Most antianxiety drugs (anxiolytics) work by modulating neurotransmitters in the brain. Benzodiazepines are fast and effective anxiolytic drugs; however, their long-term use is limited by the development of tolerance and withdrawal symptoms. Ligands of the translocator protein [18 kilodaltons (kD)] may promote the synthesis of endogenous neurosteroids, which also exert anxiolytic effects in animal models. Here, we found that the translocator protein (18 kD) ligand XBD173 enhanced gamma-aminobutyric acid-mediated neurotransmission and counteracted induced panic attacks in rodents in the absence of sedation and tolerance development. XBD173 also exerted antipanic activity in humans and, in contrast to benzodiazepines, did not cause sedation or withdrawal symptoms. Thus, translocator protein (18 kD) ligands are promising candidates for fast-acting anxiolytic drugs with less severe side effects than benzodiazepines.

Histamine H 3 receptor inverse agonists are known to enhance the activity of histaminergic neurons in brain and thereby promote vigilance and cognition. 1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride (BF2.649) is a novel, potent, and selective nonimidazole inverse agonist at the recombinant human H 3 receptor. On the stimulation of guanosine 5Ј-O-(3-[35 S]thio)triphosphate binding to this receptor, BF2.649 behaved as a competitive antagonist with a K i value of 0.16 nM and as an inverse agonist with an EC 50 value of 1.5 nM and an intrinsic activity ϳ50% higher than that of ciproxifan. Its in vitro potency was ϳ6 times lower at the rodent receptor. In mice, the oral bioavailability coefficient, i.e., the ratio of plasma areas under the curve after oral and i.v. administrations, respectively, was 84%. BF2.649 dose dependently enhanced tele-methylhistamine levels in mouse brain, an index of histaminergic neuron activity, with an ED 50 value of 1.6 mg/kg p.o., a response that persisted after repeated administrations for 17 days. In rats, the drug enhanced dopamine and acetylcholine levels in microdialysates of the prefrontal cortex. In cats, it markedly enhanced wakefulness at the expense of sleep states and also enhanced fast cortical rhythms of the electroencephalogram, known to be associated with improved vigilance. On the two-trial object recognition test in mice, a promnesiant effect was shown regarding either scopolamine-induced or natural forgetting. These preclinical data suggest that BF2.649 is a valuable drug candidate to be developed in wakefulness or memory deficits and other cognitive disorders.The cerebral histaminergic neurons seem to play a critical role in the maintenance of wakefulness and higher cerebral functions, e.g., attention or learning (for review, see Schwartz et al., 1991;Haas and Panula, 2003). Hence, druginduced activation of histaminergic neurotransmission in the central nervous system represents a promising therapeutic target in a large variety of neuropsychiatric disorders in which these functions are compromised and for which available therapeutic opportunities are limited in this respect .Stimulation of postsynaptic H 1 and/or H 2 receptors by agonists is, however, not acceptable due to unavoidable and detrimental actions of these drugs at peripheral, i.e., mainly cardiovascular and gastric targets. In contrast, presynaptic H 3 receptors are almost exclusively expressed in the central nervous system, and their blockade by drugs such as thioperamide markedly enhances the activity of histaminergic neurons, as shown namely by the increases in histamine (HA) release and turnover in rodent brain (Arrang et al., Article, publication date, and citation information can be found at

The need to develop a blood substitute is now urgent because of the increasing concern over Europe's BSE outbreak and the worldwide HIV/AIDS epidemic, which have cut blood supplies. Extracellular soluble hemoglobin has long been studied for its possible use as a safe and effective alternative to blood transfusion, but this has met with little success. Clinical trials have revealed undesirable side effects-oxidative damage and vasoconstriction-that hamper the application of cell-free hemoglobin as a blood substitute. We have addressed these problems and have found a new promising extracellular blood substitute: the natural giant extracellular polymeric hemoglobin of the polychaete annelid Arenicola marina. Here we show that it is less likely to cause immunogenic response; its functional and structural properties should prevent the side effects often associated with the administration of extracellular hemoglobin. Moreover, its intrinsic properties are of interest for other therapeutic applications often associated with hemorrhagic shock (ischemia reperfusion, treatment of septic shock and for organ preservation prior to transplantation). Moreover, using natural hemoglobin is particularly useful since recombinant DNA techniques could be used to express the protein in large quantities.

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To confirm the antidepressant-like activity of agomelatine (S 20098), a melatonin agonist and 5-hydroxytryptamine2C antagonist, already reported in the chronic mild stress and forced swimming tests, the effects of agomelatine were investigated in the learned helplessness test and compared with those of imipramine, melatonin and a selective 5-hydroxytryptamine2C antagonist, SB-242 084. Agomelatine was administered for 5 days either once a day or twice a day, and the effects of pretreatment by a melatonin receptor antagonist, S 22153 (20 mg/kg/day), were studied. A deficit in avoidance learning was observed in helpless control animals. Agomelatine (10 mg/kg/day) administered once a day significantly reduced this deficit with an effect similar to that of imipramine. Effects of agomelatine were abolished by S 22153 pretreatment. Melatonin or SB-242 084 did not reduce the deficit of helpless control animals. These results confirm the antidepressant-like activity of agomelatine and suggest a role of melatonin receptors in its mechanism of action.