Apomorphine (Apo) administration induces a persistent bout of pecking in pigeons and other birds. Repeated injections of Apo in pigeons lead to sensitization, i.e. the pecking response to a particular dose increases up to a dose-dependent asymptotic level. It is also known that Apo-induced pecking can be classically conditioned to the cage environment where the animals experience the effect of the drug. Here we address the question of whether, and to what extent, the sensitization effect arises as a consequence of a conditioning or of a pharmacological process. An extinction experiment demonstrated that an extinction procedure supposed to be effective in inhibiting the conditioned pecking response was not effective in suppressing the sensitization to Apo, thus casting provisional doubt on the conditioning hypothesis. However, a conditioning experiment demonstrated that the sensitization effect undoubtedly involved an important component of conditioning to an experimental cage environment, but also suggested that there was an additional component possibly not due to learning. A generalization experiment, however, showed that this second component was very probably due to a stimulus generalization effect deriving from conditioning to the home cage, suggesting that learning can account for most, if not all, of the increase in Apo-induced pecking and that an exclusively pharmacological sensitization process plays, at best, a minor role. The apparent contrast between the results of the first experiment, indicating that the sensitization is not affected by inhibitory conditioning, and the results of the last two experiments, suggesting that the sensitization is due to excitatory conditioning, can be re olved by liSSuming that Apo induces a drug-state-dependent conditioning. These results are related to findings and arguments concerning the sensitization to psychostimulant drugs in mammals.

The dopamine agonist apomorphine (apo) elicits stereotyped pecking bouts in pigeons, a response which increases with successive apo injections. The present study sought, first, to confirm the hypothesis that this sensitization arises through a Pavlovian conditioning driven by both external and internal cues; and, secondly, to advance the hypothesis that during this learning the dopaminergic activation only initiates a process that probably ends in glutamatergic synapse modifications. The conditioned nature of the sensitization to apo was examined in two separate experiments that compared context contingent and context uncontingent apo treatments. The role of dopaminergic mechanisms in the acquisition, maintenance and retrieval of sensitization-conditioned pecking was examined by administering the dopamine antagonist haloperidol (hal) either before, during or after apo sensitization treatments. A contingency between context and apo was found to be essential for the acquisition and retrieval of apo-sensitized pecking. A pretreatment with hal did not curtail a subsequent sensitization to apo. When hal was co-administrated with apo it suppressed the initial pecking response to apo and blocked the acquisition of sensitized responding. A pecking response normally observed when apo-sensitized pigeons are challenged with saline (sal) in the same cage in which they were sensitized, was also absent. When hal was co-administered with apo after the sensitization was complete this led at first to an only partial apo response suppression. When treated with hal in the same cage, already sensitized pigeons responded much as if they had been challenged with sal. The sensitization induced by apo was thus blocked by hal co-administered during acquisition, but during the maintenance or retrieval phase hal did not impair a previously sensitized responding. It is concluded that when pigeons are sensitized to apo, dopaminergic mechanisms are implicated in initiating the neural modifications that underlie the conditioned sensitization, but that they themselves are not importantly altered.

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Der Verhaltenseffekt der Psychostimulanzien Kokain und Amphetamin, vornehmlich indirekte Dopaminagonisten, steigert sich bei wiederholter Einnahme ein und derselben Dosis. Wahrscheinlich spielt diese Sensitivierung bei der Suchtentstehung eine wichtige Rolle. Mehrfache Gaben vorn direkten, nicht suchtbildenden Dopaminagonist Apomorphin (Apo) führen ebenfalls zu einer Sen si ti vierung. Wir berichten, dass diese Empfindlichkeitssteigerung besonders gut an den Pickanfällen, die Apo bei Vögeln auslöst, untersucht werden kann. Es werden Versuchsergebnisse vorgestellt, die zeigen, dass die Sensitivierung auf einen langwährenden Pawlovschen Lernvorgang zurückgeht. Die Sensitivierung ist ausgesprochen umgetungsspezifisch, auch hinsichtlich der Pick ziele. Einige Besonderheiten der Sensitivierung erklären sich dadurch, dass Apo ein unkonditionierter Reiz ist, der gleichzeitig auch Eigenschaften eines konditionierten Reizes hat. Neuropharmakologische Ergebnisse suggerieren, dass die Sensitivierung auf Apo auf eine synaptische Interaktion zurückgeht, die zu einer Effektivitätssteigerung der glutamatergen Übertragung im ventralen Striatum führt.

MOLECULAR BIOMARKERS OF HUMAN DISEASE: FUNDAMENTAL CONCEPTS, RESEARCH MODELS AND CLINICAL APPLICATIONS. Molecular biomarkers correspond to all endogenous or exogenous biomolecules, whose presence or alteration in metabolic pathways indicate the response of a biological system to a disturbance caused by internal or external factors. The search for biomarkers has allowed deepening the knowledge of complex pathophysiological mechanisms of diseases, interactions with potential drugs, and the improvement of diagnostic and therapeutic tests, establishing itself as a central point in personalized medicine. In addition, the development of the omics sciences has fostered an increasing exploration in this field of research. This review presents essential and relevant concepts in biomarker research, explores the various definitions and classifications of biomarkers according to their purpose, the critical aspects to be considered in experimental design, the primary employed study models (in vivo, in vitro, and in silico) and the factors that have hindered their ultimate implementation. Finally, important, and current clinical and pharmacological research areas in which biomarker research play a central role are presented.

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