Objective: Sedation/somnolence are major side effects of pharmacotherapies for depression, and negatively affect long-term treatment compliance in depressed patients. Use of mirtazapine (MIR), an atypical antidepressant approved for the treatment of moderate to severe depression with comorbid anxiety disorders, is associated with significant sedation/somnolence, especially in short-term therapy. Nonetheless, studies with human subjects suggest that MIR-induced sedation is transient, especially when high and repeated doses are used. The purpose of this study was to explore the effects of acute and chronic administration of different doses of MIR on sedation in the rat. Methods: Assessment of sedation was carried out behaviorally using the rotarod, spontaneous locomotor activity, and fixed-bar tests. Results: A 15-mg/kg dose of MIR induced sedative effects for up to 60 minutes, whereas 30 mg/kg or more produced sedation within minutes and only in the first few days of administration. Conclusion: These results suggest that 30 mg/kg is a safe, well-tolerated dose of MIR which generates only temporary sedative effects.

Abstract: Introduction: New therapeutic strategies against cocaine overdose toxicity have been developed. These new approaches are based on the design and synthesis of proteins involved in the destruction of cocaine before it has a chance to penetrate nerve tissue. Objective: To review the progress in the effect of the increase in the catalytic activity of BChE and hCE enzymes produced for the treatment of patients in cocaine overdose toxicity conditions in order to determine the advantages and disadvantages of its use. Its potential future use in patients channeled by a cocaine overdose is also explored. Method: A bibliographic search was conducted using PubMed; descriptors were "cocaine", "hydrolase", "esterase" and "butyrylcholinesterase". 220 papers were obtained and 126 papers were used for these review. Results: The BChE, COCH and Coce bacterial enzymes significantly decrease the levels of cocaine in blood and brain and thereby attenuate the effects of a cocaine overdose. Discussion and conclusion: The results obtained in animal models suggest the potential therapeutic use of these enzymes in humans to rapidly inactivate cocaine and develop treatments to stop deaths associated with cocaine overdose intoxication. These enzymatic approaches offer a novel therapeutic application to treat cocaine overdose.

Resumen: Introducción: Se han desarrollado nuevas estrategias terapéuticas contra la toxicidad por sobredosis de cocaína basadas en el aumento en la actividad catalítica de enzimas que participan en la destrucción de su molécula, antes de que tenga la oportunidad de penetrar el tejido nervioso. Objetivo: Describir los avances en el efecto del aumento en la actividad catalítica de las enzimas BChE y las hCE, producidas para el tratamiento de pacientes en condiciones de toxicidad por sobredosis de cocaína, así como mencionar sus ventajas y desventajas y su potencial uso futuro en pacientes internados por una sobredosis de cocaína. Método: Se realizó una búsqueda bibliográfica por medio del PubMed, usando como descriptores las palabras "Cocaine", "hydrolase", "esterase" y "butyrylcholinesterase". Se obtuvieron 220 artículos de los cuales se usaron 126 para esta revisión. Resultados: Las enzimas BChE, COCH y CoCe bacteriana disminuyeron significativamente los niveles de cocaína en la sangre y el cerebro y con ello atenuaron los efectos de una sobredosis de cocaína. Discusión y conclusión: Los resultados obtenidos en modelos animales sugieren el potencial terapéutico del uso de estas enzimas en humanos, para inactivar rápidamente a la cocaína y desarrollar tratamientos para evitar las muertes asociadas con la intoxicación por sobredosis. Estas metodologías enzimáticas ofrecen una aplicación terapéutica novedosa para el tratamiento de la sobredosis.

INTRODUCTION: The classic pharmacopoeia used to attenuate cocaine dependence has proved a poor therapeutic efficacy. Based on this discouraging clinical and therapeutic panorama, since more than a decade, various researchers have developed new therapeutic strategies against cocaine addiction. These new experimental strategies are based on the structural design and synthesis of therapeutic vaccine formulations against cocaine addiction. OBJECTIVE: To describe the development and therapeutic evaluation of active immunization against cocaine. METHOD: A bibliographical search was made using PubMed, using as descriptors the words "Cocaine" and "Vaccine." 155 articles were obtained which were used for these review 46 items. RESULTS: At preclinical level, active vaccination generates high levels of antibodies capable of recognizing with high specificity the cocaine present in the bloodstream, which attenuates the behavioral changes induced by different doses of cocaine. DISCUSSION AND CONCLUSION: Preclinical and clinical results have reinforced "proof of concept" active therapeutic vaccination to pharmacological control to cocaine use relapse in humans, but gave guidelines to the postulation and justification of synthesizing new models of anti-cocaine vaccines for human use. This experimental pharmacological strategy of "immunoprotective" nature has proven an effective treatment that significantly reduces drug-seeking behaviors, both at pre-clinical levels in the rodent model as well as in humans.

INTRODUCCIÓN: La farmacopea clásica, empleada para atenuar la dependencia a ciertas drogas de abuso ilegal, como la cocaína, ha demostrado una pobre eficacia terapéutica. Basado en este desalentador panorama clínico-terapéutico, desde hace más de una década diversos investigadores han desarrollado nuevas estrategias terapéuticas contra la adicción a la cocaína. Estas nuevas estrategias experimentales están basadas en el diseño y la síntesis de formulaciones estructurales de vacunas terapéuticas contra la adicción a la cocaína. OBJETIVO: Realizar una descripción del desarrollo y la validación terapéutica de la inmunización activa contra la cocaína. MÉTODO: Se realizó una búsqueda bibliográfica con el uso del PubMed, usando como descriptores las palabras "Cocaine" y "Vaccine". Se obtuvieron 155 artículos, de los cuales se usaron 46 para esta revisión. RESULTADOS: A nivel preclínico, la vacunación activa genera altos niveles de anticuerpos capaces de reconocer con alta especificidad a la cocaína dentro del torrente sanguíneo, atenuando las alteraciones conductuales inducidas por diversas dosis de cocaína. DISCUSIÓN Y CONCLUSIÓN: Los resultados preclínicos y clínicos han reforzado "la prueba de concepto" terapéutica de la vacunación activa para el control farmacológico de la recaída al consumo adictivo de la cocaína en el humano, sin embargo, dieron pauta a la postulación y a la justificación de sintetizar nuevos modelos de uso humano de vacunas anticocaína. Esta estrategia farmacológica experimental, de naturaleza "inmunoprotectora", ha demostrado ser un tratamiento eficaz al atenuar significativamente las conductas de búsqueda y consumo adictivo a la cocaína, tanto a nivel pre-clínico, en el modelo del roedor, como en el humano.

Drug addiction is one of the most important health problems in the world. This psychiatry disease results in the death of about 500 000 individuals annually in the world. Despite this scenario, the development of effective drug therapies against this disease has been slow and not very successful. In recent years, new alternative pharmacological strategies against drug addiction have been designed and validated. Among them are vaccines against drugs like nicotine, morphine or cocaine and their subsequent use in immunotherapeutic pharmacological procedures for the treatment of addictive behaviors of drug consumption, both in animal models and in humans. These strategies are based on the experimental design and synthesis of various structural formulations of therapeutic vaccines against drugs of abuse. When dosed in active immunization schedules, they induce the production of specific antibodies, which recognize and bind these substances in the intravascular space and prevent the drug permeability through the blood brain barrier, resulting in decreased effects of drugs into the brain. In 2006, our research group at the National Institute of Psychiatry Ramón de la Fuente Muñiz (INPRFM) achieved and consolidated the design, synthesis, application and validation of immunoprotective therapeutic effects against relapse to morphine/heroin addiction in a rodent animal model, a model vaccine for potential human use against addiction to morphine/heroin. This model shows immunogenic capacities (high and sustained titers of highly specific antibodies) and immunoprotection (attenuates the effect up to 15mg/kg sc morphine) that the structural vaccine models competing have not been matched, which makes it the leading vaccine model against the addictive effects of heroin and morphine.

La adicción a una droga de abuso representa uno de los problemas sanitarios más importantes ya que esta patología genera la muerte de cerca de 500 000 sujetos anualmente en el mundo. A pesar de este panorama, el desarrollo de terapias farmacológicas efectivas contra esta enfermedad es lento y poco exitoso. En los últimos años se han diseñado y validado nuevas estrategias farmacológicas alternativas contra la adicción a drogas de abuso, como las vacunas y su uso en procedimientos farmacológicos inmunoterapéuticos para el tratamiento de esas conductas tanto en modelos de animales como en el humano. Estas nuevas estrategias experimentales están basadas en el diseño y síntesis de diversas formulaciones estructurales de vacunas terapéuticas contra las sustancias de abuso las cuales, al ser dosificadas en esquemas de inmunización activa, inducen la producción de anticuerpos séricos específicos que reconocen y se unen a estas sustancias en el espacio intravascular sistémico e impiden que crucen la barrera hematoencefálica, con lo cual disminuyen sus efectos en el cerebro. En el año 2006 nuestro grupo de trabajo en el Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz (INPRFM) logró y consolidó el diseño, síntesis, aplicación y validación de efectos terapéuticos inmunoprotectores contra recaídas al consumo adictivo de morfina/heroína, en un modelo animal con roedores y su escalamiento potencial para uso humano contra la adicción a esas sustancias. Este modelo muestra capacidades inmunogénicas (títulos altos y sostenidos de anticuerpos altamente específicos) y de inmunoprotección (atenúa el efecto de hasta 15mg/Kg sc de morfina) que los modelos estructurales de vacuna desarrollados por otros grupos de investigadores no han podido igualar. Esto lo convierte en un modelo líder de vacuna contra los efectos adictivos de la heroína y morfina.

SUMMARY One of the most important functions in which the circadian system participates is to assess that the behavioural and physiological variables adjust appropriately to daily events in the environment, a process referred to as entrainment. Since in the nature the food disposition and predators’ activity also are cyclical, the temporary relation between the circadian rhythm and periodic environmental signals maximizes the survival of each species in its temporary niche. Thus, through this mechanism, the organisms adapt to their environment through circadian system which entrain the organism activities to different external signals. In nature environments the predominance of photic entrainment like primary zeitgeber of the biological clock (suprachiasmatic nucleus) is a clear adaptation to the earthly life; nevertheless other biological advantages can be conferred to an individual if the circadian system also is sensible to other environmental signals that they provide from the external time. In such way, the light is not the only synchronizer affecting the biological clock. Other stimuli like the temperature and locomotor activity induced by novel stimuli and certain drugs are also able to entrain the biological clock. These signals have been described like non-photic stimuli. The general effects of the non-photic signals are able to generate phase response and entrain a free running rhythm, only during the subjective day, time in which the biological clock is sensible to these signals which are able to generate phase advances. These phase response are of great magnitude, even of greater magnitude than the induced ones by a light signal. The non-photic signals are also able to induce residual effects (after-effects) on entrainment process, thereby generating changes in the endogenous period, therefore affecting the phase angle in a cycle L:O and promoting the development of locomotor activity rhythm splitting. Furthermore, the light entrainment has been characterized in a wide variety of diurnal and nocturnal species. While, the non-photic entrainment only appears in nocturnal rodents. Being the hamster’s biological clock one of that responds to the greater number of biological non-photic signals such as the acute exposition to sexual odors, social interactions, as well as by simple injection of saline solution, all of these non-photic signals are able to induce phase advances of the locomotor activity rhythm in free running when they are applied onto the subjective day. The entrainment to a non-photic stimulus is also observed in humans. Among the non-photic stimuli we can have the pharmacological treatments, social stimuli, stress, food restriction and communication between mother and product in the foetal and neonatal life. These later stimuli are of a particular importance to optimize the circadian function and sensitize the newborn to external environment. Thus the non-photic stimuli could be categorized like behavioural or pharmacological stimuli. These manipulations involve an increase in the locomotor activity, excitation or states able to phase resetting the circadian clock and peripheral oscillators in different species. The non-photic stimuli can affect to the biological clock through an afferent projection from the SCN that translate the non-photic information and is able to induce phase responses. Additionally, non-photic stimuli could also affect the biological clock through the action of a peripheral oscillator, which is sensitive to this type of signals. These peripheral oscillators translate the non-photic information and it communicates with the SCN, through synaptic and no-synaptic mechanisms. With regard to the physiological mechanisms involved on this process, there has been suggested to participate four neurotransmitter systems in the circadian system: a) the serotonergic system originating from the raphe nucleus, b) the NPY system from the leaflet intergeniculate (IGL), c) the GABAergic system, which it is present in most of the neurons of the SCN and IGL (the afferent projections of the raphe and the IGL nucleus make synapse with GABAergic neurons in the SCN) and 4) finally a neural system involving dopamine and melatonin signals, which have been importantly implicated in the brain in the foetal and neonatal live. In comparison to the cascade of intracellular signals caused by glutamatergic stimulation associated to photic entrainment, which excites to the SCN cells, the transmitters implicated in the nonphotic entrainment typically inhibit the SCN neurons. For example the melatonin’s main action on the SCN neurons is inhibiting adenylyl cyclase and the translation of related signals driven by the AMPc, such inhibition of activity of the protein kinase depended of AMPc (PKA), which give rise to a decreased phospho- rylation of the transcription factor CREB. In this way, the phase responses induced by non-photic stimuli are not associate with the phosphorylation of the transcription factor (CREB) associated to responsive DNA-elements to binding AMPciclic or with the transcription of early expression genes in the SCN, events of metabothrophic signalling pathway of the photic entrainment. The phase responses generated by the non-photic signals occur during the subjective day, time in which the spontaneous expression of clock genes is high in diurnal and nocturnal animals. A reason why the phase resetting of biological clock to non-photic signals can be generated by a fast suppression in the expression levels of the genes clock. The decrease of Per1 and Per2 messenger RNA’s expression levels in the SCN generated by non-photic stimuli occurs during a half of the subjective day, not during the subjective night, which suggests that these genes may participate in the phase resetting of biological clock during the subjective day. The interactions between phase response induced by the light and those induced by non-photic stimuli have been described previously. When a photic stimulus is applied after a non-photic signal during subjective day, with the purpose of studying the interaction between photic stimuli and non-photic stimuli, the photic stimulus blocks or attenuates the phase advances generated in response to different non-photic stimuli applied, such as the forced locomotor activity, sleep privation, NPY administration, or serotonergic agonists (8-OH-DPAT) administration. If the genes clock responds to the non-photic stimuli, then the lack of some of them will have to generate alterations in the response to non-photic signals. In the Clock mutant mice, the biological clock responses to the non-photic signals applied during the subjective day generate phase responses in opposed direction from those generated by intact subjects. This latter suggests that different genes clock participate in the generation of the phase response to a non-photic stimulus. The non-photic entrainment of the circadian system has a biological and/or social importance in several contexts. In the early products life, the communication of circadian information from the mother is important in regulating the biological clock of the foetus or newborn before they are sensitive to light. Under circumstances where the social and work routines are altered, by changes of constant “work turn” (shift work), the biological clock receives photic and non-photic signals which generate a dysfunction and poor work efficiency. The absence of non-photic signals followed by a social abstinence can induce alterations in the mental health (depression). The sleep disorder, experimented blind subject can arise from a lost of the social entrainment, therefore a decrease in the efficiency of the clock mechanism. Thus latter alterations of the clock, it could be possible to develop new forms of pharmacological and behavioural treatments.

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Abstract: Organisms adapt their temporary niche with two complementary mechanisms. The first mechanism is referred to as entrainment of the endogenous biological clock, which circumscribes temporarily the activity of the subject into day or night. The second mechanism is defined as masking, and this refers to an alternative route which does not involve the activity of the pacemaker. It involves, instead, a sharp response of the animal during light-time, inhibiting or enhancing the expression of locomotor activities in nocturnal or diurnal species, respectively. Masking describes the direct and immediate effects on the expression of any biological rhythm induced by the season-dependent signals present in the environment. Moreover, this masking mechanism appears to complement the biological clock entrainment, which is used by organismsto adapt to their specific nocturnal or diurnal niche. Several constraints arise when trying to study the biological clock entrainment or the light-associated oscillators system. Theseare due to the fact that the zeitgeber influences the biological clock and affects the output response of the circadian clock. According to the aforementioned description, it appears the masking effects occur as a natural event and result from an inevitable consequence to the season-dependent life of living organisms. Circadian rhythms do not only reflect the physiological output responses of the biological clocks as their activities also result from a mixture of responses arising either from the masking effects and/or from the entrainment mechanisms driving the timing of the biological clock within the animal. Although conspicuous differences do exist between maskingand entrained- rhythms, both rhythms follow a similar timecourse. Nevertheless, the transition between light and darkness (environmental change) under the masking rhythm results in abrupt changes in the animal behavior activity (i.e, from a resting to an ambulatory activity or viceversa). In contrast, when the environment acts as a zeitgeber under the biological clock entrainment, the behavioural transition of the animal appears to be less abrupt and, therefore, the environment factors affecting the biological rhythms never match. Based on different chronobiological studies in animals, several authors have described different forms of masking mechanisms used by the brain, and classified according to the light-induced decrease or increase locomotor activity responses: a) Positive Masking refers to the increase or decrease of locomotor activity response in a diurnal or nocturnal animal, respectively, as a result of the increase in lighting; b) Negative Masking refers to the decrease of locomotor activity responses as a result of decrease in lighting in a diurnal animal, or an increase in lighting in a nocturnal animal; c) Paradoxical Positive Masking refers either to the increase locomotor activity responses of a nocturnal animal exposed to increase lighting or an increase in locomotor activity responses in a diurnal animal after lighting decreases; d) Paradoxical Negative Masking refers to the decrease of locomotor activity responses in a nocturnal animal when lighting is decreased, or to the decrease of locomotor activity responses in a diurnal animal when lighting is increased. In addition to the aforementioned classification of different masking mechanisms on the behavioral locomotor activity responses in both diurnal and nocturnal animals, other authors classify different forms of masking, based on the neural mechanisms that generate the masking effects. Authors defined the occurence of different forms of masking effects when enviromental factors (i.e, light, darkness) produce direct or indirect effects on the cyrcadian rhythm in an animal. Thus, a) Type I masking occurs when the environment produces a direct effect on the circadian rhythm output; b) Type II masking occurs when behavioral changes in the animal affect other physiological brainrhythms, for instance, an increase or decrease of behavioral locomotor activity may affect the temperature rhythm of an organism, enhancing the expression of an altered activity on the biological clock; c) Type III masking occurs when physiological or biochemical changes alter the neural output of the biological clock that conveys the time-related information of the biological rhythm; for instance, physiological or pathological conditions have been shown to affect the functional activity of specific neural pathways and their membrane receptors involved in the regulation of the body temperature. Such situations appear to modify the phase of the body temperature rhythm with the phase of the biological clock, which both rhythms appear to match under basal conditions. The sensibility limits necessary to generate the inhibition of the synthesis and release of melatonine, in rats and hamster, suggest the involvement of the rods, the predominant photoreceptor in the rodent retina. Nevertheless, studies the mutant mice rd/rd (the mutation rd generates the total loss of photoreceptors type rods and a considerable loss of photoreceptors type cones) presented an inhibition in the synthesis and release of the melatonine and locomotor activity induced by the light. This suggests that the photoreceptors type cones and rods are not necessary to mediate the effects of the light on the locomotor activity and that the light masking depends on another type of contained photoreceptor in the retina. Some studies report the loss of the rhythmycity in drinking, locomotion or sleep-wakefulness, not only when the animals are kept in light constant, also when the animals are kept under lightdarkness cycles (L:D). Other studies that involve to mutant mice of the two genescryptocromos, which they are arrhythmic in constant conditions; they show a SCN functional diminished, light pulses applied in the subjective night do not generate alterations in the inhibition of the locomotor activity induced by the light. This suggests the loss of the masking responses induced by light. Certainly, these results point to a loss or attenuation of the masking by the SCN lesion. On the other hand, other works showing a persistence of the masking pd drinking and locomotor activity in L:D conditions after the SCN lesions. The lesions of other structures of the rodent visual system alter the light masking. It is more a significant increase of the masking in subjects with IGL lesion is observed. Subsequently, it was reported that the masking induced by the light was more significant in mice that were submitted to an NGLd lesions, which suggests that the increase in the masking to the light observed after the IGL lesions are probably due to an incidental damage of the NGLd. It also has been reported that the light masking increase after the visual cortex lesions in hamster and mice. The mutant mice clock shows brilliant light pulses: between 100 to 1600 lux they induce a complete suppression of the locomotor activity (negative masking). On the other hand, dim light pulses induce an increment of the basal levels of the locomotor activity (positive masking) in a similar way to that of the normal subjects. The participation of other genes clock in the regulation of the light-masking has not been specific. The masking is not a limited phenomenon to conditions of laboratory. There are few examples of the direct effects of light on the temporary organization of the behavior in wildlife. An impressive case is the owl primate (Aotus lemurinus griseimembra), which shows a pattern of locomotor activity that depends on the lunar cycle. This primate is nocturnal, but its activity increases (positive masking) when the luminescence is found between 0.1 and 0.5 lux, the luminescence generated precisely by the brightness of the moon. Intensities of light lower to this diminish the locomotor activity (negative masking) of the subject. The masking mechanism is an important process in the adaptation of an organism to its environment as it confers this the capacity to respond quickly to a sudden change in environmental conditions. Since the functional point of view the masking contributes to an increment in the amplitude of a entrainment rhythm, promotes direct responses to geophysical variables that the organism selects that they optimize its evolution and its adaptation to its temporary niche, all this contributes to an increase in the probability of survival of the subject to its environment.

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Abstract The periodic fluctuations in diverse physiological parameters are a general property of all organisms. Furthermore, when these fluctuations occur to intervals regulates these are considered as «biological rhythms». The biological rhythms are generated by an endogenous mechanism of the organism. The biological rhythms appear in wide interval in frequencies of oscillation, which go from a cycle by millisecond to a cycle per year. Additionally, the geophysical environment is characterized by the existence of cycles deriving from movements of the earth and the moon with regard to sun. These environmental or geophysical cycles are the days, tides, lunar phases and seasons of the year. When the frequency of a biological rhythm approaches that of an environmental cycle, the prefix "circa" is used to refer to it. Likewise, 24-hour biological rhythms are designated as circadian rhythms. The circadian rhythms represent one of the most ubiquitous adaptive characteristics of the organism. In mammals, they represent an important process through which events of the internal milieu are organized in an appropriate temporary sequence, thus enhancing a maximum adaptation to external milieu. This characteristic allows organisms to predict and to be prepared for changes in the geophysical environment associated with the day and the night. To carry out this adaptive role, the circadian rhythms require the biological system having the capacity to measure the biological time. Thus, the circadian rhythm should be generated endogenously, adjusting the geographical time. Moreover, under usual environmental conditions, the period of the oscillator is adjusted to the period of the environmental cycle. The endogenous origin of the biological rhythms is based on the fact that, in temporary environmental signs isolation conditions, the biological rhythm persists with a light but significant variation in the value of the period of oscillation. The afore mentioned considerations suggest that the rhythm observed does not depend on cyclic geophysical phenomena. Thus, the rhythm maintained under constant conditions reflects an internal organism's process. This essential ability of the organism to maintain circadian rhythms, even in the absence of periodic environmental cues, is known as rhythm in spontaneous oscillation or free-running. Nevertheless, the organism is never isolated from temporary signals and it keeps a narrow temporary relation with the environmental cues by which the phase and the period of the overt rhythm can be adjusted to the phase and period of the environmental cyclic changes. This process is called «entrainment». It is considered that the three fundamental properties of circadian rhythms are the persisting free-running rhythm, the temperature compensation and the entrainment. Literally, the word entrainment means «to get aboard a train» (from the French word entramen «to carry along»). In this context, the entrainment of a biological clock is generated through a controllers stimuli train with a specific period, which induces a biological clock with a different endogenous period from 24 hours to be adjusted for the period of the periodic environmental cycle. The entrainment of the biological clock provides to internal milieu of a reckoned of the external time. This process can occur for a modulation of the period and/or of the phase of the biological rhythm, that is, the endogenous period of the biological rhythm is adjusted to the period of the zeitgeber with a relation phase stable (or phase angle) between the zeitgeber and the oscillation entrained. Studies where subjects were submitted to a rigorous temporary isolation indicated that only certain environmental variables are capable of acting as temporary signals for the circadian system. In 1951, Aschoff coined the word «Zeitgeber» from the German «given of time», which describes an environmental cycle capable of affecting the period and the phase of a biological clock. In nature, multiple environmental cues oscillate under a daily cycle, including light, darkness, temperature, humidity, availability of food and social signals. Some of these factors may act as zeitgebers of the biological clock, but the most consistent and predictable environmental signal is the 24-hour cycle of light-darkness (L:O) (photic entrainment). Nevertheless, organisms can be entrained for other stimuli (non-photic entrainment) such as temperature, electromagnetic fields, environmental pressure, sound, availability of food and social signals. Researchers have developed two theoretical models to explain the mechanism(s) by which the circadian clock is entrained to an environmental cycle: the discreet model (non-parametric or phasic) and the continuous model (parametric or tonic). The model of continuous entrainment is based on the observation that the period in free running (POE) to depend of the intensity light and suggests that the light has a continuous action on the biological clock to entrain it to a cycle light-darkness (L:O). The mechanism suggested for this is the acceleration and deceleration of the POE (angular velocity), due to daily changes in the intensity of the light, these permit to circadian pacemaker is continuously adjusted along the environmental cycle. The discreet model has been the most utilized model to explain the entrainment to environmental cycles. The basic premise of this model is that the circadian pacemaker entrained this in equilibrium with the cycle light: darkness (L:D), which consists of brief pulses of light (zeitgeber). When a brief pulse of light falls in a specific phase of the biological clock, this produces an phase response equal to the difference between the POE and the period of the cycle entrained. The day-night cycles generated by the rotation of the earth around its axis influence the life of the organism to a large extension. Many organisms coordinate their activities to these cycles. Some of them are diurnal, while other ones nocturnal. Moreover other animals escape from the daily periodic environment and they organize their life in constant environments as in the depth of the ocean or in natural caverns. It is not clear how and because biological clocks with a period of approximately 24 hours evolved in cyclic environments of exactly 24 hours. A possible explanation is that the cycles L:D provide an optimum stability for their expression. There has been as were that the cycle L:D is the first environmental signal behind the emergency and maintenance of the circadian clocks. A large number of cell functions are affected by the light, and is being speculated that the original organisms could have restricted some of their outstanding metabolic processes at night, thus avoiding the adverse effects of the light. In fact, some organisms adjust several of their sensitive cell processes to the light. For example, there is an augmented replication of the DNA, at night to avoid the exposition to deleterious ultraviolet radiation. Thus it is possible to propose a hypothesis of how the circadian clocks could evolve at phylogenetically level: the ancient organisms generated a temporary program, where sensitive processes to the light were temporarily restricted to avoid the damage induced by the sunlight; these temporary programs turned out to be advantageous and thus they were selected through evolution of species.

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