Pathophysiology of Glutamate Dependence - Essay Example

?RUNNING HEAD: Glutamate and Addiction Glutamate and Addiction of the Under the guidance of Harvard Format Word Count:Date of submission Glutamate and Addiction Abstract Addiction of various substances which act on the central nervous system is a major social and health problem. When the person takes the drug or alcohol for the first time, the intention is only to ‘try’. The pleasure derived from these substances makes the individual take the drug again and again which triggers a reward circuit and causes addiction. Addiction is due to many complex neurobiological and physiological factors and understanding of these is important to treat and conduct research on pharmacotherapeutics. One of the theories of addiction is the glutaminergic theory in which the substance glutamate is incriminated in the neurobiological neurophysiological changes that underlie addiction and addiction related behaviors. In this essay, the role of glutamate in the development of addiction will be explored and discussed through review of suitable literature. Introduction Pleasure, a complex neurobiological phenomenon, is a state of happiness and satisfaction. It is very much essential for a content living. A biological mechanism that motivates events associated with pleasure is known as 'reward' (Esch and Stefano, 2003). Pleasure can lead to good effects like health and productivity, and cognition and, at the same time cause negative behaviors like addiction. Pleasure depends on the reward circuitry which is nothing but limbic activity (Esch and Stefano, 2004). Dopaminergic signaling is the most important neurotransmitter system involved in pleasure. While natural rewarding activities are crucial for appetite motivation and survival of any individual, artificial pleasurable activities have detrimental effects not only on the health of the individual, but also on the family and society (Esch and Stefano, 2004). Drugs and alcohol are the most common sources of artificial pleasurable activities. These substances cause effect by acting on the various neurotransmitter systems of the brain. Persistent intake of these substances results in addiction. People who are addicted to a particular substance cannot quit taking that substance on their own. Hence it can be said that addiction is a type of illness and needs treatment. There are many causes for the development of addiction behavior. While the drug itself leads to drug-seeking behavior, research has shown that many changes in the brain can be the main contributing factors for this condition. According to the current model that explains addiction behavior, addiction begins in the brain through pleasure and reward circuits involving dopamine. Addiction may be defined as "a compulsion to use alcohol or other drugs and the occurrence of withdrawal symptoms when long-term consumption ceases" (Roberts and Koob, 1997). From a behavioral point of view, addiction may be defined as "repeated self-administration of alcohol or other drugs (AODs) despite knowledge of adverse medical and social consequences, and attempts to abstain from AOD use" (Roberts and Koob, 1997). There are 3 important components in drug addiction, namely developmental attachment, social phylogeny and pharmacological mechanism (Saah, 2005). The two important characteristics of addiction are: compulsive feeling to use the drug and withdrawal syndrome. Withdrawal may be defined as "appearance of a cluster of symptoms when the drug is withheld after a period of its continuous consumption” ((Roberts and Koob, 1997). Symptoms of withdrawal depend on the substance to which the person is addicted to. For example, addiction of alcohol leads to withdrawal symptoms in 6 to 48 hours after the last drink has been taken The symptoms include increased heart rate, elevated blood pressure, tremors and seizures and also certain changes in the mental state like craving, anxiety and negative emotional state (Roberts and Koob, 1997). Withdrawal and tolerance are indicators of physical dependence. In addiction, the individual develops 'loss of control' to stop using the drug. Most of the times, addicted individuals do not have an insight into their capacity to stop talking the drug further and infact, they strongly believe that they have control over intake of the drug and can stop anytime they want to do so. This is known as denial (Nash, 2007). Addiction occurs only after a certain pattern of behavior is established over a period of time. Mechanism of addiction Addiction is a complex brain disease. The main substances which cause addiction are alcohol, opiates, hallucinogens, cocaine and amphetamines (Cohagan and Worthington, 2007). Individuals with addiction have cravings towards the substance despite negative consequences of the intake of the substance. If the drug or alcohol that the individual is addicted to is not taken, the individual develops withdrawal symptoms. Research has shown that certain biological traits and genetic susceptibilities play an important role in the development of addiction. This is further shaped by the environment of the individual. There are basically 2 factors that modulate and contribute to the addictive process. They are neuroadaptation and reinforcement. Reinforcement is a theoretical construct where a stimulus increases the response's probability. The stimulus can be conditioning type or non-conditioning type. An example of the former is drug taking paraphernalia and that for the latter is the drug itself. Neuroadaptation refers to processes by which the effects of the drug are either attenuated or enhanced. Both reinforcement and neuroadaptive changes work together and motivate short-term responses to the drug and also long-term craving for it and thus cause addiction (Roberts and Koob, 1997). There are 2 types of reinforcement, the positive one and the negative. Positive reinforcement refers to a rewarding stimulus that increases the probability of responses such as continued substance intake. In negative reinforcement, the drugs are taken to relieve oneself from pain or unpleasant states like withdrawal. Even the consumed drugs can motivate behavior through stimulation of the drug-associated environment. For example, the drug paraphernalia or the location where the drugs are taken may elicit a state of euphoria similar to that which is produced after taking the drug really. This effect is known as conditioned negative reinforcement (Roberts and Koob, 1997). An example of conditioned negative reinforcement is development of withdrawal symptoms despite exposure to stimulus but with periods of abstinence (Roberts and Koob, 1997). While positive reinforcement is essential for the establishment of addictive behavior, both positive and negative reinforcements are important for continuing drug intake. The positive and negative reinforcements are caused by neuroadaptive changes that occur as a result of chronic drug abuse. Some of the neuroadaptive changes are sensitization and counteradaptation. Repeated administration of a particular drug leads to increased response to that particular drug. This is known as sensitization. Sensitization causes more drug intake and thus results in drug addiction. Repeated exposure increases the sense of 'wanting' for the drug. As 'wanting' increases due to repeated AOD exposures, there is increased likelihood of relapse after abstinence, thus contributing to compulsive drug use (Roberts and Koob, 1997). Processes which are initiated to counter the drug's acute effects are known as counteradaptation. Tolerance and withdrawal are good examples of counter adaptation. Repeated use of drug results in the reduction of the effect of the drug and this is known as tolerance. When tolerance develops to a desired effect of the drug, the individual increases the intake of the drug to re-experience the initial effect of the drug. This is known as counteradaptation (Roberts and Koob, 1997). In withdrawal, the symptoms are exactly opposite to those of the original effects of the drug, because, the processes initiated to counter the acute effects of the drug come to surface when the drug is removed (Roberts and Koob, 1997). 20 years of research in addiction has shown that most of the abused drugs, except for benzodiazepines increase the levels of dopamine in the mesolimbic dopaminergic system (Refer to Fig.2). The increased dopamine levels in the nucleus accumbens mediate positive reinforcement of the substances (Koob and Le Moal, 2001). According to Volkow et al (1999), euphoria and pleasure after taking drugs like cocaine and methylphenidate are because of the increase in dopamine levels in the brain. This fact was proved by the researchers through a series of neuroimaging studies. One interesting aspect is, in drug-naive individuals, low dopamine D2 receptors are associated with pleasure but high receptor levels are associated with unpleasant feelings. These differences explain the reason why drugs cause pleasurable feeling in some and unpleasant feelings in others. Other than positive reinforcement, dopamine has a role in negative reinforcement too. In a study by Shultz et al (2001), the researchers trained primates to associate a cue with a pleasurable experience like food. Whenever the primates saw cue (and not food), there was a soar in their dopaminergic levels. If food was not presented at that time, the dopamine levels dropped and the primates felt dysphoric. Hence it can be said that decreased dopamine levels is associated with negative effect. In the study by Volkow et al (1999), neuroimaging studies in those with opiate, cocaine and alcohol abuse showed decreased D2 receptor levels in early abstinence and withdrawal phases. There are other important neurotransmiiter systems which either directly cause reward or, act through dopaminergic system to cause reward. Opioid system is one of such neurotransmitter pathways. This system has 3 receptor subtypes namely, mu, kappa and delta receptors. The mu receptor is involved in the addiction of opiates (Shippenberg et al, 2008). Research has shown that lack of this receptor causes neither reward nor withdrawal symptoms. Increased receptor levels in the anterior cingulate has been proposed to be one of the causes of cocaine or opiate addiction. Other receptors also have a role in addiction. Stimulation of kappa receptors reduces the dopamine function in nucleus accumbens and thus may contribute to dysphoria. Delta-agonists have a role in reinforcement of alcohol (Hughes and Nutt, 2003). Glutamate is the most important excitatory neurotransmitter of the brain. It has 3 receptors namely, N-methyl-D-aspartate or NMDA, kainate and alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate or AMPA. The glutaminergic neurons from the amygdala and prefrontal cortex project onto the mesolimbic system which is a reward pathway. From here, the dopaminergic projections arise. The glutaminergic pathway has an important role in stimulant addiction. It reinstates stimulant-seeking behavior. The NMDA receptor is implicated in the addiction of various substances like ethanol, benzodiazepine and cannabinoids. NMDA antagonists act by inhibiting the enhanced responses to stimulants like amphetamine and cocaine (Hughes and Nutt, 2003). Transmission in the cortico-striatal glutamate system has been implicated in not only the initiation of addiction related behaviors but also in the expression of the behaviors like sensitization of the locomotor system and drug-seeking behaviors (Kalivas, Lalumiere, Knackstedt, Shen, 2009). Transient plasticity in the ventral tegmental area occurs when glutamate is transmitted on the dopamine cells of that region. This pathological change is responsible for addiction-related behaviors. However, it is the glutamatergic plasticity of the nucleus accumbens that is responsible for expression of these behaviors (Kalivas et al, 2009). Many neurotransmitters are involved in the addiction of alcohol, the most important of which are glutamergic system and gamma-aminobutyric acid-ergic system. Research has shown that in alcohol withdrawal, there is increased function of glutamatergic NMDA which leads to increased Ca2+ influx through calcium channels. This causes seizures and also cell death. The site in the brain for glutamatergic hyperactivity is hippocampus (Hughes and Nutt, 2003). Serotonin system also has been incriminated in the addiction of alcohol. Benzodiazepines, one of the most misused drugs increase the activity of GABA by modulating GABA-benzodiazepine receptors and thus causing inhibitory activity in brain (Hughes and Nutt, 2003). Conclusion Repeated intake of substances which cause pleasure leads to addiction through reward circuit. Addiction makes an individual dependent on the substance physically and emotionally. Drugs which cause addiction have many deleterious effects on the health and society of the individual. Most of the drugs cause addiction by their actions on the neurotransmitter systems, especially dopaminergic and the glutaminergic systemm. Understanding of the neurobiological mechanisms of addiction has led to the development of many drugs which claim to act on the receptors of the various neurotransmitter systems and thus break the reward circuit. References Esch, T., and Stefano, G.B. (2004). The neurobiology of pleasure, reward processes, addiction and their health implications. Neuroendocrinol Lett, 25(4), 235–251. Hughes, A.L., and Nutt, D. (2003). Neurobiology of addiction and implications for treatment. The British Journal of Psychiatry, 182, 97-100. Kalivas, P.W., Lalumiere, R.T., Knackstedt, L., and Shen, H. (2009). Glutamate transmission in addiction. Neuropharmacology, 56 (1), 169-173 Koob, G. F. & Le Moal, M. (2001) Drug addiction, dysregulation of reward, and allostastis. Neuropsychopharmacology, 24, 97-129. Nash, M.C. (2007). Addiction. EmedicineHealth. Retrieved on August 8th, 2011 from http://www.emedicinehealth.com/addiction/article_em.htm#Addiction%20Overview Roberts, A.J., and Koob, G.F. (1997). 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