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Neuropharmacology of drug addiction syndrome

Brain

Expert Pharmacologist
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Nowadays, there are a few pharmacological methods which are used for treating drug addiction. These existing methods have low effectiveness in many people. This may be due to permanent changes in brain functions induced by drug use and medications, and also due to an individual phenotype of addiction. The regular use of drugs associated with addiction affects the structure and function of brain cells and pathways that underlie addictive behavior, for example, drug search and a tendency to relapse. Therefore, the identification of target mechanisms that control functional changes in the brain are an important step in the study of the addiction etiology and in the development of new treatment methods. This will require a comprehensive understanding of the neurobiological processes which underlie addiction, including the role of gene expression and regulation of their expression, changes in the structure and in function of neurons induced by drug use.

It is believed that epigenetic changes, induced by substances, contribute to cellular functions impairment by affecting the processes associated with DNA. That explains the pathogenesis of drug addiction. There is promising therapeutic potential in targeting key epigenetic modifications to treat addiction.

Posttranslational modifications (PTM) of histones change the spatial structure of chromatin, controlling the processes associated with DNA. Histone subunits can be modified by acetylation, methylation, phosphorylation, ADP ribosylation, ubiquitylation and sumoylation, etc. Histone PTMs are reversible: they are dynamically carried out by writer proteins, which are recognized by reading proteins that mediate the cellular response, and are removed by eraser proteins. The expression and function of numerous writer, eraser and reader proteins are changed both in people with addiction and in animal models of addiction. Restoring the normal function of these proteins thanks to pharmacotherapy is a new niche for the development of new treatment for drug addiction.

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in the absence of drug use, the medium spiny neurons in the nucleus accumbens receive dopaminergic signals from the ventral tegmental area and glutamatergic signals from several cortical and thalamic regions of the brain. These medium spiny neurons receive and integrate signals of the reward system. And the balance of enzymes that write and erase in the nuclei of these neurons ensure normal processing of reward signals, necessary for the survival. There are two types of medium spiny neurons in the nucleus accumbens: D1-type and D2-type, named after the dopamine receptor that they predominantly express. The image shows only neurons of type D1. Bottom: Chronic drug use disrupts the balance of regulatory proteins that write and erase, which leads to epigenetic adaptations at certain loci in the nucleus of medium spiny neurons.

Adaptations and drug induction of transcription factors (for example, DFosB) cause transcription changes in many genes, including genes encoding neurotransmitter receptors, cytoskeletal proteins and ion channels. As a result of these transcriptional adaptations, the morphology of the medium spiny neurons (for example, dendritic spine density increase is shown) changes, and the physiological function of reward processes changes as well. This is the basis of behavioral maladaptations that determine addiction.

The reward circuitry of the brain is similar across species and is activated by drugs of abuse. The major brain regions involved in the mesolimbic reward pathway are depicted in the human (A) and rodent (B) brain: dopaminergic neurons (green) in the ventral tegmental area (VTA) project to the nucleus accumbens (NAC), prefrontal cortex (PFC), amygdala (AMY), and hippocampus (HPC). The NAC also receives glutamatergic (red) innervation from the PFC, AMY, and HPC. While the mechanisms of action are specific for each drug, most drugs of abuse increase dopaminergic signaling from the VTA to other regions of the reward circuitry. Studies investigating the contribution of genetic factors to the addicted phenotype have focused on identifying markers in vulnerable human subjects that presumably result in altered sensitivity and function of the mesolimbic dopamine system. On the other hand, studies investigating epigenetic mechanisms of drug abuse have focused on the NAC in animal models of addiction, as it is a major region of integration for rewarding stimuli.

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Addiction is a complex phenotype that is regulated by both genetic and environmental factors. Information from the environment is recognized by the brain or body and in turn elicits a response, which often involves changes in gene expression, as indicated by the blue arrows. These genes–environment interactions are relayed by epigenetic mechanisms, including chromatin modifications, DNA methylation, and the expression of noncoding RNAs. Vulnerability to substance abuse has both genetic and environmental risk factors that act in concert to produce the phenotype, but exposure to drugs of abuse (indicated with the red arrow) is necessary for the behavioral phenotype to emerge. The details of genes–environment interactions through the full life cycle of addiction are highly iterative and remain incompletely understood. AMY, amygdala; HPC, hippocampus; PFC, prefrontal cortex; SNPs, single-nucleotide polymorphisms; VTA, ventral tegmental area.
Studies on selectively bred rat strains with high and low susceptibility to morphine addiction confirmed the role of a genetic component in drug addiction development. Follow-up studies and the use of selective breeding in animal models revealed a genetic component in preference of methamphetamine and ethanol.

Synaptic plasticity associated with drug addiction
Synaptic plasticity is the possibility of changing the strength of the synapse (the magnitude of the change in the transmembrane potential) in response to the activation of postsynaptic receptors. The initial dose of the narcotic drug potentiates the excitatory afferent fibers to the dopamine neurons of the ventral tegmental area. The potentiation of excitatory glutamatergic afferents from the medial prefrontal cortex and ventral hippocampus to the medium spiny neurons of the nucleus accumbens, expressing the D1 receptor, is associated with drug search. Dopamine is usually required to induce such plasticity. The mechanisms of expression vary, and metabotropic glutamate receptors may limit the potentiation. A characteristic feature of excitatory synaptic transmission is the insertion of glutamate AMPA receptors and, in some cases, the insertion of calcium-permeable AMPA receptors without GluA2 into the postsynaptic plasma membrane. The drug-induced plasticity of GABA transmission is expressed by a presynaptic mechanism that alters the release of GABA. Neurons of the nucleus accumbens also express calcium-permeable AMPA receptors after exposure to the drug, especially when using cocaine.

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Exposure to cocaine and opiates regulates the total number of functional glutamatergic synapses on the nucleus accumbens of medium spiny neurons, since silent synapses express the NMDA receptor and do not express the AMPA receptor.

The AMPA receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid receptor, AMPAR), re-localized after the first exposure to narcotic drugs, are replaced by GluA2-containing receptors that are synthesized de novo. In the nucleus accumbens, the activation of the D1R and N-methyl-D-aspartate (NMDAR) receptors triggers the MAP-kinase-ERK pathway, which affects transcription. The nucleus accumbens pathways underlying habit and addiction and several areas above, that innervate the nucleus accumbens through glutamatergic neurons— the prefrontal cortex, ventral hippocampus, basolateral amygdala and thalamus, receive dopamine from dopamine neurons in the ventral tegmental region and appear to be the main loci of dopamine pathway remodeling. The area that receives the most attention is the medial prefrontal cortex, with descending glutamatergic pathways from the medial prefrontal cortex to the nucleus accumbens and several other subcortical areas associated with maladaptive behavior and individual vulnerability.

For example, histone acetylation is associated with transcriptional activation, which is in turn associated with an increase in the distance between nucleosomes, controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Repeated chronic exposure to cocaine or other psychostimulants increases the overall histone acetylation level in the nucleus accumbens (NAc), a key area of the brain that provides "reward". A short-term increase in the histone acetylation level determines a behavioral response to the act of cocaine use by changing the expression of BDNF b Cdk5 promoters. This causes the desensitization of c-Fos expression.

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Synaptic potentiation was observed in the afferent fibers of the projection medium spiny neurons D1 and D2 and was mediated by the postsynaptic expression mechanism. The induction mechanisms of these synaptic changes are insufficiently studied. With chronic drug exposure, more and more nodes and pathways may get involved. In fact, anatomical knowledge and experiments confirm this concept.

Stimulation of the more dorsal prelimbic region promotes drug use, while stimulation of the more ventral infralimbic region inhibits relapse after neuron death. Both areas can lead and restrain the search for drugs, depending on the current situation and the patient's initial data. The improved model considers the pathways of projections of individual neurons of the medial prefrontal cortex/nucleus accumbens, which interconnect in the pre-limbic and infralimbic regions to reach the nucleus accumbens and it's shell. With regular drug administration, the activity of the infralimbic region prevails over the activity of the prelimbic region, and infralimbic region inactivation restores purposeful behavior. This model assumes that the usual indicators are reached when switching from the pre-limbic to the infralimbic region. Other areas of the prefrontal cortex are also involved, such as orbitofrontal cortex, which dysfunction can contribute to drug abuse. If the medial prefrontal cortex and the orbitofrontal cortex play a role in renewal of affective value of stimuli and the action result during purposeful behavior, their dysfunction can be a part of pathological conditions with dependence as a key symptom.

The development of drug addiction begins with the first intake and gradually consolidates during repeated, but controlled drug use. As the intake increases, drug use becomes vital, leading to loss of control. This development may depend on the habit formation, which gradually becomes more and more pronounced, and ultimately qualifies as an addiction.
 
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