Genetically Engineered Dopamine-Deficient - Essay Example

1) Aim of the paper "Distinguishing whether dopamine regulates liking, wanting and/or learning about reward" by S.Robinson, S. M. Sandstrom, V.H. Denenberg,R. D. Palmiter was to establish whether the influence of endogenous dopamine on genetically engineered dopamine-deficient (DD) mice in respect to liking, wanting and learning regulation exists. Besides, authors tried to determine which exactly components of goal-directed behavior were affected. The experiment was aimed at achieving more precise results because the course of the experiments made it possible to keep dopamine neurons in DD mice intact that enabled to control the mice ability to restore endogenous dopamine signaling. L-dihydroxyphenylalanine that was restored under the influence of endogenous dopamine in DD mice changed mice behavior. They became hypoactive and hypophagic and could carry out complicated tasks that are impossible to implement without both activation and plasticity. "Additional goal of this study was to separate performance factors from cognitive processes as described by Denenberg, Kim and Palmiter (2004)2 It was rather difficult to design the experiments in a proper way because of some things. First, learning, liking and wanting are not alternative behaviors. Second, animals tend to be hypoactive and hyperphagic under the influence of dopamine. Some hypotheses were posited. The one concerning hedonia assumes that "dopamine mediates the sensory pleasure of rewards, such as food"3 (Wise, 2004). The evidence was caused by the observation that dopamine leads to the growing reward consumption. The hypothesis about learning presumes that if we want to make animals associate rewards with special clues we must intake them dopamine. The last hypothesis in respect to wanting supposes that dopamine does not influence the interconnection liking-reward and learning- reward. But it's responsible for "recognition of motivational conditions" (Salamone, 1996) "converting a neutral stimulus into an attractive wanted stimulus. Two experiments were conducted. The object of the experiments is genetically engineered dopamine-deficient (DD) mice. Authors tested influence of endogenous dopamine signaling on mice ability for acquisition of an appetitive T-maze. On the basis of two experiments authors came to the conclusion that dopamine had only an impact on the fact whether the mice want reward in the process of goal-directed behavior. However, mice are absolutely indifferent to dopamine influence in regard to liking and learning about rewards. For the experimental design the doze of endogenous dopamine was very important. Too little as well as too much dopamine interferes with reversal learning. Methods: first experiment had lasted for twenty-three days, the second one - for twenty days with two groups of mice: controlled and under the LD-treated mice. They had to perform their learning, liking and wanting skills by finding rewards in a T-maze, reaching the intersection, making right arm entries, latency to begin consumption and the number of rewards consumed. All these data were thoroughly recorded. At the experiment one which consisted of two phases at first controlled and DD mice under the LD-influence had to find rewards and remember the way to rewards, then rewards were changed and mice had to find a new way to rewards, studying in such a way their learning ability. The number of pieces consumed in the second phase after switching rewards evidence the degree of liking and the speed with which they began consumption showed the degree of wanting. Experiment two was conducted on two mice groups that tested saline-LD or caffeine-LD (caffeine was used as a stimulant) and LD-LD 10 times per day for 20 days. In the first part of the experiment mice received one of substances SAL (saline), CAF (caffeine) or LD. During the second half all mice were injected with LD. Some alternatives were for the assumption that if dopamine did not influence learning ability the mice must behave as LD-treated mice in Phase 1. However, if impact exists difference in the behavior of LD mice in Phase 1 is not an evidence Results: experiment 1 did not reveal any differences in behavior between controlled and LD-treated mice on a T-maze task. Simultaneously this experiment underlined threat in reversal learning in LD-treated group perhaps caused by excessive striatal signals. Experiment 2 showed unchanged ability to learning and liking at the mice group treated without dopamine, however, the ability to quick reaction while approaching rewards was not shown probably as a result of dopamine deficit. If mice treated without LD only with CAF or SAL showed learning abilities it can be concluded that learning does not depend on dopamine. The experiment 2 Phase 2 was conducted with the aim to neglect possible mistakes of the first phase. It means that learning can be masked by performance deficit in Phase 1 in without LD treated-mice. In such a way emerged a necessity for conducting phase 2. Phase 2 shows that SAL-LD strongly differs from the behavior of CAF-LD and LD-LD regarding the number of right correct entries that proves that mice can learn even without dopamine In the Phase 1 LD-treated mice consumed much more awards than the other two groups that differ from each other with the number of consumed food too. However, during the Phase 2 equal quantity of rewards was consumed that is why the degree of liking is not evident 2) Methods used in the experiment mainly support the conclusion. The dopamine influences the mice behavior only in respect to wanting. Experiment 2 proved the influence of dopamine on the degree of wanting and imparity in regard to learning and liking. It's necessary to underline that from one side experimental design is not objective enough because, for instance, mice with the lack of dopamine might not show learning activities not because of its lack but due to a deficit in performance substances. However, the authors draw our attention to the fact that as learning, liking and wanting are not mutually interchangeable the role of dopamine in goal-directed behavior can not be fully and impassive elucidated. Undoubtedly dopamine was correctly selected as a chemical influence element for researches. It's produced in the body in the brain and released by the hypothalamus. "Its main function as a hormone is to prohibit the release of prolactin from the anteriopr lobe pf the pituitary" (Wikipedia). However, we must take into account that this element not crossing the blood-brain barrier being used as a drug has an indirect impact on the central nervous system. Regarding the procedures I hold the opinion that they were conducted in a proper way. All parts of the procedures were recorded in details, the maze was sanitirized after each ten mice trials. Conclusions were made at the process of the experiments which were considered as intermediate one as well as after its ending. After two experiments data summarizing was carried out and the authors came to the appropriate conclusions. Though the experimental process was full of objective difficulties caused by the speciality of the studied subject design "permitted the authors to separate performance factors from cognitive processes and to conclude that learning the location of reward is possible without dopamine signing". 2 Thus, the same can be mentioned about controls. Mice were examined after each experiment, their actions were carefully analyzed and on the basis of these actions special diagrams were built. The authors also took into account possible deviations, error bars and their reasons that enabled to get maximally precise research results 3) The use of animals, mainly, rats, rabbits and primates for scientific purposes draws even more and more attention but in our case the results of the research can be much more beneficial that an expected harm. Researchers must be always ready to take up a dialogue with media and general public concerning ethical problems the project gives rise to. The qualifications, education and training of researchers and animal technicians must be at high level so that these people should realize that they deal with live creatures and they should do their best not to injure them if there is a slightest possibility to avoid or at least minimize pain in the animals. The following ethical aspects must always be taken into account: the instrumental versus intrinsic value of an experimental animal; the hybrid status of the animal; the objectives of animal rights movements; the balance between the human benefit of an animal experiment and the discomfort for the animal; the problem of animal rights and animal suffering and pain. The number of animals that participate in these two experiments was 42 mice that is not very big comparing to the importance of the project. In this very case we must consider the fact that mice were not injured and pain was not felt that is why we can talk about very human type of experiment. However, some mental functions can be lost or unpredictably changed forever that infringes animal's rights. Unfortunately we do not know if researchers had cooperated with the Committee for Research and Ethical Issues and had sought their advice. The aim of the research is to get to know the influence of dopamine that in future can be used for creating a new medicine healing ill people with Parkinson's disease. Unfortunately we must sacrifice something for the sake of happiness and health of thousands of people in the future. 4) The main finding of the research includes the reply to the question " which component of reward is lacking in dopamine-deficient mutant mice: reward learning, reward "liking" or reward "wanting". The scientists came to the conclusion that dopamine is necessary in order to want rewards but it's not required for learning and liking rewards. The research helps to understand the mechanism of the development Parkinson's disease because dopamine-deficient mice exhibit classical symptoms similar to severe Parkinson's disease symptoms. SS mice show akinesia, aphagia and adipsia so that they could not eat and drink sufficient amount of food and water to survive. Another useful discovery was made: DD mice treated with L-dopa which is often prescribed to human Parkinson's patients show a temporary recovery in their ability to eat and drink enough to keep themselves in good health. The real use and "beauty of the paper lies in the second experiment. It cleverly uses the samemwo-phase design to exploit latent learning acquired in the first phase, even without dopamine. The learning is expressed later in the second phase, when dopamine is present, after L-dopa is given to all dopamine-deficient mice to enable and equate their performance capacity. L-dopa increased the ability od DD-treated mice to make much more correct choices that is why we can assume that L-dopa treatment for ill with Parkinson's disease may help them to make their movements more exact. Frankly speaking, we must say some words about the most recognized limitation in this research that can influence the final conclusion. It's the possibility that a targeted mutation might have unpredicted additional effects, including counteradaptations during development that oppose the original congenital mutation effect, or otherwise rewire neural circuits in a way that regains some relevant functions. However, in the meantime, there are reasonable grounds for confidence that conclusions from existing dopamine mutants based on the experiments will stand. The mutant DD-mice behaved as they ought to, supporting the hypothesis that their brain dopamine function changed as intended. These features give hope that these mutants may also be giving accurate insights into the role of dopamine in learning, "liking" and "wanting" components of reward. Thus, Robinson, Sandstrom, Denenberg and Palmiter in their issue took us all a decisive step forward understanding the role of dopamine in reward. 5) Scientists' understanding of how the brain works has greatly increased in recent years, leading many observers to believe that a cure for Parkinson's and similar neurodegenerative diseases may be imminent. Others are more cautious, pointing out that even the most promising therapies will require several years of clinical trials and other studies to ensure safety and effectiveness. There is little doubt, however, that increased research (which can only be achieved through increased funding, both public and private) will hasten the discovery of a cure or therapies that can halt the diseases' progression. It is impossible to estimate when that will happen. However, the paper "Distinguishing Whether Dopamine Regulates Liking, Wanting and/or Learning About Rewards" written by Robinson, Sandstrom, Denenberg and Palmiter makes neuroscientists really think more about dopamine influence on the brain and will lead to the increased number of researches in this field. Doctors can take one vitally important conclusion as advice. To increase the amount of dopamine in the brain of patients with diseases such as Parkinson's disease, a synthetic precursor to dopamine such as L-DOPA can be given, since this will cross the blood-brain barrier. Scientists and doctors know that shortage of dopamine leads to Parkinson's disease that is why we may suppose that this research was as original step made toward recovery from this awful illness if doctors are aware how to stop shortening, and death of dopamine neurons in the nigrostriatal pathway. Researchers must realize what a great discovery they can do. All the nightmares that life of old people full of that can easily come true at their age may be in the past: loss of the ability to execute smooth, controlled movements, constant trembling. Symptoms also include postural instability. Other features include rigidity, flexed posture, freezing phenomenon and loss of postural reflexes. Patients can experience depression, sleep disturbances, dizziness and problems with speech, swallowing and sexual functioning. However, scientists must think over again and again over the fact that at present, there is no cure for PD, but a variety of medications provide dramatic relief from the symptoms. PD is both chronic, meaning it persists over a long period of time, and progressive, meaning its symptoms grow worse over time. Although some people become severely disabled, others experience only minor motor disruptions. Tremor is the major symptom for some patients, while for others tremor is only a minor complaint and other symptoms are more troublesome. No one can predict which symptoms will affect an individual patient, and the intensity of the symptoms also varies from person to person. Current research programs are using animal models (for instance, mice as it was in our research) to study how the disease progresses and to develop new drug therapies. Scientists looking for the cause of PD continue to search for possible environmental factors, such as toxins, that may trigger the disorder, and study genetic factors to determine how defective genes play a role. Other scientists are working to develop new protective drugs that can delay, prevent, or reverse the disease. Certainly we should submit that not everything is so simple and perhaps that link between dopamine and neural activation and neural function is more complex than we thought. The paper has a great impact on future researches connected with the development of medicine for increasing dopamine in the brain. As it was mentioned before, L-dopa is used to provide relief for dopamine deficient patients. Levodopa (L-dopa) is the most widely used agent for Parkinson's disease symptoms. Nerve cells Until recently, researchers have been stymied in their quest to answer these and other questions about Parkinson's disease by the lack of a good animal model. Levodopa can be used to make dopamine and replenish the brain's diminished supply. In the United States L-dopa is sold under the brand name Sinemet. Levodopa is taken up by the brain and changed into dopamine. In most patients, it significantly improves mobility and allows them to function relatively normally. As Parkinson's disease worsens over time, larger doses must be taken. The drug also has debilitating side effects for some patients, including dyskinesia (involuntary movements and tics) and hallucinations. Currently the main treatment for Parkinson's disease is the use of the drug levodopa which is converted into dopamine in the brain. However, the problem with this drug and similar therapies is that they lose their effectiveness over time. Thus, we can conclude that the research has a great impact on the subsequent researches in this area and can lead to discovering a medicine that will heal people ill with Parkinson's disease Reference 1. Behavioral Neuroscience 2005, Vol. 119, No. 1, 5-15 "Distinguishing Whether Dopamine Regulates Liking, Wanting and/or Learning About Rewards", S. Robinson, S. M. Sandstrom, V. H. Denenberg, R. D. Palmiter 2. Behavioral Neuroscience 2005, Vol. 119, No.1, 336-341 "Commentaries: Espresso Reward Learning, Hold the Dopamine: Theoretical Comment on Robinson et. al. (2005), Kent C. Berridge 3. Wikipedia, the Free Encyclopedia http://en.wikipedia.org/wiki/Dopamine 4. Wise, R.A. (2004). Dopamine, learning and motivation. Nature Reviews. Neurosciences, 5, 483-494 5. Olsson A. & Sandoe P. "Guidelines for Ethical Conduct with Animals - Comparative Genimics of Man and Pig", Centre for Bioethics and Risk Assessment, Copenhagen, Denmark Read More