A Thalamic Contribution to Arousal-induced, Non-photic Entrainment of the Circadian Clock of the Syrian Hamster

It is well established that the circadian clock of the suprachiasmatic nuclei (SCN) is entrained by light. More recently, the potent effects of arousing, non-photic cues on the clock have been recognized. The neural mediators of non-photic entrainment are yet to be identified. To examine the contribution of the thalamic intergeniculate leaflet (IGL) and its NPY-immunopositive projection, the geniculo-hypothalamic tract to non-photic entrainment by arousal, male Syrian hamsters received lesions of the IGL (IGLX) which ablated NPY-immunoreactivity in the SCN. Their circadian responses to both photic and non-photic cues were then tested. Lesions resulted in a delay in the timing of activity onset following lights out, but had no effect on the behavioural or cellular circadian responses to phase-advancing light pulses presented at circadian time (CT) CT19 (where CT12 represents the time of activity onset). Injection with a benzodiazepine (chlordiazepoxide, 100 mg/kg) at CT6 suppressed wheel-running, increased general locomotion of intact controls and induced large phase advances of the circadian rhythm of wheel-running. Chlordiazepoxide also inhibited wheel-running in lesioned animals, but there was no significant increase in general locomotion and the lesioned animals did not phase advance. Serial arousal by injection of saline at intervals of 23.5 h for 6 days entrained the circadian rhythm of wheel-running of intact hamsters and was associated with an increase in general locomotor activity. Entrainment by serial arousal was abolished by IGLX. However, the lesioned animals did show a clear behavioural response to every presentation of the non-photic cue. These results show that the IGL is a necessary component of the neural pathways mediating both arousal- and benzodiazepine-induced non-photic entrainment.     

The effects of alcohol and benzodiazepines on the severity of ski accidents.

Urine samples from 402 victims of ski accidents were analyzed for the presence of benzodiazepines (BZD) and alcohol. Eighty-one (20%) samples were positive for alcohol; BZD were detected in 34 (8.5%) cases. Ten of the samples (2.5%) were found to be positive for both alcohol and BZD. Subjects who were positive for either alcohol or BZD or both were older than the other persons examined. The prevalence of alcohol was significantly higher among male accident victims. BZD intake could be demonstrated to have a significant influence on the severity of injuries. Besides an increased awareness of the need for skier education regarding drug use, heightened attention of medical caregivers is warranted to inform their patients about potential accident hazards in sport activities when BZD are prescribed.     

Dissimilarities between benzodiazepine-binding sites and adenosine uptake sites in astrocytes and neurons in primary cultures

The question whether the benzodiazepine receptor site in astrocytes or in neurons might be identical to the adenosine uptake site was studied by determining pharmacological profiles, inhibition types, and the effects of benzodiazepine antagonsts in primary cultures of either astrocytes or neurons. Fourteen different benzodiazepines and five different adenosine uptake inhibitors displaced [³H] diazepam and inhibited adenosine uptake in both astrocytes and neurons. However, the rank orders (determined as IC₅₀ values) with which these two parameters were affected were profoundly different, indicating dissimilarities between these two sites. For several of the compounds a difference in inhibition type (competitive vs. noncompetitive) was observed between the benzodiazepine-binding site and the adenosine uptake site in astrocytes and/or neurons, which further corroborated the conclusion of a difference between the benzodiazepine-binding site and the adenosine uptake site. Finally, the neuronal benzodiazepine antagonists RO 15-1788 and CGS-8216 and the astrocytic benzodiazepine antagonist PK 11195, which reverse the action of benzodiazepines, were not able to reverse inhibition of adenosine uptake by diazepam but exerted an inhibitory effect of their own.     

Regulation of peripheral-type benzodiazepine receptors in cultured astrocytes by monoamine and amino acid neurotransmitters

Exposure of primary cultured astrocytes for 3 days to 1 μM of either dopamine, serotonin or norepinephrine resulted in upregulation (25–34% increase in B_max) of the peripheral-type benzodiazepine receptors (PBRs) labeled with [³H]Ro5-4864. A similar treatment with γ-aminobutyric acid [GABA] caused a 2-fold increase in the affinity (K_d) of [³H]Ro5-4864. The monoamines tested and GABA had no effect on the binding parameters of [³H]PK 11195, another selective PBR ligand. The present study indicates that Ro5-4864 binding sites are susceptible to regulation by specific neurotransmitters and provides further evidence for the distinction between Ro5-4864 and PK 11195 binding sites of the PBRs in cultured astrocytes.     

Saturation analysis of specific 11C Ro 15-1788 binding to the human neocortex using positron emission tomography

The ¹¹C-labelled benzodiazepine antagonist Ro 15–1788 (flumazenil) and positron emission tomography (PET) were used to determine quantitative characteristics of benzodiazepine receptor binding in the neocortex of healthy young men. Saturating doses of unlabelled flumazenil administered i.v., before or together with the ligand-reduced ¹¹C-flumazenil accumulation in the neocortex by about 90 per cent. Saturating doses of unlabelled flumazenil had little effect on the accumulation of radioactivity in the benzodiazepine receptor-poor regions such as pons or white matter. By giving graded doses of unlabelled flumazenil together with the tracer, saturation isotherms were obtained allowing the calculation of receptor density (B_max) and equilibrium dissociation constant (K_d) values on the basis of certain assumptions B_max values were in the order of 90 pmol/g and K_d values in the order of 10 nM in the neocortex. Scatchard and Hill plots of the radioactivity data indicated that ¹¹C-flumazenil binds to saturable sites of a homogeneous population. The data indicate that intravenous doses of 1 or 2 mg flumazenil result in a benzodiazepine receptor occupancy of about 50 per cent. The method described should be useful for studying regional differences in benzodiazepine receptor characteristics in the living human brain in healthy subjects and neuropsychiatric disorders, and also in relation to treatment with drugs interacting with benzodiazepine receptors.     

长期饮酒对大鼠睾丸睾酮合成和雄激素结合蛋白mRNA表达的影响

目的探讨饮酒对大鼠睾丸组织睾酮合成和雄激素结合蛋白（ABP）mRNA表达的影响。方法雄性Wistar大鼠40只，按体重随机分为4组，每组10只，即对照组（蒸馏水5g·kg^-1·d^-1）；大剂量饮酒组（酒精量5g·kg^-1·d^-1）；中剂量饮酒组（酒精量2．5g·kg^-1·d^-1）；小剂量饮酒组（酒精量0．5g·kg^-1·d^-1），喂养时间5个月。ELISA测定睾酮含量，RT—PCR测定睾丸组织外周型苯二氮革受体（PBR）、PPARα和ABP mRNA水平。结果与对照组相比，（1）大剂量饮酒组大鼠睾丸组织睾酮含量下降31．13％（P〈0．05），中剂量饮酒组下降26．8％（P〈0．05），小剂量饮酒组下降14．2％（P〉0．05）；（2）各饮酒组PBR mRNA水平明显降低（均P〈0．05），PPARα mRNA水平也明显降低（均P〈0．05）；（3）各饮酒组ABP mRNA水平明显下降（均P〈0．05）。结论长期饮酒可显著降低大鼠睾酮合成，PBR和PPARα表达降低是其可能机制之一；长期饮酒还可抑制大鼠ABP表达，影响睾酮生物学效应的发挥。     

Neuropsychological changes during steady-state drug use,withdrawal and abstinence in primary benzodiazepine-dependent patients

Impairment on neuropsychological tests during steady-state drug use and withdrawal, and after discontinuation of benzodiazepines, was studied in primary benzodiazepine-dependent patients. One group of patients was tested before and the other group after the initiation of a gradual tapering-off of the drug, and both groups were tested approximately 1 year later. At the initial assessment, both groups of patients showed impairment on most of the tests of general intelligence and on several of the tests in the Halstead-Reitan battery, as well as on a test of nonverbal memory, in comparison with healthy controls. At follow-up the patient groups had reached the level of the control group. This study confirmed earlier observations of neuropsychological deficits in long-term benzodiazepine-using patients and demonstrated that these changes are at least partly reversible by discontinuing drug intake.