Plasticity in Addiction

Brain on Drugs [16]
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Synaptic plasticity within the mesolimbic dopamine system is known to cause critical adaptations underlying addiction. Many studies show that these neural adaptations develop after prolonged drug use over a long period time and that these adaptations can affect the brain circuitry permanently.[1] Plasticity, within the realm of addiction, not only affects the circuitry of the brain, but they can also have long-lasting effects on the individual’s behaviour.[2] These prolonged drug experiences presented on the brain leave traces within the circuitry that lead to the development and the persistence of addiction.[3] Various studies have shown that the LTP and LTD have significant roles in the learning and memory pathways, which are two basic pathways that contribute to the persistence of the behavioural abnormalities that underlie addiction, as well as the synaptic plasticity within the brain.[1]The mesolimbic dopamine system is important, not only as a major site of that addictive drugs act on, but also as a system in converting “motivations into goal-directed actions.”[3] Within the mesolimbic dopamine system, the ventral tegmental area, nucleus accumbens and prefrontal cortex are the major structures that are affected and changed by addictive drugs.[3] In addition, studies have shown that other structures in the brain, such as the bed nucleus of the stria terminalis and the amygdala, as well as the hippocampus, contribute to the reward process and the learning and memory pathways.[2][3] Furthermore, the neurons involved in the development of addiction play an important role by facilitating the initial changes in the brain, which lead to the permanent synaptic plasticity underlying addiction.

Re-wiring of the Brain due to Drugs [15]
Dr. Sanjay Gupta Explains Synaptic Changes on the Brain due to Drugs

Changes in the Reward-Dependent Learning and Memory Pathway

Changes in the brain circuitry due to continued drug use affects various functions, including the learning and memory pathway. The changes in this pathway enables for the development and persistence of addiction.[4] The learning and memory pathway plays an important role in behaviours associated and define addiction.[2] The underlying mechanisms that strengthen and weaken the synapses of the brain circuitry may be affected by continuous drug intake. Long-term potentiation (LTP) and Long-term depression (LTD) are two mechanisms that underlie changes in synaptic plasticity and along with continued drug use, which leads to robust changes within the brain, can lead to adaptive changes that ultimately underlie the persistent behaviours of addiction.[1]

Addictive substances that are always paired with external stimuli enable an individual to acquire a certain motivational incentive, which overtime will accumulate and invoke an expectation of the drug.[9] As drug intake increase, certain synapses will strengthen and other synapses will weaken, thus only the synapses that are associated with the drugs will become a more robust synapse. Therefore addictive substances that affect the learning and memory pathway, through the mechanisms of LTP and LTD will enable their synapses to become robust and permanent overtime, which play prominent roles in the behavioural adaptations that define addiction.[5]

A study conducted on rats in a chamber showed how this learning and memory pathway is heavily influenced by addictive substances. A rat was placed in a rectangular chamber, in which a drug injection was experienced on the left side of the chamber, whereas saline was injected in the right side of the chamber.[4] Once injected, the rats were able to choose which side of the chamber they had frequently stayed at the most, and found that the left side of the chamber was favoured.[4] The learning and memory pathway had exhibited strong synaptic plasticity that caused natural rewards and allowed the rat to anticipate another drug injection for the same reward.

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Figure 1: Graph indicates the increase in A/N ratio due to addictive drugs [12]

Other studies have also shown that the A/N ratio is specifically increased by addictive substances.[12] The figure on the right shows how a variety of addictive drugs, despite their different effects, all exhibit an increase in A/N ratio, which in turn signifies an increase in AMPA transmission and thus strengthened synapse involved in addiction.[12]

LTP

Long-term potentiation (LTP) is the mechanism that underlies synaptic strengthening within the brain.[5] LTP in the learning and memory pathway strengthen by mediating forms of plasticity that are dependent on experiences.[5] It occurs in various regions of the brain, including the ventral tegmental area and the nucleus accumbens in drug addicted individuals.[3] In individuals of addicition, LTP is usually assumed to have occurred when the AMPA-mediated versus the NMDA-mediated excitatory post-synapses (A/N) have increased.[3] An increase in the A/N ratio reflects the increasing of AMPA receptors transmission[6] and therefore an increase in synaptic strength.[1]

LTD

Long-term depression (LTD) is the weakening of the synapses in plasticity.[5] Like LTP, occurs in various regions of the brain, including the nucleus accumbens and the prefrontal cortex.[3] Individuals who have a decline in the A/N ratio are assumed to have experienced LTD for the AMPA receptors have been reduced.[3]

Brain Regions in Addiction [2]
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Structures Involved in Synaptic Plasticity in Addiction

The structures that various literature focus on when explaining where and how synaptic plasticity in addiction occurs are the structures involved in the mesolimbic dopamine system. This system mainly consists of the ventral tegmental area (VTA), the nucleus accumbens (NAc) and the prefrontal cortex (PFC).[3] Numerous literature states that this system is constructed within a hierarchical structure[6], where the VTA is the structure that projects to the NAc and the PFC.[3] Although, the majority of the literature focuses on the three structures mentioned above, other structures such as the bed nucleus of stria terminalis (BNST), amygdala and the hippocampus have shown to have a prominent role in the underlying mechanism of addiction.[6][7]

Ventral Tegmental Area

Studies conducted within the ventral tegmental area (VTA) has shown evidence for the occurrence of synaptic plasticity.[3] With regards to addiction, the VTA has shown that dopamine levels have increased when excitatory synapses have been stimulated by drug exposure.[3] Even a single dose of an addictive drug leads to long-term changes in the brain circuitry.[3] Thereby, suggesting that the influence that addictive drugs have on the brain is high. In addition, an increase in the A/N ratio is seen in numerous studies to show that LTP does occur within the VTA, and that this LTP elicits robust changes stimulated by drug exposure.[3] It is also been shown that the VTA is a common target of all drugs and that all individuals exhibit an increase in levels of dopamine within the VTA after drug exposure.[3] This increase is suggested to have a prominent role in producing natural rewards, which in turn can lead to uncontrolled drug intake regardless of the adverse effects that are associated with drugs.[3] Further, it is shown that the VTA plays an important role in behavioural sensitization, where evidence has shown that the VTA triggers this sensitization in drug induced individuals.[1]

Nucleus Accumbens

Although various addictive drugs provide different effects, all addictive drugs increase the dopamine release levels within the nucleus accumbens (NAc).[1] In addition, the NAc is essential for the expression of behavioural sensitization.[1] Behavioural sensitization is associated with long-lasting adaptations in the dopaminergic system.[4] The dopaminergic transmission from the VTA to the NAc is also shown to be affected by the continuous drug intake.[6] Further, a decline in the synaptic strength during periods of withdrawal,[3] studies have shown that there is also a decline in the A/N ratio, and that there has also been a reduction in AMPA receptors.[12]

Prefrontal Cortex

Even though it is known that the prefrontal cortex (PFC) is one of the prominent structures involved in synaptic plasticity in addiction, most of the studies to show evidence for such plasticity have the majority of the focus on the VTA or NAc. It is known that the AMPA-mediated and the NMDA-mediated excitatory postsynaptic synapses (A/N) has shown a decline, and the reduction in AMPA receptors due to the subunit decrease in GluA2 and GluA3.[6] Furthermore, studies show that glutamate receptors may have been reorganized within the neurons of the PFC.[3]

BNST, Amygdala and Hippocampus

Studies have shown that the bed nucleus of stria terminalis (BNST) is known to be involved in drug-seeking behaviours.[6] In addiction, evidence has shown that dopamine levels within the BNST increase after drug intake, which aids in maintaining the excitatory presence of dopamine.[3] Furthermore, a study conducted on cocaine self-administered rats had shown that there was an increase in the A/N ratio within the BNST, which suggests that the long-term synaptic changes is similar to those found in the VTA.[6]

Literature has suggested that the synaptic changes within the amygdala play a critical role in seeking of rewards and motivational incentives.[6] In addition, within the amygdala, the basolateral nucleus has demonstrated that it plays an underlying role in making decisions and choices during learning.[6] Thus, it may play a role in rewards associated with drug intake for an addicted individual would learn that the addictive substances provides them with rewards and, thereby will learn that deciding to continue to take drugs will elicit desirable rewards.

The hippocampus is most known as a structure involved in learning and memory.[7] A study conducted on nicotinic users has shown that the hippocampus can recruit memories based on environmental stimuli, which will then elicit nicotinic cravings.[7] It shows the importance that memories play in addiction due to addictive drugs and that the addictive substances can recall a certain memory based on external stimuli learned from previous drug events, which in turn will elicit drug-seeking behaviours.

Behaviours Defining Addiction [17]
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Behavioural Changes in Developing and Maintaining Addiction

The synaptic plasticity that underlies the mechanisms for developing and maintaining addiction not only has cellular adaptations within the brain circuitry, but they also have behavioural adaptations. The synaptic adaptations within the brain lead to the behavioural changes that underlie and define addiction. Various literatures discuss the synaptic adaptations that lead to and underlie craving, withdrawal and relapse.[8]

Craving

Craving is one of the major behavioural adaptations that define addiction. It is known to occur after synaptic adaptations have already occurred within the brain circuitry. Craving has shown to elicit drug-seeking through associative learning.[9] In a study conducted on cannabis users, the experiment was able to show that visual cues of cannabis elevated cravings in users.[10] Further, the results had shown that the VTA region was activated when users had visual contact of the cues.[10] Thereby, after continued consumption has occurred, the brain has already adapted to such changes and therefore visual, olfactory or even temporal cues may elicit such cravings in individuals that have developed and maintained robust synaptic plasticity.

Withdrawal

Withdrawal is one of the behavioural adaptations important in defining addiction. A study conducted on nicotine addicts, individuals that had undergone nicotine withdrawal had shown that re-administration of nicotine had enabled for plasticity to be re-established.[11] When the individual had undergone withdrawal, the LTP plasticity was prevented from being induced and the plasticity had become absent.[11] After the individual had been re-introduced to the drug, the brain had re-established the nicotinic plasticity connections, and thus re-established the plasticity that the nicotine had invoked on the brain circuitry of the individuals.[11] In another study conducted on cocaine users, the experiment had shown that prolonged withdrawal reduced the synaptic strength within the NAc, more specifically on the medium spiny neurons.[12] Therefore, after the brain has undergone robust changes due to continued drug consumption, even periods of drug re-administration after absence will restore plasticity that the drugs had secured.

Relapse

Relapse is one of the most important, if not the important, behaviours that define addiction. Relapse is known to be generated by external stimuli that the learning and memory mechanisms had previously associated with addictive drugs.[13] The urge to intake addictive substances is driven by the elevated strength in glutamatergic synapses among the afferents of the PFC and the NAc’s medium spiny neurons.[13]

Neurotrophic Factors in Addiction

There are various neurotrophic factors within the brain. Current literature show that the important neurotrophic factors in addiction are brain-derived neurotrophic factor (BDNF) or factors related to BNDF.[14] BDNF is a factor involved in neural maintenance, therefore it is involved in the growth and proliferation of neuronal spines.[14] Literature show that these neurotrophic factors target the VTA-NAc pathway and other downstream structures, and the adaptations that they produce affect the facilitation in motivational incentive.[14] Further, literature shows that BDNF levels in reward regions of the brain increased after prolonged withdrawal, as well increased BDNF levels have shown to be involved in the pathological behaviours defining addiction.[14]

Bibliography
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2. Nestler EJ. Molecular basis of long-term plasticity underlying addiction. Nature Reviews Neuroscience. (2001) 2:119-128.
3. Lücher C, Malenka RC. Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron. (2011) 69(4):650-663.
4. Camí J, Farré M. Mechanisms of disease drug addiction. The New England Journal of Medicine. (2003) 349(10):957-986.
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11. Grundey J, Thirugnanasambandam N, Kaminsky K, Drees A, Skwirba AC, Land N, Paulus W, Nitsche MA. Neuroplasticity in cigarette smokers is latered under withdrawal and partially restituted by nicotine exposition. The Journal of Neuroscience. (2012) 32(12):4156-4162.
12. Saal D, Malenka RC. The role of synaptic plasticity in addiction. Clinical Neuroscience Research. (2005) 5:141-146.
13. Gipson CD, Kupchik YM, Kalivas PW. Rapid, transient synaptic plasticity in addiction. Neuropharmacology. (2014) 76:276-286.
14. Russo SJ, Mazei-Robinson MS, Ables JL, Nestler EJ. Neurotrophic factors and structural plasticity in addiction. Neuropharmacology. (2009) 56:73-82.
15. Youtube, CNN. (2012) How addiction changes your brain [video]. Youtube. Retrivied from: http://www.youtube.com/watch?&v=5f1nmqiHIII

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