Potential anti-anxiety, anti-addictive effects of LY 354740, a selective group II glutamate metabotropic receptors agonist in animal models

Despite there being a lot of biochemical data about metabotropic glutamate (mGlu) receptors, our knowledge of the behavioural effects of mGlu receptor agonists/antagonists is still inadequate. LY 354740 is a systemically active agonist of group II mGlu receptors. After peripheral administration, LY 354740 produced anxiolytic-like effects in the conflict drinking test in rats and a four-plate test in mice. It was also found that LY 354740 decreased spontaneous locomotor activity in mice, but did not disturb motor coordination. In behavioural models of depression including the despair test and a tail suspension test, LY 354740 did not produce antidepressant-like effects. LY 354740 inhibited the naloxone-induced symptoms of morphine withdrawal in morphine-dependent mice. The above results indicate that agonists of group II mGlu receptors may play a role in the therapy of anxiety and/or drug-dependence states. The brain sites of action of LY 354740 need to be identified and the mechanism of both the above described effects remains to be elucidated.     

Naloxone reverses disinhibitory/aggressive behavior in 5,7-DHT-lesioned rats; involvement of GABA(A) receptor blockade?

Effective medical treatment for impulsive aggression and several impulse control disorders is needed. Disinhibited, impulsive behavior of e.g. murderers, arsonists, suicidal patients, and patients suffering from antisocial personality or substance abuse disorders has been associated with signs of a deficiency in brain serotonin (5-HT) systems. Depletion of brain 5-HT consistently produces disinhibition and aggression also in experimental animals. The present series of experiments using a modified Vogel’s conflict test indicates that the disinhibitory behavior of 5-HT-lesioned rats can be reversed by the commonly used opiate receptor antagonist naloxone at doses (0.1–5.0 mg/kg, s.c.) that do not significantly affect behavior in sham-lesioned controls. Moreover, this effect of naloxone, which resembles that previously observed after administration of negative modulators of γ-aminobutyric acid_A (GABA_A)/benzodiazepine receptor complexes, was reversed by a low inert dose (2.0 mg/kg, i.p.) of amobarbital. Furthermore, both naloxone (5.0 mg/kg, s.c.) and Ro 15-4513 (1.0 mg/kg, p.o.; a partial inverse agonist at benzodiazepine receptors) significantly decreased the number of attacks and the time spent in aggressive acts in 5,7-DHT-lesioned male residents. These results taken together with previous behavioral and neurochemical data suggest that the behavioral effects of naloxone observed here may involve an antagonistic action at brain γ-aminobutyric acid_A (GABA_A)/benzodiazepine receptor complexes. Thus, naloxone, its stable analogue naltrexone or other weak negative modulators of brain GABA_A/benzodiazepine receptor complexes may represent a new pharmacological principle for the treatment of impulse control disorders.     

Depletion of brain norepinephrine: differential influence on anxiolyic treatment effects

Rationale: Previous studies have demonstrated that anxiolytic-like anticonflict effects can be produced by either (1) acute administration of traditional anti-anxiety compounds (benzodiazepines or barbiturates) or (2) chronic administration of tricyclic (TCA) or monoamine oxidase inhibitor (MAOI) antidepressants. Objective: The present study determined the effects of noradrenergic neuronal depletion on these distinct anticonflict treatments. Methods: After 3 weeks of training in a repeated measures drink suppression conflict paradigm, water-restricted rats consumed 11–14 ml water/session (unpunished responding) and accepted 25–40 shocks/session (punished responding) during control (i.e., non-drug) 10-min test sessions. The noradrenergic neurotoxin DSP4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride; 65 mg/kg, IP] or its vehicle (saline; 1 ml/kg) was administered after 3 weeks of conflict testing. Conflict behavior was then evaluated for 8 weeks post-treatment. In separate groups of DSP4- and vehicle-pretreated subjects, the effects of acute administration (10-min pretreatment) of phenobarbital (5–40 mg/kg) or alprazolam (0.3–2.5 mg/kg) were determined. In a third experiment, the effects of chronic treatment with the TCA desipramine (DMI; 5 mg/kg, twice daily for 8 weeks) or the non-selective MAOI phenelzine (4.0 mg/kg, twice daily for 8 weeks) on conflict behavior were determined in additional groups of DSP4- or vehicle-pretreated subjects. Results: DSP4 treatment produced a modest yet statistically significant decrease in punished responding (i.e., anxiogenic-like effect) relative to vehicle controls. DSP4 pretreatment did not alter the anticonflict effects of acute alprazolam or phenobarbital treatment. In contrast, DSP4 treatment completely abolished the anticonflict effects produced by chronic DMI or chronic phenelzine treatment. Conclusions: Thus, noradrenergic neuronal integrity appears to be required for the anxiolytic-like effects of chronic antidepressant treatment, but not for the anxiolytic-like effects of acute treatment with barbiturates and benzodiazepines. Received: 6 August 1998/Final version: 16 October 1998     

Lack of central 5-hydroxytryptamine influence on the anticonflict activity of diazepam

This study examined the effects of various drug treatments (IP injections) proposed to modify central 5-hydroxytryptamine (5-HT) activity on a conditioned suppression of drinking behavior in water-deprived rats. The subjects were trained to drink their daily water requirement during a 10-min session. Intermittent tone periods of 7 s were then introduced, the last 5 s of which the drinking tube was electrified. The animals gradually suppressed tube contacts during the tone to a low constant level within 2 weeks of training. Diazepam increased punished responding dramatically. The 5-HT antagonists methysergide (1–18 mg/kg), cyproheptadine (1–18 mg/kg), metergoline (0,25–2.0 mg/kg) and cinanserin (10–100 mg/kg) failed to induce large, reliable increases in punished responding. When a low dose of diazepam was combined with 5-HT antagonists, only one treatment, methysergide at 3 mg/kg, potentiated the anticonflict activity of diazepam. Acute or chronic treatment with PCPA increased behavior suppressed by punishment, but this effect was weak, brief, and poorly related to the depletion of brain 5-HT. LSD (0.3–100 g/kg) administered 1,10, or 30 min before the test was ineffective in overcoming suppression by punishment. Mescaline (6–30 mg/kg) had no significant effect on punished responding. 5-HTP (18 mg/kg) decreased the number of shocks accepted, but not after pretreating with carbidopa. Pretreatment with carbidopa plus 5-HTP potentiated the anticonflict effect of diazepam. The 5-HT agonist mCPP (0.25–2.0 mg/kg) enhanced suppression due to punishment, but only in doses that interfered with unpunished responding. The 5-HT-releasing agent fenfluramine (0.25–1.0 mg/kg) did not affect this behavior. Amitriptyline pretreatment in a dose not affecting unpunished behavior (5.6 mg/kg) potentiated the diazepam-induced increase in punished responding. These results are difficult to reconcile with the proposal that suppression of behavior consequent to punishment is related to brain 5-HT activity.     

"Conflict" situation based on intracranial self-stimulation behavior and the effect of benzodiazepines

Based on lateral hypothalamic self-stimulation behavior of the rat in a Skinner box, a "conflict" situation was established by combining foot shock punishment with brain stimulation. Diazepam (10-20 mg/kg, PO) caused a marked increase in the lever pressing response in the punished period without affecting the unpunished response. Bromazepam (10--20 mg/kg PO) also caused an increase in the lever pressing response in the punished period and a decrease of the punished response. These results indicate that a "conflict" situation based on self-stimulation behavior is useful for the evaluation of antianxiety action.     

Legal and ethical issues in telemedicine and robotics.

Modern medical concerns with telemedicine and robotics practiced across national or other jurisdictional boundaries engage the historical, complex area of law called conflict of laws. An initial concern is whether a practitioner licensed only in jurisdiction A who treats a patient in jurisdiction B violates B's laws. Further concerns are whether a practitioner in A who violates a contract or treats a patient in B negligently incurs liability in B, A, or both, and, if treatment lawful in A is unlawful in B, whether the practitioner commits a crime. Judicial procedures are set by courts in which proceedings are initiated, but courts may decline jurisdiction due to inconvenience to parties. If courts accept jurisdiction, they may apply their own substantive legal rules, but may find that the rules of a conflicting jurisdiction should apply. Cross-border care should not change usual medical ethics, for instance on confidentiality, but may mitigate or aggravate migration of specialists.     

Fall injuries in Baghdad from 2003 to 2014: Results of a randomised household cluster survey

IntroductionFalls incur nearly 35 million disability-adjusted life-years annually; 75% of which occur in low- and middle-income countries. The epidemiology of civilian injuries during conflict is relatively unknown, yet important for planning prevention initiatives, health policy and humanitarian assistance. This study aimed to determine the death and disability and household consequences of fall injuries in post-invasion Baghdad.MethodsA two-stage, cluster randomised, community-based household survey was performed in May of 2014 to determine the civilian burden of injury from 2003 to 2014 in Baghdad. In addition to questions about household member death, households were interviewed regarding injury specifics, healthcare required, disability, relatedness to conflict and resultant financial hardship.ResultsNine hundred households totaling 5148 individuals were interviewed. There were 138 fall injuries (25% of all injuries reported); fall was the most common mechanism of civilian injury in Baghdad. The rate of serious fall injuries increased from 78 to 466 per 100,000 persons in 2003 and 2013, respectively. Fall was the most common mechanism among the injured elderly (i.e. ≥65 years; 15/24 elderly unintentional injuries; 63%). However, 46 fall injuries were children aged <15 years (49% of unintentional injuries) and 77 were respondents aged 15–64 years (36%). Respondents who spent significant time within the home (i.e. unemployed, retired, homemaker) had three times greater odds of having suffered a fall injury than student referents (aOR 3.34; 95%CI 1.30–8.60). Almost 80% of fall injured were left with life-limiting disability. Affected households often borrowed substantial sums of money (34 households; 30% of affected households) and/or suffered food insecurity after a family member's fall (52; 46%).ConclusionFalls were the most common cause of civilian injury in Baghdad. In part due to the effect of prolonged insecurity on a fragile health system, many injuries resulted in life-limiting disabilities. In turn, households shouldered much of the burden after fall injury due to loss of income and/or medical expenditure, often resulting in food insecurity. Given ongoing conflict, civilian injury control initiatives, trauma care strengthening efforts and support for households of the injured is urgently needed.     

Decoding disclosure: Comparing conflict of interest policy among the United States,France, and Australia

“Sunshine” policy, aimed at making financial ties between health professionals and industry publicly transparent, has recently gone global. Given that transparency is not the sole means of managing conflict of interest, and is unlikely to be effective on its own, it is important to understand why disclosure has emerged as a predominant public policy solution, and what the effects of this focus on transparency might be. We used Carol Bacchi’s problem-questioning approach to policy analysis to compare the Sunshine policies in three different jurisdictions, the United States, France and Australia. We found that transparency had emerged as a solution to several different problems including misuse of tax dollars, patient safety and public trust. Despite these differences in the origins of disclosure policies, all were underpinned by the questionable assumption that informed consumers could address conflicts of interest. We conclude that, while transparency reports have provided an unprecedented opportunity to understand the reach of industry within healthcare, policymakers should build upon these insights and begin to develop policy solutions that address systemic commercial influence.     

Gunshot injuries in Benghazi–Libya in 2011: The Libyan conflict and beyond

BackgroundSince independence, Libya has never experienced personal ownership of arms. That changed during the Libyan conflict where weapons became widespread in the society. As a result gunshot injuries became a concern for surgeons at our principal surgical hospital (Al-Jalaa). This study aims at analyzing the gunshot injuries that took place during 2011 and highlighting the peculiarities in the Libyan scenario.MethodsPatient records were obtained and gunshot injuries were analyzed for various parameters. Statistical analyses were made taking into consideration situations faced by neighbouring countries.ResultsIn 2011, 1761 patients were admitted with over 95% being male and over 97% were Libyan. The average age of a GSI patient was 28.32 ± 10.01 years. Patients aged 18–35 formed over 70% of the cases with half of all cases being treated by the orthopedics department. Sixty-eight percent of cases were injured in the extremities followed by chest (12.5%) and abdomen injuries (7.8%). The mortality rate for GSI's was found to be 5.6% overall with young age, site of injury (i.e. chest and head) and cause of injury (i.e. war or civilian fighting) being important risk factors.ConclusionsTaking into consideration the difficult operating conditions and limited resources, surgeons at our hospital were able to maintain a low mortality rate. Disarmament needs to begin as soon as possible because these injuries will continue to occur so long firearms are available in society.