In previous papers, we observed that dendrimers of peptide mimotopes of the nicotinic receptor ligand site are strong antidotes against the lethality of the nicotinic receptor ligand ␣-bungarotoxin. Although their in vitro activity is identical to that of dendrimers, the corresponding monomeric peptide mimotopes are not effective in vivo. Because the higher in vivo efficiency of dendrimers could not in this case be related to polyvalent interaction, the stability to blood protease activity of monomeric versus tetrabranched dendrimeric mimotope peptides was compared here by incubating three different mimotopes with human plasma and serum. Unmodified peptides and cleaved sequences were followed by high pressure liquid chromatography and mass spectrometry. Tetrabranched peptides were shown to be much more stable in plasma and also in serum. To assess the notable stability of multimeric peptides, different bioactive neuropeptides, including enkephalins, neurotensin and nociceptin, were synthesized in monomeric and tetrabranched forms and incubated with human plasma and serum and with rat brain membrane extracts. All the tetrabranched neuropeptides fully retained biological activity and generally showed much greater stability to blood and brain protease activity. Some tetrabranched peptides were also resistant to trypsin and chymotrypsin. Our findings provide new insights into the possible therapeutic use of bioactive peptides.Hundreds of peptides with potential therapeutic activities have been identified. These include naturally occurring peptide hormones and neurotransmitters, which influence and control series of vital functions, such as cell proliferation, tissue development, metabolism, immune defense, perception of pain, reproduction, behavior, and blood pressure. Selective agonists or antagonists of these natural peptides are extremely useful for the investigation of peptidergic systems and are also potential therapeutic agents (1). Moreover, several peptide fragments or mimotopes derived from potential therapeutic proteins show promising biological activity (2).However, the use of peptides as therapeutic drugs has largely been limited by their short half-life in vivo. Because peptides are mainly broken down by proteases and peptidases, peptide delivery is the bottleneck in the development of new peptide drugs. To increase peptide half-life, many strategies involving different levels of chemical modification are possible (3, 4). The introduction of D-amino acids, or pseudo amino acids, and peptide cyclization are the most common strategies to increase peptide stability. However, these modifications may profoundly alter peptide activity. Alternatively, peptidomimetic molecules can be developed by the synthesis of conformationally restricted compounds, in which the peptide is locally or globally constrained in order to reproduce the active conformation. The resulting structures are mostly non-peptide molecules, more resistant to degrading enzymes.In general, peptide molecules have the advantage of good specifici...

A markedly reduced interest or pleasure in activities previously considered pleasurable is a main symptom in mood disorder and psychosis and is often present in other psychiatric disorders and neurodegenerative diseases. This condition can be labeled as “anhedonia,” although in its most rigorous connotation the term refers to the lost capacity to feel pleasure that is one aspect of the complex phenomenon of processing and responding to reward. The responses to rewarding stimuli are relatively easy to study in rodents, and the experimental conditions that consistently and persistently impair these responses are used to model anhedonia. To this end, long-term exposure to environmental aversive conditions is primarily used, and the resulting deficits in reward responses are often accompanied by other deficits that are mainly reminiscent of clinical depressive symptoms. The different components of impaired reward responses induced by environmental aversive events can be assessed by different tests or protocols that require different degrees of time allocation, technical resources, and equipment. Rodent models of anhedonia are valuable tools in the study of the neurobiological mechanisms underpinning impaired behavioral responses and in the screening and characterization of drugs that may reverse these behavioral deficits. In particular, the antianhedonic or promotivational effects are relevant features in the spectrum of activities of drugs used in mood disorders or psychosis. Thus, more than the model, it is the choice of tests that is crucial since it influences which facets of anhedonia will be detected and should be tuned to the purpose of the study.

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Rats exposed to acute unavoidable stress develop a de®cit in escaping avoidable aversive stimuli that lasts as long as unavoidable stress exposure is repeated. A 3-week exposure to unavoidable stress also reduces dopamine (DA) output in the nucleus accumbens shell (NAcS). This study showed that a 7-day exposure to unavoidable stress induced in rats an escape de®cit and a decrease in extraneuronal DA basal concentration in the NAcS. Moreover, animals had reduced DA and serotonin (5-HT) accumulation after cocaine administration in the medial pre-frontal cortex (mPFC) and NAcS, compared with control animals. After a 3-week exposure to unavoidable stress, escape de®cit and reduced DA output in the NAcS were still signi®cant at day 14 after the last stress administration. In the mPFC we observed: (i) a short-term reduction in DA basal levels that was back to control values at day 14; (ii) a decrease in DA accumulation at day 3 followed by a signi®cant increase beyond control values at day 14; (iii) a signi®cant reduction in 5-HT extraneuronal basal levels at day 3, but not at day 14. Finally, a signi®cant decrease in 5-HT accumulation following cocaine administration was present in the NAcS and mPFC at day 3, but not at day 14. In conclusion, a long-term stress exposure induced long-lasting behavioral sequelae associated with reproducible neurochemical modi®cations.