Addiction-related structural neuroplasticity

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Addiction is a state characterized by compulsive engagement in rewarding stimuli, despite adverse consequences. The process of developing an addiction occurs through instrumental learning, which is otherwise known as operant conditioning.

Contents

Neuroscientists believe that drug addicts’ behavior is a direct correlation to some physiological change in their brain, caused by using drugs. This view believes there is a bodily function in the brain causing the addiction. This is brought on by a change in the brain caused by brain damage or adaptation from chronic drug use. [1] [2]

In humans, addiction is diagnosed according to diagnostic models such as the Diagnostic and Statistical Manual of Mental Disorders, through observed behaviors. There has been significant advancement in understanding the structural changes that occur in parts of the brain involved in the reward pathway (mesolimbic system) that underlies addiction. [3] Most research has focused on two portions of the brain: the ventral tegmental area, (VTA) and the nucleus accumbens (NAc). [4]

The VTA is the portion of the mesolimbic system responsible for spreading dopamine to the whole system. The VTA is stimulated by ″rewarding experiences″. The release of dopamine by the VTA induces pleasure, thus reinforcing behaviors that lead to the reward. [5] Drugs of abuse increase the VTA's ability to project dopamine to the rest of the reward circuit. [6] These structural changes only last 7–10 days, [7] however, indicating that the VTA cannot be the only part of the brain that is affected by drug use, and changed during the development of addiction.

The nucleus accumbens (NAc) plays an essential part in the formation of addiction. Almost every drug with addictive potential induces the release of dopamine into the NAc. [8] In contrast to the VTA, the NAc shows long-term structural changes. Drugs of abuse weaken the connections within the NAc after habitual use, [9] as well as after use then withdrawal. [10]

Structural changes of learning

Learning by experience occurs through modifications of the structural circuits of the brain. These circuits are composed of many neurons and their connections, called synapses, which occur between the axon of one neuron and the dendrite of another. A single neuron generally has many dendrites which are called dendritic branches, each of which can be synapsed by many axons.

Along dendritic branches there can be hundreds or even thousands of dendritic spines, structural protrusions that are sites of excitatory synapses. These spines increase the number of axons from which the dendrite can receive information. Dendritic spines are very plastic, meaning they can be formed and eliminated very quickly, in the order of a few hours.[ citation needed ] More spines grow on a dendrite when it is repetitively activated. Dendritic spine changes have been correlated with long-term potentiation (LTP) and long-term depression (LTD). [11] [12]

LTP is the way that connections between neurons and synapses are strengthened. LTD is the process by which synapses are weakened. For LTP to occur, NMDA receptors on the dendritic spine send intracellular signals to increase the number of AMPA receptors on the post synaptic neuron. If a spine is stabilized by repeated activation, the spine becomes mushroom shaped and acquires many more AMPA receptors. This structural change, which is the basis of LTP, persists for months and may be an explanation for some of the long-term behavioral changes that are associated with learned behaviors including addiction to drugs. [13]

Research methodologies

Animal models

Animal models, especially rats and mice, are used for many types of biological research. The animal models of addiction are particularly useful because animals that are addicted to a substance show behaviors similar to human addicts. This implies that the structural changes that can be observed after the animal ingests a drug can be correlated with an animal's behavioral changes, as well as with similar changes occurring in humans.

Administration protocols

Administration of drugs that are often abused can be done either by the experimenter (non-contingent), or by a self-administration (contingent) method. The latter usually involves the animal pressing a lever to receive a drug. Non-contingent models are generally used for convenience, being useful for examining the pharmacological and structural effects of the drugs. Contingent methods are more realistic because the animal controls when and how much of the drug it receives. This is generally considered a better method for studying the behaviors associated with addiction. Contingent administration of drugs has been shown to produce larger structural changes in certain parts of the brain, in comparison to non-contingent administration. [14]

Types of drugs

All abused drugs directly or indirectly promote dopamine signaling in the mesolimbic dopamine neurons which project from the ventral tegmental area to the nucleus accumbens (NAc). [8] The types of drugs used in experimentation increase this dopamine release through different mechanisms.

Opiates

Opiates are a class of sedative with the capacity for pain relief. Morphine is an opiate that is commonly used in animal testing of addiction. Opiates stimulate dopamine neurons in the brain indirectly by inhibiting GABA release from modulatory interneurons that synapse onto the dopamine neurons. GABA is an inhibitory neurotransmitter that decreases the probability that the target neuron will send a subsequent signal.

Stimulants

Stimulants used regularly in neuroscience experimentation are cocaine and amphetamine. These drugs induce an increase in synaptic dopamine by inhibiting the reuptake of dopamine from the synaptic cleft, effectively increasing the amount of dopamine that reaches the target neuron.

Form of neuroplasticity
or behavioral plasticity 		Type of reinforcer Sources
OpiatesPsychostimulantsHigh fat or sugar food Sexual intercourse Physical exercise
(aerobic) 		Environmental
enrichment
ΔFosB expression in
nucleus accumbens D1-type MSNs Tooltip medium spiny neurons		↑↑↑↑↑↑ [15]
Behavioral plasticity
Escalation of intakeYesYesYes [15]
Psychostimulant
cross-sensitization 		YesNot applicableYesYesAttenuatedAttenuated [15]
Psychostimulant
self-administration 		↑↑↓↓↓ [15]
Psychostimulant
conditioned place preference 		↑↑↓↑↓↑ [15]
Reinstatement of drug-seeking behavior ↑↑↓↓ [15]
Neurochemical plasticity
CREB Tooltip cAMP response element-binding protein phosphorylation
in the nucleus accumbens		↓↓↓↓↓ [15]
Sensitized dopamine response
in the nucleus accumbens		NoYesNoYes [15]
Altered striatal dopamine signaling ↓DRD2, ↑DRD3 ↑DRD1, ↓DRD2, ↑DRD3 ↑DRD1, ↓DRD2, ↑DRD3 ↑DRD2 ↑DRD2 [15]
Altered striatal opioid signaling No change or
↑μ-opioid receptors 		↑μ-opioid receptors
↑κ-opioid receptors 		↑μ-opioid receptors ↑μ-opioid receptors No changeNo change [15]
Changes in striatal opioid peptides ↑dynorphin
No change: enkephalin 		↑dynorphin ↓enkephalin ↑dynorphin ↑dynorphin [15]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens↓↑↑ [15]
Dendritic spine density in
the nucleus accumbens		↓↑↑ [15]

The reward pathway

The reward pathway, also called the mesolimbic system of the brain, is the part of the brain that registers reward and pleasure. This circuit reinforces the behavior that leads to a positive and pleasurable outcome. In drug addiction, the drug-seeking behaviors become reinforced by the rush of dopamine that follows the administration of a drug of abuse. The effects of drugs of abuse on the ventral tegmental area (VTA) and the nucleus accumbens (NAc) have been studied extensively. [16]

Drugs of abuse change the complexity of dendritic branching as well as the number and size of the branches in both the VTA and the NAc. [17] [7] By correlation, these structural changes have been linked to addictive behaviors. The effect of these structural changes on behavior is uncertain and studies have produced conflicting results. Two studies [18] [19] have shown that an increase in dendritic spine density due to cocaine exposure facilitates behavioral sensitization, while two other studies [20] [21] produce contradicting evidence.

In response to drugs of abuse, structural changes can be observed in the size of neurons [22] and the shape and number of the synapses between them. [23] The nature of the structural changes is specific to the type of drug used in the experiment. Opiates and stimulants produce opposite effects in structural plasticity in the reward pathway. It is not expected that these drugs would induce opposing structural changes in the brain because these two classes of drugs, opiates and stimulants, both cause similar behavioral phenotypes.

Both of these drugs induce increased locomotor activity acutely, escalated self-administration chronically, and dysphoria when the drug is taken away. [24] Although their effects on structural plasticity are opposite, there are two possible explanations as to why these drugs still produce the same indicators of addiction: Either these changes produce the same behavioral phenotype when any change from baseline is produced, or the critical changes that cause the addictive behavior cannot be quantified by measuring dendritic spine density.[ citation needed ]

Opiates decrease spine density and dendrite complexity in the nucleus accumbens (NAc). [24] Morphine decreases spine density regardless of the treatment paradigm (with one exception: "chronic morphine increases spine number on orbitofrontal cortex (oPFC) pyramidal neurons"). [24] Either chronic or intermittent administration of morphine will produce the same effect. [14] The only case where opiates increase dendritic density is with chronic morphine exposure, which increases spine density on pyramidal neurons in the orbitofrontal cortex. [25] Stimulants increase spinal density and dendritic complexity in the nucleus accumbens (NAc), [21] [23] [26] [27] ventral tegmental area (VTA), [28] and other structures in the reward circuit. [23] [26] [27]

Ventral tegmental area

There are neurons with cell bodies in the VTA that release dopamine onto specific parts of the brain, including many of the limbic regions such as the NAc, the medial prefrontal cortex (mPFC), dorsal striatum, amygdala, and the hippocampus. The VTA has both dopaminergic and GABAergic neurons that both project to the NAc and mPFC. [29] [30] GABAergic neurons in the VTA also synapse on local dopamine cells. [31] In non-drug models, the VTA dopamine neurons are stimulated by rewarding experiences. [5] A release of dopamine from the VTA neurons seems to be the driving action behind drug-induced pleasure and reward.

Exposure to drugs of abuse elicits LTP at excitatory synapses on VTA dopamine neurons. [6] Excitatory synapses in brain slices from the VTA taken 24 hours after a single cocaine exposure showed an increase in AMPA receptors in comparison to a saline control. [32] Additional LTP could not be induced in these synapses. This is thought to be because the maximal amount of LTP had already been induced by the administration of cocaine.[ citation needed ] LTP is only seen on the dopamine neurons, not on neighboring GABAergic neurons. This is of interest because the administration of drugs of abuse increases the excitation of VTA dopamine neurons, but does not increase inhibition.[ citation needed ] Excitatory inputs into the VTA will activate the dopamine neurons 200%, but do not increase activation of GABA neurons which are important in local inhibition. [33]

This effect of inducing LTP in VTA slices 24 hours after drug exposure has been shown using morphine, nicotine, ethanol, cocaine, and amphetamines. These drugs have very little in common except that they are all potentially addictive. This is evidence supporting a link between structural changes in the VTA and the development of addiction.[ citation needed ]

Changes other than LTP have been observed in the VTA after treatment with drugs of abuse. For example, neuronal body size decreased in response to opiates. [8] [14] [22] [34]

Although the structural changes in the VTA invoked by exposure to an addictive drug generally disappear after a week or two, the target regions of the VTA, including the NAc, may be where the longer-term changes associated with addiction occur during the development of the addiction. [7] [35] [36]

Nucleus accumbens

The nucleus accumbens plays an integral role in addiction. Almost every addictive drug of abuse induces the release of dopamine into the nucleus accumbens. [8] [37] [38] The NAc is particularly important for instrumental learning, including cue-induced reinstatement of drug-seeking behavior. [39] It is also involved in mediating the initial reinforcing effects of addictive drugs. [40] [41] The most common cell type in the NAc is the GABAergic medium spiny neuron. [42] These neurons project inhibitory connections to the VTA and receive excitatory input from various other structures in the limbic system. Changes in the excitatory synaptic inputs into these neurons have been shown to be important in mediating addiction-related behaviors. [43] It has been shown that LTP and LTD occurs at NAc excitatory synapses. [44]

Unlike the VTA, a single dose of cocaine induces no change in potentiation in the excitatory synapses of the NAc. [45] LTD was observed in the medium spiny neurons in the NAc following two different protocols: a daily cocaine administration for five days [9] or a single dose followed by 10–14 days of withdrawal. [10] This suggests that the structural changes in the NAc are associated with long-term behaviors (rather than acute responses) associated with addiction such as drug seeking. [46]

Human relevance

Relapse

Neuroscientists studying addiction define relapse as the reinstatement of drug-seeking behavior after a period of abstinence. The structural changes in the VTA are hypothesized to contribute to relapse. [47] As the molecular mechanisms of relapse are better understood, pharmacological treatments to prevent relapse are further refined. [48]

Risk of relapse is a serious and long-term problem for recovering addicts. [49] [50] An addict can be forced to abstain from using drugs while they are admitted in a treatment clinic, but once they leave the clinic they are at risk of relapse. [51] Relapse can be triggered by stress, cues associated with past drug use, or re-exposure to the substance. Animal models of relapse can be triggered in the same way. [47]

Search for a cure for addiction

The goal of addiction research is to find ways to prevent and reverse the effects of addiction on the brain. Theoretically, if the structural changes in the brain associated with addiction can be blocked, then the negative behaviors associated with the disease should never develop.

Structural changes associated with addiction can be inhibited by NMDA receptor antagonists which block the activity of NMDA receptors. [47] NMDA receptors are essential in the process of LTP and LTD. [32] Drugs of this class are unlikely candidates for pharmacological prevention of addiction because these drugs themselves are used recreationally. Examples of NMDAR antagonists are ketamine, dextromethorphan (DXM), phencyclidine (PCP).

Related Research Articles

<span class="mw-page-title-main">Neurotransmitter</span> Chemical substance that enables neurotransmission

A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.

<span class="mw-page-title-main">Striatum</span> Nucleus in the basal ganglia of the brain

The striatum, or corpus striatum, is a nucleus in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamatergic and dopaminergic inputs from different sources; and serves as the primary input to the rest of the basal ganglia.

<span class="mw-page-title-main">Long-term potentiation</span> Persistent strengthening of synapses based on recent patterns of activity

In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons. The opposite of LTP is long-term depression, which produces a long-lasting decrease in synaptic strength.

The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the forebrain. The ventral striatum includes the nucleus accumbens and the olfactory tubercle.

In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuits in the brain, synaptic plasticity is one of the important neurochemical foundations of learning and memory.

In neurophysiology, long-term depression (LTD) is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long patterned stimulus. LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress.

<span class="mw-page-title-main">Nucleus accumbens</span> Region of the basal forebrain

The nucleus accumbens is a region in the basal forebrain rostral to the preoptic area of the hypothalamus. The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum. The ventral striatum and dorsal striatum collectively form the striatum, which is the main component of the basal ganglia. The dopaminergic neurons of the mesolimbic pathway project onto the GABAergic medium spiny neurons of the nucleus accumbens and olfactory tubercle. Each cerebral hemisphere has its own nucleus accumbens, which can be divided into two structures: the nucleus accumbens core and the nucleus accumbens shell. These substructures have different morphology and functions.

<span class="mw-page-title-main">Dopaminergic pathways</span> Projection neurons in the brain that synthesize and release dopamine

Dopaminergic pathways in the human brain are involved in both physiological and behavioral processes including movement, cognition, executive functions, reward, motivation, and neuroendocrine control. Each pathway is a set of projection neurons, consisting of individual dopaminergic neurons.

<span class="mw-page-title-main">Ventral tegmental area</span> Group of neurons on the floor of the midbrain

The ventral tegmental area (VTA), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the origin of the dopaminergic cell bodies of the mesocorticolimbic dopamine system and other dopamine pathways; it is widely implicated in the drug and natural reward circuitry of the brain. The VTA plays an important role in a number of processes, including reward cognition and orgasm, among others, as well as several psychiatric disorders. Neurons in the VTA project to numerous areas of the brain, ranging from the prefrontal cortex to the caudal brainstem and several regions in between.

Motivational salience is a cognitive process and a form of attention that motivates or propels an individual's behavior towards or away from a particular object, perceived event or outcome. Motivational salience regulates the intensity of behaviors that facilitate the attainment of a particular goal, the amount of time and energy that an individual is willing to expend to attain a particular goal, and the amount of risk that an individual is willing to accept while working to attain a particular goal.

Neuropharmacology is the study of how drugs affect function in the nervous system, and the neural mechanisms through which they influence behavior. There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior (neuropsychopharmacology), including the study of how drug dependence and addiction affect the human brain. Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, with the overall goal of developing drugs that have beneficial effects on neurological function. Both of these fields are closely connected, since both are concerned with the interactions of neurotransmitters, neuropeptides, neurohormones, neuromodulators, enzymes, second messengers, co-transporters, ion channels, and receptor proteins in the central and peripheral nervous systems. Studying these interactions, researchers are developing drugs to treat many different neurological disorders, including pain, neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, psychological disorders, addiction, and many others.

<span class="mw-page-title-main">Reward system</span> Group of neural structures responsible for motivation and desire

The reward system is a group of neural structures responsible for incentive salience, associative learning, and positively-valenced emotions, particularly ones involving pleasure as a core component. Reward is the attractive and motivational property of a stimulus that induces appetitive behavior, also known as approach behavior, and consummatory behavior. A rewarding stimulus has been described as "any stimulus, object, event, activity, or situation that has the potential to make us approach and consume it is by definition a reward". In operant conditioning, rewarding stimuli function as positive reinforcers; however, the converse statement also holds true: positive reinforcers are rewarding.

<span class="mw-page-title-main">FOSB</span> Protein

Protein fosB, also known as FosB and G0/G1 switch regulatory protein 3 (G0S3), is a protein that in humans is encoded by the FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene.

Synaptic tagging, or the synaptic tagging hypothesis, was first proposed in 1997 by Julietta U. Frey and Richard G. Morris; it seeks to explain how neural signaling at a particular synapse creates a target for subsequent plasticity-related product (PRP) trafficking essential for sustained LTP and LTD. Although the molecular identity of the tags remains unknown, it has been established that they form as a result of high or low frequency stimulation, interact with incoming PRPs, and have a limited lifespan.

<span class="mw-page-title-main">Addiction</span> Disorder resulting in compulsive behaviours

Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behaviour that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use often alters brain function in ways that perpetuate craving, and weakens self-control. This phenomenon – drugs reshaping brain function – has led to an understanding of addiction as a brain disorder with a complex variety of psychosocial as well as neurobiological factors that are implicated in addiction's development. Classic signs of addiction include compulsive engagement in rewarding stimuli, preoccupation with substances or behavior, and continued use despite negative consequences. Habits and patterns associated with addiction are typically characterized by immediate gratification, coupled with delayed deleterious effects.

Cocaine addiction is the compulsive use of cocaine despite adverse consequences. It arises through epigenetic modification and transcriptional regulation of genes in the nucleus accumbens.

<span class="mw-page-title-main">Antonello Bonci</span> American physician

Antonello Bonci is an Italian-American neurologist and a neuropsychopharmacologist specialized in the long-term effects of drug exposure on the brain. In August 2019, he became president of Global Institutes on Addictions Miami. Bonci was previously the scientific director of the National Institute on Drug Abuse and a professor at the University of California, San Francisco.

Camilla Bellone is an Italian neuroscientist and assistant professor in the Department of Basic Neuroscience at the University of Geneva, in Switzerland. Bellone's laboratory explores the molecular mechanisms and neural circuits underlying social behavior and probes how defects at the molecular and circuit level give rise to psychiatric disease states such as Autism Spectrum Disorders. 

Marina Elizabeth Wolf is an American neuroscientist and Professor of Behavioral Neuroscience at Oregon Health & Science University. Previously she served as Professor and Chair of the Department of Neuroscience in the Chicago Medical School at Rosalind Franklin University of Medicine and Science. She has been a pioneer in studying the role of neuronal plasticity in drug addiction. Her laboratory is particularly interested in understanding why individuals recovering from substance use disorder remain vulnerable to drug craving and relapse even after long periods of abstinence.

Terry Earl Robinson is a biopsychologist and neuroscientist, and the Elliot S. Valenstein Distinguished University Professor of Psychology & Neuroscience at The University of Michigan.

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