Serotonin 2C receptor antagonists induce fast-onset antidepressant effects.

Current antidepressants must be administered for several weeks to produce therapeutic effects. We show that selective serotonin 2C (5-HT2C) antagonists exert antidepressant actions with a faster-onset (5 days) than that of current antidepressants (14 days) in mice. Subchronic (5 days) treatment with 5-HT2C antagonists induced antidepressant behavioral effects in the chronic forced swim test (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy paradigm. This treatment regimen also induced classical markers of antidepressant action: activation of cAMP response element-binding protein (CREB) and induction of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC). None of these effects were induced by subchronic treatment with citalopram, a prototypical selective serotonin reuptake inhibitor (SSRI). Local infusion of 5-HT2C antagonists into the ventral tegmental area was sufficient to induce BDNF in the mPFC, and dopamine D1 receptor antagonist treatment blocked the antidepressant behavioral effects of 5-HT2C antagonists. 5-HT2C antagonists also activated mammalian target of rapamycin (mTOR) and eukaryotic elongation factor 2 (eEF2) in the mPFC, effects recently linked to rapid antidepressant action. Furthermore, 5-HT2C antagonists reversed CMS-induced atrophy of mPFC pyramidal neurons. Subchronic SSRI treatment, which does not induce antidepressant behavioral effects, also activated mTOR and eEF2 and reversed CMS-induced neuronal atrophy, indicating that these effects are not sufficient for antidepressant onset. Our findings reveal that 5-HT2C antagonists are putative fast-onset antidepressants, which act through enhancement of mesocortical dopaminergic signaling.

Peptide libraries: determination of relative reaction rates of protected amino acids in competitive couplings.

In the solid phase preparation of synthetic peptide libraries, equimolarity of the resultant peptides in the mixture simplifies the identification of active compounds. Two primary methods for the preparation of combinatorial peptide mixtures are currently used. In the first method, the starting resin is divided into equal aliquots, individual amino acids are coupled to each aliquot, and the resin is then recombined. This process is repeated for each position. However, due to the physical process, each resin bead contains only one peptide sequence. Statistically, for mixtures of longer sequences, an ever-increasing amount of resin is necessary to ensure complete representation of each peptide in the library. Thus, each peptide will be represented in the library if a sufficient number of resin beads are used. In addition, the concentration of each peptide in the library depends on both the number of mixture positions in the library and the amount of resin used. In the second method, mixtures of amino acids are coupled simultaneously at each addition step. The proportion of each amino acid in the reaction mixture is varied inversely to its reaction rate such that, ideally, an equimolar mixture of each peptide is synthesized. An advantage of this method over the previous method is that each peptide is ensured to be represented in the library, although not necessarily in equimolar amounts. It is known that not only do the coupling rates of each amino acid vary, but the coupling rates of individual amino acids also change when coupled to different amino acid resins.(ABSTRACT TRUNCATED AT 250 WORDS)

Injuries from the wichita falls tornado: implications for prevention.

We examined the circumstances of death and injury among victims of the tornado that struck Wichita Falls, Texas, on 10 April 1979. We also assessed the protective measures taken by a representative sample of community residents who suffered no major injury in order to estimate the relative risk of injury to people directly in the tornado's path. Twenty-six (60 percent) of the 43 traumatic deaths and 30 (51 percent) of the 59 serious injuries occurred in people who, despite ample warning, went to their cars to drive out of the storm's path. These people had a risk of serious or fatal injury of 23 per 1000. People who remained indoors and in stationary homes were at relatively low risk (3 per 1000) if they took simple precautions; people in mobile homes were at greatest risk (85 per 1000). Current safety recommendations and housing codes for single family homes and mobile homes need to be amended to decrease the impact of future tornadoes on human health.

Epidural analgesia and its effects on the "normal" progress of labor.

The effects of epidural analgesia on the duration of labor have been a controversal subject since its increased use in recent years. A total of 598 patients receiving this form of analgesia were studied as to progress in labor and eventual outcome. The mean cervical changes during epidural analgesia with a single drug, bupivacaine, 0.125%, with epinephrine, 1:200,000, have been calculated. The labor curves are characterized by constant acceleration in dilatation without deceleration at approximately the same rate for nulliparous and multiparous patients after dilatation of 5 cm. has been reached. Examination of maternal and fetal profiles failed to demonstrate any consistent variables that produce abnormal labor.