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Traditional & Functional Neuro Scientific Definitions to Substance Use Disorder/Addiction: Chemical Dependency, Addiction, Tolerance & Withdrawal

Addiction is defined in literature as a brain disorder characterized by prolonged and compulsive use of a drug or substance despite adverse consequences. Individuals with substance use disorders may experience intense cravings, have impaired control of their substance use as well as develop physical dependence on their substance of abuse. It is shown that continual, consistent substance abuse has often been seen as a “bad choice,” but repeated and long-term drug use both cause physiological adaptations deep in the primitive brain where it destabilizes voluntary control. It is now generally understood by the addiction community that addiction is a disease of the brain. Substance use, misuse and abuse by drug using individuals is being described as a result of abnormal brain functioning. Globally neuroscientists are continually conducting and reproducing extensive brain imaging studies of individuals with addiction to understand the underlying biological and physiological processes of addiction. Additionally, several specific and complex midbrain regions are affected in addiction which include but not limited to those that regulate pleasure, reward, motivation, and control. Another important component of drug addiction is tolerance which is scientifically defined as cellular neuroadaptation following drug exposure. Both illicit and nonillicit drugs are being proven to increase dopamine levels in various ways. First, they can prevent reuptake or cause release of dopamine by the vesicles further leading to higher dopamine levels in the dopaminergic synapse. “This increased amount of dopamine provides an over stimulation of the dopamine receptors leading to desensitization. Desensitization is also known as tolerance.”(Principles of Addiction). This over stimulation is best described by receptors becoming less responsive to a neurotransmitter. Case in point, when an individual continually uses the same amount of a drug, eventually tolerance will occur and larger amounts of the drug will be needed over time to produce the “high effect” the drug user has initially experienced. It is also found that this over stimulation of dopamine receptors can also decrease the number of available receptors by the down regulation of internal cellular mechanism like G coupled proteins signaling the production of the receptor at the transcription and translation level of a cell. Withdrawal is defined as the discontinuation of drug use after chronic use leading to withdrawal symptoms. This physiological response can range from mood disturbances such as anxiety and depression to life-threatening seizures. Of course this sequela depends largely on the drug of use as well as the drug users duration of use. Withdrawal symptoms are caused by a wide range of biochemical and physiological cellular adaptations found in chronic drug use. Animal studies as well as human PET Scan Metabolic Studies provide data that withdrawal shows a prominent decrease in the concentration of extracellular dopamine in the nucleus accumbens as well as reduced firing of neurons in the mesolimbic dopaminergic system. These changes can be stopped and symptoms may be alleviated when the drug of abuse is administered. Further animal studies show that drug dependent animals have increased thresholds for reward during withdrawal where drug users often seek to alleviate withdrawal symptoms by the administration of the same or other substances. Describe the main neurotransmitter and brain regions involved in the process of addiction, and discuss how they are involved. A Substance Use Disorder is a complex condition that involves multiple brain rgions. Chronic drug use and intermittent drug abuse induces both positive and negative reinforcing effects in the brain. Recent studies of drug abuse are testing the biological causes of addiction focused on the sites of action of the chemical substance structure in relation to the response within the brain, The research further provides evidence of a many physiological changes throughout the central nervous system. The site of action is defined as the “access point by which a drug produces a specific response” (Dobrin and Roberts). This biochemical approach refers to both the CNS neurotransmitter systems as well as CNS regions that facilitate a particular response. Sites of action are being studied to determine where in the brain and how in the these regions they exert their mass effect. This has been reinforced in and throughout the course literature found in many animal in vitro studies to determine binding sites of specific chemical substances within midbrain structures such as the mesolimbic system. The limbic system is the primary brain system implicated in drug addiction. The limbic system is a phylogenetically older brain system which is sometimes called the primitive brain. Today this concept is being used used to describe brain function at its core structures. These primitive regions are primarily responsible for emotional responses as well as the automatic or involuntary primitive“fight or flight” response. This region is found to involve the facilitation and control of human learning, memory, concrete associations, and emotions. Scientists sometimes do not universally agree on what brain regions constitute the limbic or mesolimbic system, but it is thought to include “the orbital frontal cortex, cingulate gyrus, subcallosal area and hippocampus, as well as subcortical structures such as the hypothalamus and amygdala.” (Principles of Addiction) These gross anatomic areas comprise many interconnected brain regions and it is on of the main sources of information transmission between the neocortex and hypothalamus which control all of the bodies metabolism and function within its many organ systems. Many drugs of abuse have their sites of action within the limbic or mesolimbic system and there is found histologically to be a very detailed and sensitive area within these regions where unlimited neurochemical and biological reactions are occurring simultaneously. It is no wonder and quite logical to associate and deduce that any changes whether larger or small occurring in the limbic system in fact occurs during drug abuse and addiction. The basal ganglia are also associated with substance abuse, especially at the interface with the limbic system where the regions are involved in cognitive tasks as well as memory formation. Together with the limbic system the basal ganglia is responsible for creating motivated behaviors. Importantly, “the basal ganglia includes the striatum, which includes the nucleus accumbens (nucleus accumbens and ventral striatum are used synonymously). The nucleus accumbens is where motivations start to become actions and it is an important site in terms of behavioral as well as physiological responses to drug use and drug reinforcement. The nucleus accumbens is believed to be the site of the acute reinforcement effect. The interconnected prefrontal cortex (PFC), which is involved in controlling behavior and decision making in its communiction with the nucleus accumbens and is found to be most relevant in addiction. The PFC contains the orbitofrontal cortex as well as the ventromedial areas which are the hubs of reward processing as seen reproduced in many studies. Animal model studies have been a valuable tool in the study of the neuroanatomy of addiction where“Addiction-like drug use has been induced and observed in primates, dogs, cats, rabbits, rats, and other mammals. Self administration as well as continued use of substances has been observed in these animal models as well”(Principles of Addiction) Neurotransmitters are endogenous chemicals that transmit signals from one nerve cell to another. Many neurotransmitters are involved in drug abuse and addiction, but dopamine is the most prominent. All drugs of abuse have effects on dopamine and all affect dopaminergic signaling. “The neurotransmitters GABA, glutamate, acetylcholine, and noradrenaline are also involved in drug reinforcement and the subsequent association made within substance use disorders. Dopamine, epinephrine and norepinephrine, are catecholamine neurotransmitters. Most dopamine in the brain is produced by neurons in the midbrain withing the substantia nigra and ventral tegmental area. They send projections to the striatum which includes the nucleus accumbens, amygdala, and PFC where Dopamine acts directly on dopamine receptors. Dopaminergic Receptors are grouped into two classes, D1 or D2 receptors and all dopamine receptors are found to have G-protein signaling.” The Neurotransmitter dopamine is important for a wide arrangement of functions, including but not limited to movement, motivation, reward-seeking, learning, memory, and attention. It is also the primary neurotransmitter believed to produce the neurobiological adaptations associated with addiction. Studies are reproducing with accuracy that drug exposure affects the dopaminergic pathways and subsequently modulates end point dopamine release in both humans and animals. As discussed, all drugs of abuse act to stimulate and most times overstimulate dopamine release. Some drugs even act directly on the dopamine pathways deep within the brain by blocking dopamine transporters as well as preventing the reuptake of dopamine producing a major accumulation of dopamine. While most drugs affect dopamine pathways directly other act indirectly through the GABAergic, glutamatergic, nicotinic and opioid receptors found on neurons which control their dopamine release. Discuss the mechanisms (naming the receptors involved) by which tolerance and withdrawal occur in abuse of marijuana, cocaine, and heroin. Marijuana: The CB1 cannabinoid receptor is necessary for development of tolerance and dependence on THC. THC tolerance increases amounts of the drug required to produce the initial effect and dependence occurs when an organism only responds “normally” in the presence of the drug. This has been observed in several species besides humans, including rats, mice, rabbits, and monkeys. “Chronic cannabinoid exposure leads to neuronal desensitization and downstream deregulation of CB1 receptors most prominently in the cerebellum and hippocampus. Additionally, decreases in CB1 receptor binding affinity has also been observed. Decreases in cannabinoid sensitivity in GABA and glutamatergic synapses in the nucleus accumbens demonstrate that CB1 receptors are functionally tolerant to cannabinoids.” Such decreases in CB1 receptor number and efficacy are the brain’s way of adapting to and compensating for the high levels of THC activity at these receptors. When THC is removed a lower than normal level of receptor activity may be responsible for many of the withdrawal symptoms. This has shown to occur until the brain readapts to normal levels of CB1 receptor activation. “Cannabinoid tolerance and dependence may also prove to be quite disruptive in the G-protein signaling which is evidenced by a decrease in G-protein mRNA and subsequent new receptor formation.” Principles of Addiction) Many studies have been conducted on the long term neurological and cognitive effects of chronic and heavy marijuana use. Brain scans of chronic users of marijuana show smaller amygdala and hippocampal volumes as well. “These effects can be evident even decades after use has stopped and it is unclear whether these changes in amygdala and hippocampal volumes reflect preexisting conditions or from direct consequence of heavy marijuana use. Heavy and prolonged use of marijuana can also induce physical and psychological symptoms of withdrawal, including sleep and mood disturbances, anxiety, depression, anger, agitation, tremors and sweating. Withdrawal from THC is dependent on the presence and activation of the CB1 receptors as seen in laboratory studies where rodents lacking CB1 receptors failed to exhibit any withdrawal response from THC.” (Principles of Addiction) Results of these studies show dopamine levels to be significantly lower during withdrawal from marijuana where the dopamine activity is reduced in the ventral tegmental area as well as in the nucleus accumbens. There is also evidence of increased extracellular levels of CRF in central nucleus of amygdala during withdrawal, which likely mediates increased anxiety in THC addiction. It is a valid resultant effect that withdrawal actually ceases when THC is administered again in laboratory animals in quite a few studies to date. Cocaine: Tolerance to stimulants occurs following high doses as well as frequent administration and it has been observed in both humans. In simple terms, tolerance is said to be most noted in the reinforcing effects of the brain causing the need for for more of the drug to obtain an initial high. Animal studies have shown and are showing that acute phase tolerance to cocaine or amphetamines develops whether the substance is taken chronically or intermittently. This reaction develops as a result of the desensitization of dopaminergic receptors to the stimulant as well as changes in signal transduction pathways. In lieu of these reactions, tolerance is shown to play a major role in the dose escalation and subsequent development of dependence. Withdrawal from stimulants such as cocaine and amphetamines are biphasic processes that involve many neurological changes. “During withdrawal from cocaine or methamphetamine the initial increases in dopamine and expression of dopamine receptors are followed by a significant decrease in dopamine concentration, dopamine receptors, and mu and kappa opioid receptors.” (Principles of Addiction) Due to this, there are increases in dopamine receptor binding sites during the withdrawal phase in cocaine users which may contribute to the powerful force of relapse. Conversely, during early abstinence and withdrawal phases from methamphetamine there are deficiencies in the anterior cingulate cortex and amygdala. Heroin: Opioid tolerance is defined as the reduction in responsiveness to opioid use. This chronic use of opioids result in the need for increasing amounts of dosing to achieve the initial effect the user once had. Opioid tolerance is one of the main factors implicated in compulsive opioid use and recurrent relapse behaviors. Tolerance is shown to be caused by homeostatic adaptations at multiple levels of the nervous system that counteract the high level of opioid receptor stimulation induced by exogenous opioid administration.( Principles of Addiction) This receptor tolerance provides a major loss of function of opioid receptors over time which result in the decreased sensitivity and signaling responses to opioid binding sites. The mechanism is not fully understood, but is thought involve decreased receptor expression and decreased affinity for G protein effectors.(Principles of Addiction) Changes in intracellular signaling pathways downstream from opioid receptors account for some aspects of tolerance at the cellular and systemic level. Learning behaviors also play significant roles in some aspects of tolerance. In individuals who are tolerant to high doses of opioids in fact are shown to cause much greater effect that a times may even be lethal. Opiate withdrawal involves the physiological and psychological effects associated with the discontinuance of use. Many effects such as hypersensitivity to pain and depressed are the opposite of those that result from opioid administration. This is thought to occur because the nervous system has adapted to high levels of opioids at the receptor site in order to maintain a relatively normal function. In one example, “anxiety is reduced when opioids inhibit the activity of noradrenergic neurons by inhibiting an enzyme involved in the synthesis of the neurotransmitter norepinephrine.” Chronic opioid use leads to an increase in the activity of the enzyme processes in the fromation of these catacholamines and it is shown biochemically that during abstinence from opioids this enzyme activity will be abnormally high leading to massive releases of norepinephrine which subsequently may cause the increased anxiety. Dopamine signaling whether upstream or downstream are reduced upon cessation of chronic opioid administration. This behavior plays a role in withdrawal symptoms. Ultimately, the educed dopamine release from the GABA inhibitions is most likely responsible for symptoms such as dysphoria or depressed mood). Additionally, it is outlined that CRF levels are also increased during withdrawal which may at times account for the symptomology of the anxiety symptoms.

Referrence: 1.Principles of Addiction Ries, Richard K.Fiellin, David A.Miller, Shannon C.Saitz, Richard AN: 01412562/4th_Edition/3 Edition Statement 4th Edition 2.Dr Setlow Presentation and Lecture Material

SAMHSA Substance Abuse and the Brain
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