spatial distributions within creek-marsh systems. Sediment particle size, TOC, and trace metal concentrations varied spatially within each creek-marsh system depending on the type of development in the watershed and the probable source of metals. The creek-marsh system selected to represent the industrial development had significantly higher "anthropogenic" trace metal concentrations compared to the other creek-marsh systems. This system also had trace metal distributional patterns that appeared to be associated with several localized sources of metals on the marsh surface. Both the "anthropogenic" and "natural" trace metal concentrations and spatial distributions were similar among and within the forested and suburban creek-marsh systems.http://link.springer-ny. com/link/service/journals/00244/bibs/37n4p445.html

Tidal creek and salt marsh sediments in South Carolina coastal estuaries: II. Distribution of organic contaminants.

Twenty-eight tidal creeks along the South Carolina coast were sampled during the summer of 1995 to determine the levels of sediment contamination including organic chemicals (i.e., polycyclic aromatic hydrocarbons [PAHs], polychlorinated biphenyls [PCBs], and DDT and its metabolites) associated with different types and varying levels of watershed development (i.e., industrial/urban, suburban, forested, and salt marsh). Organic analysis utilized high-performance liquid chromatography (HPLC) with fluorescence detection and capillary gas chromatography-ion trap mass spectrometry (GC-ITMS) for PAHs, and gas chromatography with electron capture detection (GC-ECD) for pesticides and PCBs. Results indicated that creeks with industrial/urban watersheds had significantly higher concentrations of PAHs, PCBs, and DDT compared with creeks with suburban and forested (reference) watersheds. The suburban watershed class of creeks had concentrations of half the PAH analytes and the total PCBs which exceeded the concentrations found in the forested watershed class of creeks. The spatial distribution of organic contaminants was evaluated in four of these tidal creek-salt marsh systems representing urban/industrial, suburban, and forested watersheds, from the creek channel to the adjacent uplands. The distribution of organic contaminants within each representative creek was not concordant with the total organic carbon or the clay content of the sediment. The representative industrial/urban creek-marsh system, Diesel Creek, had the highest concentration of PAHs in the creek channel and the highest concentration of PCBs and DDT on the marsh surface, primarily in the upper portion of the system. The representative suburban creek-marsh system, Shem Creek, had elevated levels of both PAHs and PCBs throughout the entire system. This system also had one site with a total PAH concentration of 324,000 ppb and a total DDT concentration that was 20-100 times higher than the other sites. One of the representative forested creek-marsh systems, Rathall Creek, had low levels of the three organic contaminants except for one sampling site that had PAH concentrations a factor of 10 higher than the other sites. The other representative forested creek-marsh system, Long Creek, had low levels of PAHs and PCBs, but elevated levels of DDT were observed, particularly in the upper portion on the marsh surface. The results of this study suggest that (1) anthropogenic alteration of the land cover in the watersheds of tidal creek-salt marsh systems may increase the organic contaminant loadings in the sediment, and (2) tidal creek-salt marsh sediments, particularly in the creek channel, are repositories and potentially conduits of organic contaminants from the upland environment to the deeper estuarine areas.http://link.springer-ny. com/link/service/journals/00244/bibs/37n4p458.html

Discriminative stimulus effects of drugs acting at GABA(A) receptors: differential profiles and receptor selectivity.

The GABA(A) receptor complex contains a number of binding sites at which a variety of psychotropic drugs, including benzodiazepines, barbiturates, and some neurosteroids, act to potentiate or inhibit the effect of the transmitter. Many studies have reported that these drugs can produce discriminative stimulus actions, but the cueing effects of compounds acting at different sites to enhance the effects of GABA are not identical. The discriminative stimulus effects of benzodiazepines have been analyzed in detail, and there is also a great deal of information available on the effects of nonbenzodiazepine compounds acting at BZ(omega) recognition sites, which form part of the GABA(A) receptor complex. Of particular interest are compounds with selectivity for the BZ1(omega1) receptor subtype including zolpidem, zaleplon, and CI 218,872. BZ1(omega1)-selective drugs substitute for the discriminative stimulus produced by chlordiazepoxide only partially and at sedative doses. This is consistent with the view that sedative effects of BZ(omega) receptor agonists are mediated by the BZ1(omega1) receptor subtype, whereas the discriminative stimulus produced by chlordiazepoxide may be produced by activity at the BZ2(omega2) subtype. Analysis of this hypothesis is complicated by the variety of levels of intrinsic activity shown by different drugs.