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Structural Changes of the Mesolimbic System of the Brain Associated with Addiction

The process of forming a drug addiction is a form of operant conditioning where the user learns, through the experience of using the drug of abuse, that the drug induces pleasure. All learning, including the process of forming an addiction, occurs through structural changes in the brain (i.e. Neuroplasticity).

In humans, addiction is defined by the Diagnostic and Statistical Manual of Mental Disorders by observable behaviors. The structural changes of the brain due to drugs of abuse have been implicated as the underlying cause of behavioral changes in addicts. This article will focus on the recent advancements in the understanding of the structural changes that occur in the two major portions of the brain involved in the pleasure circuit (Mesolimbic system) of the brain.

Structural Changes of Learning
Learning by experience occurs through modifications of structural circuits of the brain. Circuits in the brain are comprised of many neurons and their connections. Connections between neurons are called synapses and they 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 these dendritic branches can be synapsed on by many axons.

Along dendritic branches there can be hundreds or even thousands of dendritic spines. 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, on the order of a few hours. More spines grow when on a dendrite when it is frequently activated. Dendritic spine changes have been correlated to long-term potentiation (LTP) and long-term depression (LTD). LTP is the way that connections between neurons, 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 develops 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 addiction.

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 of abuse can be correlated with its behavioral changes.

Administration Protocols
Administration of the drugs of abuse can be done either by the experimenter (non-contingent) or by a self-administration (contingent) method that usually involves pressing a lever. Non-contingent models are generally used for convenience and good for looking at the pharmacological and structural effects of the drugs. Contingent models are a more realistic model because the animal controls when and how much drug it gets. This is generally considered a better method to study the behavior associated with addiction. Contingent administration of drugs has been shown to increase the drug’s effect on the change the dendritic spine density in certain parts of the brain in comparison to non-contingent administration.

Types of Drugs
In response to drugs of abuse, structural changes can be observed in the size of neurons and the shape and number of the synapses between them. The nature of the structural changes is specific to the type of drug used in the experiment.

All drugs of abuse increase the release of dopamine in a specific part of the brain. The types of drugs used in experimentation increase this dopamine release through different mechanisms.

Opiates
Opiates are a class of sedatives that have a 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 inbitory 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 a change in the release of dopamine from dopamine neurons by inhibiting the reuptake of dopamine from the synaptic cleft. This effectively increases the amount of dopamine that reaches the target neuron.

The Pleasure Circuit
The pleasure circuit, also called the mesolimbic system of the brain, is the part of the brain that registers reward and pleasure. This circuit is activated when you have a pleasurable experience. 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 pleasure circuit is very complicated and not well understood. The effects of drugs of abuse on the ventral tegmental area (VTA) and the nucleus accumbens (NAc) have been studied extensively.

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. By correlation, these structural changes have been linked to addictive behaviors. The effect of these structural changes on behavior is still uncertain and recent studies have produced conflicting results. Two recent studies have shown that an increase in dendritic spine density due to cocaine exposure facilitates behavioral sensitization while two other studies  produce contradicting evidence.

Interestingly, opiates and stimulants produce opposite effects in structural plasticity in the pleasure circuit. 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. Although their induced structural plasticity has opposite effects, 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.

Opiates decrease spine density and dendrite complexity in the nucleus accumbens (NAc). Morphine decreases spine density regardless of the treatment paradigm; either chronic or intermittent administration will produce the same effect. The only case where opiates increase dendritic density is that chronic morphine exposure will increase spine density on pyramidal neurons in the orbitofrontal cortex. Stimulants increase spinal density and dendritic complexity in the nucleus accumbens (NAc)     ,ventral tegmental area (VTA), and other structures in the pleasure circuit.

Ventral Tegmental Area
The neurons in the VTA induce the release of dopamine in specific parts of the brain, including many of the limbic regions. The ventral tegmental area (VTA) has both dopaminergic and GABAergic neurons that both project to the NAc and prefrontal cortex (PFC). GABAergic neurons in the VTA are projection neurons and also synapse on local dopamine cells. In non-drug models, the VTA dopamine neurons are stimulated by rewarding experiences. A release of dopamine from the VTA neurons seems to be the driving action behind drug induced pleasure and reward. The target neurons of the VTA dopamine neurons are in the NAc, mPFC, dorsal striatum, amygdala, and the hippocampus.

Exposure to drugs of abuse elicits LTP at excitatory synapses on VTA dopamine neurons. Excitatory synapses in brain slices from the VTA taken 24hrs after a single cocaine exposure showed an increase in AMPA receptors in comparison to a saline control. 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. 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 neurons, but does not increase inhibition. Excitatory inputs into the VTA will activate the dopamine neurons two times more strongly, but do not increase activation of GABA neurons which are important in local inhibition. This effect of inducing LTP in VTA slices 24 hrs 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 of the link between structural changes in the VTA to the development of addiction.

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.

Although the structural changes in the VTA invoked by exposure to an addictive drug generally goes away 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.

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. The NAc is particularly important for instrumental learning, including cue inducted reinstatement of drug seeking behavior. It is also involved in mediating the initial reinforcing effects of addictive drugs. The most common cell type in the NAc is the GABAergic medium spiny neuron. It projects inhibitory connections to the VTA and receives 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. It has been shown that LTP and LTD occurs at NAc excitatory synapses.

Unlike the VTA, a single dose of cocaine induces no change in potentiation in the excitatory synapses of the NAc. LTD was observed in the medium spiny neurons in the NAc following two treatments: a daily cocaine administration for 5 days or a single dose followed by 10-14 days of withdrawal. This suggests that the structural changes in the NAc are associated with long-term behaviors associated with addiction such as drug seeking.