“Anxiolytic” and “anxiogenic” benzodiazepines and β-carbolines: effects on aggressive and social behavior in rats and squirrel monkeys

Ethopharmacological studies on the behavior of socially housed rats and squirrel monkeys were conducted to explore the role of the benzodiazepine GABA_A-coupled ionophore receptor complex in aggressive and social interactions. Benzodiazepine receptor (BZR) antagonists, ZK 93426 (1–10 mg/kg) and flumazenil (3–10 mg/kg), the partial agonist, ZK 91296 (1–10 mg/kg) and the partial inverse agonists RO 15-4513 (0.3–10 mg/kg), were administered to (1) squirrel monkeys prior to 1 h focal observations within established social groups or to (2) resident male rats before confrontations with a naive male intruder in their home cage for 5 min. Aggression was modified in a similar manner in both species, although squirrel monkeys were more sensitive to BZR challenges. Specifically, resident male rats showed dose dependent reductions in attack bites directed at intruder males that were significant at the highest dose of ZK 93426 (10 mg/kg). In squirrel monkeys, ZK 93426 (3 and 10 mg/kg) reduced aggressive grasps, threats and displays, as well as reducing the duration of being the target of aggression from untreated group members (1–10 mg/kg). The BZR partial agonist, ZK 91296 and the antagonist, flumazenil produced few effects on social behavior, low and high intensity aggression and motor activity in both species. Flumazenil (10–30 mg/kg) and ZK 91296 (10 mg/kg), but not ZK 93426, produced significant increases in foraging and feeding behaviors in squirrel monkeys. The hyperphagic effects of ZK 91296 and flumazenil, that are typical of BZR agonists compounds, were not observed in rats. Similarly, the inverse agonist-like reductions in social interactions produced by ZK 93426 (3–10 mg/kg) were observed only in squirrel monkeys. The partial inverse agonist Ro 15-4513 reduced aggression in rats, but low doses (1 mg/kg) produced tremors or seizures in 80% of the monkeys tested. Decreases in aggressive and social behaviors are often interpreted to reflect anxiogenic drug properties, whereas increased feeding has been associated with anxiolytic actions. The concurrent emergence of these apparent opposites suggests independent actions on social and alimentary functions.     

Pharmacoepidemiology and the “Impact Factor”

The field of Pharmacoepidemiology/Drug Utilization research has been analysed by studying published research articles under the medical subject headings (MeSH terms) Pharmacoepidemiology, Drug Utilization and Drug Utilization Review. There were 1822 articles published, and stored in Medline, during the 32-month period between 1 January 2001 and 31 August 2003; these papers might represent a field of research, due to the similarity of MeSH terms used for coding and the set of journals in which the articles were published. A total of 457 articles, representing 25% of all articles in the field, were published in 14 different journals, and 50% of all articles (948) were collected in only 64 different journals. The two main journals publishing research in Pharmacoepidemiology/Drug Utilization are Pharmacoepidemiol Drug Saf and the Eur J Clin Pharmacol. These two publications are the official journals of the three main societies in the field and are at least partially focused on this subject, with 45.7% of all articles in Pharmacoepidemiol Drug Saf and 11.1% of all articles in Eur J Clin Pharmacol included under the studied MeSH terms; other journals only occasionally publish papers in this line of research. These two journals are the leaders in pharmacoepidemiology and drug utilization research, having impact factors (IFs) in 2002/2003 above (1.955/1.972 for EJCP) and a bit below (1.092/1.257 for PDS) the middle of the ranking of publications, according to the IF, in the Pharmacology and Pharmacy list of the Science Citation Index (SCI).     

Screening and Diagnosis of “Alcohol Abuse and Dependence” in Older Adults

A literature review reveals that research is warranted to improve screening for “alcohol abuse” in older adults and women. An examination of diagnostic criteria for “alcohol abuse dependence” reveals that older adults provide unique challenges to classification systems. There is a need to evaluate the sensitivity and specificity of several new screening instruments for the identification of “alcohol abuse” in the elderly. Routine screening of elderly and women presenting in primary care settings should be a priority for researchers and clini cians.     

Reconstructing Human Exposures Using Biomarkers and other “Clues”

Biomonitoring is the process by which biomarkers are measured in human tissues and specimens to evaluate exposures. Given the growing number of population-based biomonitoring surveys, there is now an escalated interest in using biomarker data to reconstruct exposures for supporting risk assessment and risk management. While detection of biomarkers is de facto evidence of exposure and absorption, biomarker data cannot be used to reconstruct exposure unless other information is available to establish the external exposure–biomarker concentration relationship. In this review, the process of using biomarker data and other information to reconstruct human exposures is examined. Information that is essential to the exposure reconstruction process includes (1) the type of biomarker based on its origin (e.g., endogenous vs. exogenous), (2) the purpose/design of the biomonitoring study (e.g., occupational monitoring), (3) exposure information (including product/chemical use scenarios and reasons for expected contact, the physicochemical properties of the chemical and nature of the residues, and likely exposure scenarios), and (4) an understanding of the biological system and mechanisms of clearance. This review also presents the use of exposure modeling, pharmacokinetic modeling, and molecular modeling to assist in integrating these various types of information.     

Determination of “safe” and “critical” nanoparticles exposure to welders in a workshop

ABSTRACT

The present study examined consequences of “safe” versus “critical” exposure to nanoparticles (NP) released during welding operations. With this aim in mind, a set of measurements regarding NP emissions was undertaken in a workshop during welding by metal active gas of carbon steel using different mixtures of argon (Ar) and carbon dioxide (CO₂) as well as different process parameters which might influence emission of (NP). If these measurements were conducted in several locations away from the welding sources, the graphical representation of the obtained observations with time enabled definition of “safe” and “critical” regions within a welding workshop in terms of welder’s exposure. This information may be combined with the results of risk analysis derived by control banding and helps to categorize the sites where regulatory measures such as operation containment or dedicated exhaust ventilation need to be implemented.     

Bioanalytical Approaches to Quantify “Total” and “Free” Therapeutic Antibodies and Their Targets: Technical Challenges and PK/PD Applications Over the Course of Drug Development

The predominant driver of bioanalysis in supporting drug development is the intended use of the data. Ligand-binding assays (LBA) are widely used for the analysis of protein biotherapeutics and target ligands (L) to support pharmacokinetics/pharmacodynamics (PK/PD) and safety assessments. For monoclonal antibody drugs (mAb), in particular, which non-covalently bind to L, multiple forms of mAb and L can exist in vivo, including free mAb, free L, and mono- and/or bivalent complexes of mAb and L. Given the complexity of the dynamic binding equilibrium occurring in the body after dosing and multiple sources of perturbation of the equilibrium during bioanalysis, it is clear that ex vivo quantification of the forms of interest (free, bound, or total mAb and L) may differ from the actual ones in vivo. LBA reagents and assay formats can be designed in principle to measure the total or free forms of mAb and L. However, confirmation of the forms being measured under the specified conditions can be technically challenging. The assay forms and issues must be clearly communicated and understood appropriately by all stakeholders as the program proceeds through the development process. This paper focuses on monoclonal antibody biotherapeutics and their circulatory L that are either secreted as soluble forms or shed from membrane receptors. It presents an investigation into the theoretical and practical considerations for total/free analyte assessment to increase awareness in the scientific community and offer bioanalytical approaches to provide appropriate PK/PD information required at specific phases of drug development.     

Pontocerebellar volume deficits and ataxia in alcoholic men and women: no evidence for “telescoping”

Introduction

Brain volume shrinkage is common in treatment-seeking patients with alcohol use disorders. Whether women are more vulnerable to brain dysmorphology than men despite lower alcohol consumption levels or shorter dependency (“telescoping effect”) remains controversial and has not been considered with respect to infratentorial structures or their potential contribution to ataxia.

Methods

The 200 participants included 64 men and 31 women with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition alcohol dependence and 105 controls. An infratentorial region (pons, cerebellar hemispheres, vermis (anterior, posterior, and inferior sectors), fissures, cisterns, fourth ventricle) was quantified with atlas-based parcellation. To enable comparison of men and women, regional tissue volumes were expressed as ratios of tissue in the volume. Participants also completed quantitative ataxia testing.

Results

Total infratentorial and vermian tissue ratios were significantly smaller in alcoholics than controls; alcoholic women did not show disproportionately greater volume deficits than alcoholic men. A re-analysis including alcoholic men and women matched in alcohol consumption, onset age, abstinence duration, and age revealed again that alcoholic women did not have disproportionately greater regional vermian volume deficits than alcoholic men. Alcoholic men and women were impaired in all measures of ataxia, which correlated with low infratentorial tissue ratios in men.

Discussion

Alcoholic men showed deficits of pontocerebellar volume ratios, yet alcoholic women did not display signs of “telescoping”. Further, alcoholic men and women both showed signs of ataxia of gait and balance, related to affected pontocerebellar systems in the men but not the women, suggesting the need to consider other neural substrates for ataxia in women.     

MDMA enhances “mind reading” of positive emotions and impairs “mind reading” of negative emotions

Rationale

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) increases sociability. The prosocial effects of MDMA may result from the release of the ??social hormone?? oxytocin and associated alterations in the processing of socioemotional stimuli.

Materials and methods

We investigated the effects of MDMA (125?mg) on the ability to infer the mental states of others from social cues of the eye region in the Reading the Mind in the Eyes Test. The study included 48 healthy volunteers (24 men, 24 women) and used a double-blind, placebo-controlled, within-subjects design. A choice reaction time test was used to exclude impairments in psychomotor function. We also measured circulating oxytocin and cortisol levels and subjective drug effects.

Results

MDMA differentially affected mind reading depending on the emotional valence of the stimuli. MDMA enhanced the accuracy of mental state decoding for positive stimuli (e.g., friendly), impaired mind reading for negative stimuli (e.g., hostile), and had no effect on mind reading for neutral stimuli (e.g., reflective). MDMA did not affect psychomotor performance, increased circulating oxytocin and cortisol levels, and produced subjective prosocial effects, including feelings of being more open, talkative, and closer to others.

Conclusions

The shift in the ability to correctly read socioemotional information toward stimuli associated with positive emotional valence, together with the prosocial feelings elicited by MDMA, may enhance social approach behavior and sociability when MDMA is used recreationally and facilitate therapeutic relationships in MDMA-assisted psychotherapeutic settings.     

What and when to “want”? Amygdala-based focusing of incentive salience upon sugar and sex

Rationale

Amygdala-related circuitry helps translate learned Pavlovian associations into appetitive and aversive motivation, especially upon subsequent encounters with cues.

Objectives

We asked whether ??-opioid stimulation via microinjections of the specific agonist d-Ala², N-MePhe⁴, Gly-ol)-enkephalin (DAMGO) in central nucleus of amygdala (CeA), or the adjacent basolateral amygdala (BLA) would magnify sucrose or sex ??wanting??, guided by available cues.

Materials and methods

CeA or BLA DAMGO enhancement of cue-triggered ??wanting?? was assessed using Pavlovian to instrumental transfer (PIT). Unconditioned food ??wanting?? was measured via intake, and male sexual ??wanting?? for an estrous female was measured in a sexual approach test. Sucrose hedonic taste ??liking?? was measured in a taste reactivity test.

Results

CeA (but not BLA) DAMGO increased the intensity of phasic peaks in instrumental sucrose seeking stimulated by Pavlovian cues over precue levels in PIT, while suppressing seeking at other moments. CeA DAMGO also enhanced food intake, as well as sexual approach and investigation of an estrous female by males. DAMGO ??wanting?? enhancements were localized to CeA, as indicated by ??Fos plume??-based anatomical maps for DAMGO causation of behavioral effects. Despite increasing ??wanting??, CeA DAMGO decreased the hedonic impact or ??liking?? for sucrose in a taste reactivity paradigm.

Conclusions

CeA ??-opioid stimulation specifically enhances incentive salience, which is dynamically guided to food or sex by available cues.     

Toxicology, Environmental Health, and the “One Health” Concept

The One Health concept promotes collaboration among veterinarians, physicians, scientists, and other professions to promote human, animal, and ecosystem health. One Health illustrates the interconnectedness and interdependence of human, animal, and ecosystem health. This concept has traditionally focused on zoonoses that are infectious diseases, not on chemical- or poison-related illnesses in animals and their relationship to the detection and prevention of human illness. The purpose of this article is to describe key experiences of scientists in the Health Studies Branch within the National Center for Environmental of Health of the Centers for Disease Control and Prevention in which the study of animal illness facilitated a public health investigation into an outbreak of chemicalassociated human disease. The experiences highlight how utilizing the One Health approach may improve chemical-associated outbreak investigations and facilitate appropriate intervention strategies. An appropriate One Health approach in toxicology and environmental health in outbreak settings should include consideration of the common environments and food sources shared by humans and animals and consideration of the potential for contaminated animal products as food sources in human exposures.     

“In vitro” and “ex vivo” effects of picotamide,a combined thromboxane A2-synthase inhibitor and -receptor antagonist,on human platelets

Summary Picotamide (G 137), a new non prostanoid inhibitor of in vitro arachidonic acid induced platelet aggregation, has been further characterized in in vitro and ex vivo studies.When whole blood was activated with collagen in the presence of picotamide 5×10^–4 M, thromboxane B₂ production was decreased, and 6-keto-PGF₁ generation was significantly increased, suggesting a reorientation of platelet endoperoxide metabolism following blockade of thromboxane synthetase. Picotamide also inhibited platelet aggregation and clot retraction induced by the endoperoxide analogue U46619 in human platelets, indicating thromboxane A₂-receptor antagonism, possibly of competitive nature.A single oral dose of picotamide 1 g in 24 healthy volunteers produced a significant inhibition of collagen, arachidonic acid and U46619-induced platelet aggregation. Serum levels of thromboxane B₂ were also reduced.Chronic administration of picotamide 1.2 g/d to patients with vascular disease resulted in a prompt and persistent fall in their increased plasma levels of -thromboglobulin.The results indicate that picotamide is a combined thromboxane B₂-synthetase inhibitor and thromboxane A₂-receptor antagonist in human platelets, and that it may prove useful as an antithrombotic agent.     

Quantitative analysis of the effects of some “atypical” and “conventional” antipsychotics on progressive ratio schedule performance

Rationale Performance on progressive ratio schedules has been proposed as a means of assessing the effects of drugs on the value or efficacy of reinforcers. A mathematical model affords a basis for quantifying the effects of drugs on progressive ratio schedule performance. According to this model, the relation between response rate and ratio size is described by a bitonic (inverted-U) function. One parameter of the function, a, expresses the motivational or activating effect of the reinforcer (duration of activation of responding produced by the reinforcer), whereas another parameter, , expresses the minimum time needed to execute a response, and is regarded as an index of motor capacity. In a previous experiment we found that the atypical antipsychotic clozapine increased a, indicating an increase in the efficacy of a food reinforcer.Objective We examined the effects of four atypical and four conventional antipsychotics on progressive ratio schedule performance.Methods Rats responded for a sucrose reinforcer (0.6 M, 50 l) on a time-constrained progressive ratio schedule (50-min sessions). After 90 preliminary training sessions, they received acute doses of antipsychotics (doses in mg kg^–1): atypical: clozapine (2, 4, 8, IP; n=15), quetiapine (1.25, 2.5, 5, 10, SC; n=23), olanzapine (0.25, 0.5, 1, IP; n=15), ziprasidone (0.625, 1.25, 2.5, IP, n=15); conventional: haloperidol (0.025, 0.05, 0.1, IP, n=15), pimozide (0.125, 0.25, 0.5, IP; n=15), raclopride (0.25, 0.5, 1, SC; n=12), cis-flupenthixol (0.2, 0.4, 0.8, SC; n=15). Values of a and were estimated from the response rate functions obtained under each treatment condition, and were compared between drug and vehicle-alone treatments.Results The atypical antipsychotics significantly increased a (indicating enhancement of reinforcer efficacy), and also increased (indicating reduction of motor capacity). Haloperidol, pimozide and raclopride significantly increased ; none of the conventional antipsychotics significantly altered a.Conclusions The results extend previous findings with clozapine to other atypical antipsychotics and suggest that enhancement of the efficacy of reinforcers may be a common feature of atypical antipsychotics not shared by conventional antipsychotics.Jonathan Francis Rickard (1979–2003), a gifted and dedicated PhD student, made a major contribution to this work.