Neurobiology: Epigenetics in Cocaine Addiction

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Introduction

Drug addiction is characterized by long-term changes in the manner in which an individual acts. Drugs of addiction are believed to initiate and maintain obstinate changes in neuronal pathways especially those of the limbic system, specifically in nucleus accumbens (NAc) medium spiny neurons (MSNs). Even though evidence exists of structural modifications in these pathways, less information is known about the molecular mechanisms involved in these modifications. Scientists have identified two forms of structural modifications; namely modification in the size of cell bodies and modifications of spine morphology.

Drugs of addiction such as morphine and cocaine have been shown to rework the density of dendritic spines on medium spiny neurons in nucleus accumbens. Even though evidence exists to support structural modifications, the role of such modifications in drug addiction has eluded scientists for a long time. In addition, research carried out has shown conflicting role of such modifications. This review aims at highlighting these pertinent issues.

Modifications due to opiate and stimulant drugs of abuse

Many studies have shown that persistent administration of drugs of abuse result in neuronal modifications in the brains reward center. Studies have shown reverse structural modifications when using opiates and stimulants, such that opiates result in a decrease in number of neuronal branching, while stimulants such as cocaine increase the branching of dendrites. As of now, there is only one concession to this observation: persistent administration of morphine fosters proliferation of spine number on orbitofrontal cortex pyramidal neurons. This is a paradoxical phenomenon, since morphine and stimulants have similar phenotypic manifestation and is as such, expected to have similar underlying molecular mechanisms.

Neurophysiological importance of drug-induced structural modifications in neuronal pathways

Research has shown that the size and shape of neurons determines largely the type of plasticity observed, either long-term potentiation (LTP) or long-term depression (LTD). Researchers believe that, the duration of activity brings about transformation of a novel spine into a mature stable spine. LTD results from repudiation of spines while LTP is a consequence of either formation of new spines or enlargement of existing ones.

These changes are believed to start at the molecular level with modification in production of cytoskeletal proteins to increase anchorage and internalization of a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptors. This may lead to either LTP or LTD depending on the stability of the involved spine. Contemporary studies have demonstrated changes in NAc MSNs that are implicated in the early stages of the addiction process.

LTP has been shown to be mediated through N-methyl-D-aspartate (NMDA) glutamate receptors with increased expression of the NR2B gene especially after administration of stimulants like cocaine. On withdrawal of cocaine, the spines have been shown to increase expression of GluR2-lacking AMPA receptors that have been implicated in causation of craving during cocaine withdrawal. Paradoxically, studies have shown downgraded interactive sensitization to cocaine even when there is intensive expression of AMPAs GluR1subunit and this requires further studies to allow for mapping of the source of the paradoxical occurrence.

Mechanisms of opiate- and stimulant-induced structural plasticity

Majority of studies carried out, have leaned towards the molecular basis of structural modifications due to stimulants as compared to opiates. Despite these limitations, it is a well-known fact that both opiates and stimulants result in molecular changes that cause addiction. It has been demonstrated that morphine reduces Homer 1 and PSD95, integral proteins of the postsynaptic cytoskeleton in NAc. The same effect has been observed with cocaine. Other genes down regulated by both morphine and cocaine include RhoA, Rac1, and Cdc42, all of which are constituents of the actin cytoskeleton. This observation has been attributed to the ability of the groups of drugs to promote activation of same transcriptional factors DFosB and cyclic AMP response element binding protein (CREB), in NAc.

Molecular mechanisms mediating cocaine-induced structural plasticity

Changes in the actin cytoskeletal framework that bring about plasticity are under the influence of GTPases that are coded by specific genes namely Rho, Cdc42, Ras and Rac. The Activation process is tyrosine kinase dependent and it involves conversion of GDP to GTP via extracellular signals mediated through TGF-², integrins and NMDA glutamate receptors. The whole process is calcium dependent and results in series of activation steps involving a myriad of regulatory genes that follows the binding of GTP to its receptor resulting in a chain of steps that eventually lead to structural modification in the cytoskeletal proteins (Scott, et al 271).

Conclusion

Studies have shown that addiction process is interplay of many factors that result in structural modifications of neuronal pathways. A variety of studies, show that neuronal adaptations are crucial in facilitating behavioral sensitization to cocaine. However, other studies show that drug-induced spine plasticity is an occurrence that is separate from sensitization. As such, further research is needed to comprehend the association of synaptic and structural modifications in addictive behaviors. Hence, currently one is unable to conclusively lean on one side of the argument.

Work Cited

Scott, Russo, et al. The addicted synapse: Mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends in Neurosciences 33.1 (2010): 267276.

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