Journal of Addiction & Addictive Disorders Category: Clinical Type: Research Article
Addiction and Evolutionary Process, Common Aspects in Physio-Pathologic Pathways Use Full in Pharmaco-Toxicological Approach
- Mauro Luisetto1*, Naseer Almukhtar2, Ghulam Rasool Mashori3, Behzad Nili Ahmadabadi4, Ram Kumar Sahu5
- 1 Applied Pharmacologist, European Specialist Lab Medicine, Independent Researcher, Italy
- 2 Department Of Physiology, College Of Medicine, University Of Babylon, Hilla, Iraq
- 3 Department Of Pharmacology, People University Of Medical & Health Sciences For Women, Nawabshah, Pakistan
- 4 Nano Drug Delivery, (a Product Development Firm), United States
- 5 Pandit Deendayal Upadhyay Memorial Health Science, Ayush University Of Chattisgarh, Raipur, India
*Corresponding Author:Mauro Luisetto
Applied Pharmacologist, European Specialist Lab Medicine, Independent Researcher, Italy
Email:M.Luisetto@ausl.pc.it / firstname.lastname@example.org
Received Date: Feb 08, 2019 Accepted Date: Feb 13, 2019 Published Date: Feb 27, 2019
Neuronal circuits of rewards, dopaminergic, glutaminergic, gabaergic (circuits play a relevant role in this mechanism). Breastfeed imply a prolactin and dopaminergic involvement as well as oxytocin, and is an evolutionary advantage towards other vertebrates.
Viviparous, Parental care of progeny, breast feed, communication abilities between individuals, associative learning, emotional control are common properties of mammalians like emotional, social behavior. (Hierarchy, communication to other member of the group of danger and so on).
MATERIAL AND METHODS
Using an observational approach from biomedical and scientific literature in PubMed is possible to verify the Neuro-pharmacolgical pathways involved in some mammalian behavior and instinct and in addiction condition. The bibliography reported is choose related the keywords and related the aim of this work.
According biomedical literature is possible to verify that
Andrew B Barron et al
Tonse NK Raju
Whether feeding at the breast is complementary to the nutritional value of human milk, which might explain the diverse range of benefits to the mother and her infant, remains to be studied. Innovative methods from different scientific disciplines, such as behavioral, cognitive, and developmental neurosciences, and social anthropology may be useful to study this unexplored territory. Among the many benefits from breastfeeding during the first year of an infant's life, the effects on long-term cognitive development and IQ have been most controversial. Researcher contends that breastfeeding should be considered the social norm, and lower cognitive scores in infants fed formula should be considered abnormal. Sullivan asked, “Is it possible that some property in the infant formula may not be conducive to full cognitive development?” It is an interesting question that needs to be elucidated in future studies.
Be that as it may, the above arguments require one to critically consider the cause-and-effect relationships between breast-feeding and cognitive outcomes. 2 recent publications answer the concerns about the causal relationships.
In a longitudinal study of neurodevelopment evaluation Jedrychowski et al., assessed 468 infants of non-smoking women at 1, 2, 3, 6, and 7 years of age. Infants who were exclusively breastfed consistently demonstrated between 2.1 and 3.8 higher IQ points at each measurement session compared with those who received mixed feeding (human milk plus infant formula). The longer the duration of exclusivity of breastfeeding, the higher was the IQ benefit. In this and similar studies, 1-4 the overall IQ advantage from breastfeeding appear to be small, but the effect size is highly significant from a public health perspective. Improvements of even a few IQ points, especially at the lower end of the IQ distribution, will reduce the number of children who might otherwise need special education” .
“We have seen in last 2 centuries different way to have a brain map using various strategies. Since from the Broadman theories we have seen the introducing of technologies to support this working methods. (Old and new) as EEG, TC, PET, FMRI, MEG, NIRS ant other with the scope to differentiates brain area in order to show their specific activity. This has made possible to produce anatomic images and map about the different brain area to be related with some different functions/disfuncions. But what we can think is to create a new anatomic brain map using the drugs and substances that show high Activity level in neurology field”. A new pharmacology brain map can be obtained using different molecules or physiopathological conditions:
• BDZ GABA receptor, Barbiturate, Opioids, Neuroleptics, antiepileptics, Antidepressive and hypnotics
• Anti-migraine, Amphetamine, Anti Parkinson, Ant dementia, Antimuscarinics, Anticholinergic
• Analgesics, General anesthetics, Antistaminics, Poisons and toxins, Antipyretics, antihypertensive
• Addiction substanties, Ethanol, Nicotine, New smart drugs, Heavy metals
• Vegetal substances, Cannabinoids, Oxygen and Co2, Toxic substances (as cyanide), insulin
• Food (involved in lepton metabolisms), carbohydrates level, metabolic toxic subst, MABS and many other drugs and substanties or phisio-phatologicalconditions .
Howard D Weiss et al
Swapnil Gupta et al
Drug addiction has been conceptualized as a complex and chronic disease process occurring in the brain, which is modulated by genetic, developmental and environmental factors. The most consistent and reproducible finding in drug addiction is that abused substances activate the mesolimbic dopamine system, which reinforces both pharmacological and natural rewards. The mesolimbic -system consists of dopaminergic neurons in the Ventral Tegmental Area (VTA) and their axonal projections to terminal fields in the Nucleus Accumbens (NAc) and the prefrontal cortex.
Opioids, alcohol, nicotine, cannabinoids and psycho stimulants all act on this system to increase synaptic levels of Dopamine (DA).All these substances have specific receptors in the brain and the increase in dopamine levels in the mesolimbic system is the final effect that they produce. Receptor-mediated activity is the principal mechanism by which any chemical messenger acts. Chemical messengers are regulatory macromolecules, usually proteins. Receptors have two major functions of recognition and transduction, each receptor has two domains, i.e., a ligand-binding and an effector domain. The ligand-binding domain has a hydrophilic and lipophilic region and is usually hetero-polymeric. The binding of the ligand causes a change in the quaternary structure of the receptor.
Receptors have various effector mechanisms, which are broadly of four types:
• G protein-coupled receptors (Gs, Gi, Gq and G13)
• Receptors with intrinsic ion channels
• Enzymatic receptors
• Receptors regulating gene expression.
One of the most dramatic advances in drug- abuse research has been the identification of the target of every major drug abusesubstantia. This advance occurred with the advent of radioligand-binding techniques, the biochemical characterization of drug binding sites and ultimately, with the application of molecular biology to clone and isolate these structures. Drugs can upregulate or downregulate their receptors and their effector mechanisms. These changes are effected through genetic mechanisms and are implicated in the development of tolerance and withdrawal. Earlier biochemical data supported that the site of action of drugs was homogeneous. It is now known that there is great diversity in drug-receptor interactions. Nicotine was thought to have a homogeneous class of binding sites in the brain. It is now known that there are many different oligomeric receptors that bind and are activated by nicotine. The diversity of the receptor types, the cross-modality of drug-receptor interactions is becoming more and more significant. It was earlier thought that drug use caused changes in the specific binding sites, inactivation mechanisms or levels of endogenous ligand. The diversity of drug receptors now forces a consideration of changes in the actual structure of the receptor molecule or changes in the distribution of these molecules on surface of the neuron. Drugs of abuse also have long-term effects resulting from the expression of genes activated as a consequence of the action of the drug” .
Kovács GL et al
Some of the greatest threats to our survival are sweeping epidemics that affect millions of individuals worldwide. Drug addiction, although often regarded as a personality disorder, may also be seen as a worldwide epidemic with evolutionary genetic, physiological, and environmental influences controlling this behavior. The use of drugs has reached all-time highs. On average, drug popularity differs from nation to nation. The United Nations Office on Drugs and Crime identified major problem drugs on each continent by analyzing treatment demand. From the 1998 to 2002, Asia, Europe, and Australia showed major problems with the opiate addiction, South America predominantly was affected by cocaine addiction; Africans were treated most often for the addiction to cannabis.
Only in North America was drug addiction distributed relatively evenly between the use of opiates, cannabis, cocaine, amphetamines, and the other narcotics. All types of drugs are consumed throughout each continent. Among the different approaches for diagnosis, prevention, treatment of drug addiction, exploring the evolutionary basis of addiction would provide us with better understanding since evolution, personality, behavior and drug abuse are tightly interlinked.It is our duty as scientists to explore the evolutionary basis and origins of drug addiction so as to uncover the underlying causes rather than continuing to solely focus on the physiological signs and global activity of this epidemic phenomena . Too often the treatment of addiction simply works to alleviate the symptoms of addiction, dealing with overcoming the physiological dependence and working through withdrawal symptoms as the body readjusts to a non-dependent state of homeostasis. We must not only concentrate on this aspect of addiction when considering the global treatments and preventative programs. We must take into consideration that it is not purely the physiology of addiction we are battling. Drug addiction is thought of as an adjunctive behavior, or a subordinate behavior catalyzed by deeper, more significant psychological and biological stimuli. It is not just a pharmacological reaction to a chemical but a mode of compensation for a decrease in Darwinian fitness. There are three main components involved in substance addiction: Developmental attachment, pharmacological mechanism, and social phylogeny including social inequality, dominance, and social dependence. Developmental attachment created by environmental influences, such as parental care or lack thereof, may influence children’s vulnerability to drug addiction. Evolutionarily speaking, children that receive care that is more erratic may focus more so on short-term risks that may have proved to be an adaptive quality for survival in ancient environments. Compounding that attachment, the pharmacological mechanism describes the concept of biological adaptation of the mesolimbic dopamine system to endogenous substance intake. These factors combined with the influence of social phylogeny create a position for predisposition to drug addiction. They attribute to the common belief that many substances of abuse have great powers to heal, and is often the driving motivation for overuse and addiction. Evolutionary perspective shows an intermediate and fleeting expected gain associated with drug addiction correlated with the conservation in most mammals of archaic neural circuitry, most often being a falsified sense of increased fitness and viability related to the three components of drug abuse. The chemical changes associated with fitness and viability is perceived by mammals as emotions, driving human behavior.
Human behavior is mediated primarily by dopaminergic and serotonergic systems, both of ancient origins probably evolving before the phylogenetic splits of vertebrates and invertebrates. 5-HT (serotonin), stimulated by a small range of drugs, mediates arousal. It is believed to be inhibited by hallucinogens and also helps control wanting for ethanol and cocaine consumption. The cortico-mesolimbic dopaminergic system, on the other hand, is believed to be the target of a wide range of drugs, including marijuana and cocaine, increasing the transmission of dopamine to the nucleus accumbens. This system mediates emotion and controls reinforcement, and is the primary pathway acted on by antipsychotic drugs such as chlorprothixene and thioridazine. Problematic use of drugs develops into addiction as the brain becomes dependent on the chemical neural homeostatic circuitry altered by the drug. No matter the theory of drug addiction, there remains one constant: Withdrawal is inevitable. As a drug is administered continuously and an individual becomes addicted, the brain becomes dependent on the presence of the drug. With an absence of the drug, withdrawal symptoms are experienced as the brain attempts to deal with the chemical changes. There are believed to be evolutionary origins of drug addiction, which will be discussed further, as well as a link between physiological addiction and the evolution of emotion .
Zimmerberg B et al
KD Broad et al
Given the fact that the evolution of our human ancestors and of animals proceeded in a world rich in drugs, an alternative theory favors the idea that drug and alcohol intake by mammals and other species has always been an everyday occurrence. Occasional and even long-term intake of psychoactive drugs produced by a variety of plants or alcohol ingestion through sugar-rich plant products susceptible to fermentation might be a behavior that has been shaped over millions of years.Interestingly, it was found that hominids adapted to metabolize alcohol long before human-directed fermentation. Using a paleogenetics approach, Carrigan et al., resurrected digestive Alcohol Dehydrogenases (ADH4) from our primate ancestors to explore the history of primate-alcohol interactions and identified a single mutation occurring roughly 10 million years ago that endowed our ancestors with a markedly enhanced ability to metabolize ethanol. This change occurred around the time that our ancestors adopted a terrestrial lifestyle. Because fruit collected from the forest floor contains higher concentrations of fermenting yeast and alcohol than similar fruits hanging from trees, this transition may also be the first time our ancestors were exposed to and adapted to substantial amounts of alcohol. These discoveries favor the idea that from an evolutionary perspective, alcohol and drug-intake behavior has been shaped over millions of years and should be considered a part of our normal behavioral repertoire. These evolutionary roots of alcohol- and drug-taking behavior in mammals support the real face validity of animal models of drug self-administration .
Adam T Shipley et al
As individuals experience repeated exposure to opiates and other psychoactive drugs, vulnerable individuals enter an addictive cycle that is triggered by several mechanisms. These drugs initially function as reinforces that strengthen behaviors associated with drug intake. After a short period of time, the resulting tolerance and dependence lead to progressively higher doses to maintain a desired effect. At this stage, compulsive drug-seeking behaviors become evident, even when paired with negative consequences. To identify useful targets for the development of future therapeutic interventions for drug-seeking behaviors, many studies explored the central components of drug-sensitive reward processes in both vertebrate and invertebrate species. Much of these efforts have been focused on an evolutionary basis of drug reward as an entrenched process within natural reward- systems. Findings from most of these studies reveal that mammalian drugs of abuse typically exploit the natural reward systems, which align with the species' adaptive needs.These drugs function by supplanting the individual's inherent pursuit of its basic needs, such as nourishment, shelter, and reproduction, with a search for the drug instead. Findings from these research studies provided the opportunity to investigate common neural substrates underlying reward in a model system that has previously shown remarkable success under similar conditions and, to date, has provided major insights into wide-ranging behavioral occurrences. The importance of invertebrate model systems in drug addiction research is then highlighted. A series of experiments that support crayfish as a powerful invertebrate model system for the study of drug addiction are discussed.
Neural pathways in drug addiction
The distinction between “wanting” and “liking” is important as it appears that drug-mediated dopamine responses progress by “wanting” something more but “liking” it less; Drugs can be associated with certain contextual cues, such as a novel environment. In example, when an organism is conditioned to receive a psychoactive drug paired with a sensory cue, associated neural functions are activated in response to the environmental cue. In the absence of the drug itself, the effect goes so far to re-activate and sustain drug seeking behavior.
The dopaminergic pathways are responsible for feelings of desire and reward in humans through their influence on the ventral tegmental region, medial forebrain bundle and the nucleus accumbens, and can modulate compulsive behavior characteristic of drug addiction in several mammalian models. Dopamine is also implicated in a more direct learning process, in which mesolimbic dopamine neurons fire unconditionally in affiliation with natural rewards often associated with survival. this dopaminergic activity will shift from firing in response to the reward itself to firing in response to the cue that is predictive of the novel reward Although reward can be grouped into a few separate processes; an object's incentive value, the connective learning process of predictive cues and the object of attraction including the object's ability to produce hedonism are distinct in their own way and they each relate to a dopaminergic response that reinforces reward; It is seemingly paradoxical, that humans and animals are susceptible to addictive effects of cocaine, a neurotoxic chemical that has been shown to be evolutionarily adapted to protect the coca plant from insect herbivory by interfering with motor control in the organisms that consume coca plant. The dopaminergic system should be affected by cues that provide reward, not a plant neurotoxin that is designed to thwart predation. Many theories have been proposed that attempt to provide an evolutionary explanation for this phenomenon, ranging from co-evolution of herbivores and plants, to simple fundamental differences in response to the chemical by mammals compared to arthropods.
The introduction of invertebrate model in evolutionarily relevant studies of drug-induced reinforcement, compulsion, withdrawal, reinstatement, and addiction has greatly broadened this field of research. These systems have shown to be powerful tools in the understanding of the neuroanatomical and behavioral processes underlying the addictive process. Benefits of invertebrates, aside from being more cost effective, offering reduced moral concerns, and behaviors patterned by experimentally accessible neural structures, are shared homologies with mammals in the key neurochemical aspects of reward, including receptor elements, neuropharmacology, mechanisms of action, deactivation, and association with similar behavioral contexts. Monoamine systems developed during the transition to metazoan life, where they were used to adapt functions of individual cells to disturbances within their environment. Dopamine and serotonin receptors predate the chordate lineage, and divergence has given rise to considerable diversity in specific subtypes within different lineages, along with some unique differences in receptor subunits and pharmacological properties in both vertebrates and invertebrates. As a result of the divergence during evolution, mammals utilize oxidation and methylation while flies use N-acetylation and β-alanylation for Dopamine (DA) metabolism. Indeed, flies lack the genes required to synthesize norepinephrine and epinephrine, and these are two major catecholamines derived from DA that function in neuromodulation signaling in mammals. A cloned dopamine receptor from D. melanogaster has similar structural-functional properties with vertebrate D1-type receptors, but the pharmacological properties are very different. The characterization of the sensitivity of D. melanogaster to cocaine in an in situ hybridization study demonstrates that Dopamine Transporter (dDAT) lacks all the structural components that are found in the mammalian catecholamine transporters. Cocaine displayed a lower affinity for dDAT when compared with serotonin transporter. This study provides evidence that the structural and pharmacological profiles of dDAT is different from the DAT of vertebrate species. It indicates that injected cocaine, methamphetamine or morphine agonists or antagonists may function differently in vertebrate and invertebrate models of addiction. Despite the differences that exist between vertebrates and invertebrates, crayfish, D. Melanonogaster and the other invertebrate model systems will continue to provide new insights into the regulatory mechanisms of DA signaling drug addiction research.
With the expansion of drug-addiction research into invertebrate models, identification of behavioral stereotypes and profiles has become evident. Fruit flies are a popular model system and have been shown to behaviorally sensitize in a fashion similar to that of the mammalian neurochemical and behavioral response to psycho stimulants. Behavioral sensitization in fruit flies is regarded to have an opposite effect of tolerance and is characterized by an increased intensity of drug cravings and associated behaviors. An important commonality between the two models suggests that catecholamine circuits in flies bear a strong resemblance to the mammalian sensitization process for behavioral sensitization to occur in both flies and rats stimulation of the pre-synaptic monoamine sites must occur. The post-synaptic sites also play an important role in the cocaine response as flies that under-express these receptors exhibit a reduced response to an initial exposure to the drug. The opposite is true for mutants that over-express the receptor. In each of these mutant cases, the flies will not sensitize as the wild-type flies do. Vertebrate dopamine receptor antagonists can block cocaine-induced behaviors in fruit flies and planarians, strongly suggesting that dopamine is implicated in the resulting altered motor behaviors. Tyramine has been revealed as a vital part of the sensitization process in a number of animal, including drosophila. Mutant individuals exhibiting lowered amounts of this amine are affected normally by the initial effects of cocaine but are less likely to sensitize. An increase in the individual's tyramine will result in a stereotypical sensitization akin to the wild type counterparts .The per gene has an interactive role with tyramine, in that those lacking the gene will not undergo a normal sensitization process when stimulated with a vertebrate D2 agonist. The recent work revealing the activity of tyramine and per gene in invertebrates has suggested that these processes could be conserved across a wide range of taxa. Tyramine has been likened to amphetamine's pharmacological profile as it inhibits membrane transporter uptake and alters synaptic catecholamines. This work on the transcription of the per gene has led to its demonstration in mammalian dorsal striatal regions receiving input from midbrain dopaminergic neurons A recent study identified genes for 34 distinct ion channel types, 17 biogenic amine and 5 GABA receptors, 28 major transmitter receptor subtypes including glutamate and acetylcholine receptors and 6 gap junction proteins-the innexins in the nervous system of Jonah crab (Cancer borealis) and the American lobster (Homarusamericanus). These genes are associated with neural function in the crustacean systems and could provide important new insights to understand the organization of circuits in the control of behaviors. Recent studies indicate that an invertebrate system is a powerful tool that can be used to investigate the neuro-anatomical, molecular and behavioral processes underlying the addictive process. Highlighting these accomplishments is vital in showing how simpler model systems can lead to exploration and discovery in mammalian systems as well.
The desire to more firmly establish invertebrate models in the study of drug addiction is driven by the lower cost, easy genetic manipulability of invertebrate models. To prove their effectiveness as a model, the biological and behavioral overlap between the 2 separate model systems needs to be demonstrated. The invertebrate model has been well established in the rewarding properties for psycho stimulants, opioids, alcohol, nicotine, caffeine. Analogous to the mammalian models, invertebrates also exhibit behavioral and motor stereotypes after the administration of cocaine. These research studies show that fruit flies and planarians exhibit increased locomotion and appetitive activities which strongly resemble corresponding behaviors in mammals. Fruit flies have also been shown to demonstrate functional tolerance via a central nervous system adaptation with the administration of ethanol, mimicking mammalian tolerance and behavioral adaptation. Land snails learn to self-administer electric current pulses into areas of the brain associated with sexual behavior and not administer treatments for areas controlling escape. This suggests that land snails feature distinct pathways involved with reward and punishment. Planarians exhibit susceptibility to place conditioning, as individuals will switch to non-preferred environments if it is paired with a psycho-stimulant. This effect could be subsequently blocked by administering selective vertebrate D1, D2 antagonists.
These research studies offer insight into potential mechanisms that remain unexplored within the crayfish model in drug addiction research. Crayfish as a model organism features a highly modular, experimentally accessible nervous system, yet capable of substantial behavioral complexity. With strongly conserved evolutionary mechanisms for behavioral sensitization, drug dependence, and drug-induced reward seeking, crayfish demonstrate significant vulnerability to human drugs of addiction. Research in crustaceans thus offers a valuable perspective for studying the neural implementation of conserved behavioral phenomena, including motivation, escape, aggression, drug-sensitive reward” .
Tara M Mandalaywala et al
Karen E Adolph et al
Motor behavior includes every kind of movement from involuntary twitches to goal-directed actions, in every part of the body from head to toe, in every physical and social context from solitary play to group interactions. The development of motor behavior bridges the entire lifespan from the first fetal movement to the last dying breath.
Although movements fundamentally depend on generating, controlling, and exploiting physical forces, managing forces requires more than muscles and biomechanics. At every point in development, adaptive control of movement relies on core psychological functions.Perception and cognition is required to plan and guide actions. Social and cultural factors spur and constrain motor behaviors.Motor behaviors, in turn, provide the raw material for perception, cognition, and social interaction. Movements generate perceptual information, provide the means for acquiring knowledge about the world, and make social interactions possible.
According to a developmental systems view, motor behaviors cannot be understood in isolation, divorced from the bodily, environmental, and social/cultural context in which they occur. Movements are inextricably nested in a body-environment system. The body and the environment develop in tandem. New or improved motor skills bring new parts of the environment into play and thereby provide new or enhanced opportunities for learning and doing.Caregiving practices facilitate and constrain motor development. As a consequence, differences in the way caregivers structure the environment and interact with their children affect the form of new skills, the ages when they first appear, and the shape of their developmental trajectory.
New motor behaviors can emerge from a mix of interacting factors, some so pervasive that we mistakenly take them for granted, and some so subtle or non-obvious that we fail to recognize the link. Developmental changes in one domain can have cascading effects on development in other domains, sometimes far afield from the original accomplishment. The context in which behavior develops can be very different for individual children, resulting in developmental pathways that sometimes converge at the same outcome and sometimes veer off in unique directions.
This research article is organized around four basic action systems-posture, locomotion, manual actions, and movements in the face and head. We focus primarily on infancy period (when basic action systems are acquired) .
Clarac Fet al
Galbally M et al
A systematic search was made of three electronic databases and other bibliographic sources for published research studies that examined oxytocin and mother-infant relations in humans, including attachment, maternal behavior, parenting, and mother-infant relations.
Eight studies were identified, all of which were unique in their methodologies, populations studied, and measures used. Seven studies found significant and strong associations between levels or patterns of oxytocin and aspects of mother-infant relations or attachment.
Oxytocin appears to be of crucial importance for understanding mother-infant relationships. The findings of this review suggest that the pioneering, but preliminary, research undertaken to date is promising and that replication with larger samples is needed. Research that draws on more robust measures of attachment and bonding, as well as improved measures of oxytocin that include both central and peripheral levels, will elucidate the role of oxytocin in human mother-infant relationships. As the production of oxytocin is by no means restricted to mothers, the extension of the oxytocin studies to fathering, as well as to alloparental caregiving, would be an intriguing next step .
Mammalians and their related instinct-behavior are a clear and a real evolutionary advantage. Various neurological systems are involved (circuits and neurotrasmitters or hormone like dopamine, oxytocin, prolactin and also other related neuronal pathways). The rewards liking circuits, compulsive behavior, craving, wanting and some other neuronal circuits are deeply involved in addictions reported in biomedical literature.
DISCUSSION AND CONCLUSION
This work is produced without any diagnostic or therapeutic intent only to submit new research hypotesys and under a physiological-pharmacological-toxicological evolutionary approach.
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Citation:Luisetto M, Almukhtar N, Mashori GR, Ahmadabadi BN, Sahu RK (2019) Addiction and Evolutionary Process, Common Aspects in Physio-Pathologic Pathways Use Full in Pharmaco-Toxicological Approach. J Addict Addictv Disord 6: 21.
Copyright: © 2019 Mauro Luisetto, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.