Cocaine is the most addictive of all forms substance abuse. It is characterized by a high compulsion and relapse. Despite several years of clinical research, scientists are yet to find an effective medication. However some studies indicate the activity of neurons in the mesolimbic dopamine system, which comprises cells in the Ventral Tegmental Area (VTA) that develop into the medial and detour prefrontal cortex, amygdala, and accumbent, motivates cocaine reward thereby contributing to high compulsion.
Based on these research activities often called neuropharmacological studies, the addiction of cocaine is caused by neuroadaptations induced by the drug. This is so reportedly because of the learning, reward-related and memory processes of the mesolimbic dopamine systems’ circuitry where dopamine projections are developed.
Neuroadaptation Cause of Cocaine Compulsion
Neuroadaptations are understood to cause very high sensitivity to cocaine. They are also believed to cause hypersensitivity to cocaine-associated electrochemical signals such as irrational decision making and irregular cultured behaviors characterized by high insensitivity to dire consequences of addiction. A major characteristics of cocaine addiction is its’s compulsive drug use despite adverse consequences and high rates of relapse during periods of abstinence. A current popular hypothesis is that compulsive cocaine use and cocaine relapse is due to drug-induced neuroadaptations in reward-related learning and memory processes, which cause hypersensitivity to cocaine-associated cues, impulsive decision making and abnormal habit-like learned behaviours that are insensitive to adverse consequences. Here, we review results from studies on the effect of cocaine exposure on selected signalling cascades, growth factors and physiological processes previously implicated in neuroplasticity underlying normal learning and memory. These include the extracellular signal-regulated kinase (ERK) signalling pathway, brain-derived neurotrophic factor (BDNF), glutamate transmission, and synaptic plasticity (primarily in the form of long-term potentiation and depression, LTP and LTD). We also discuss the degree to which these cocaine-induced neuroplasticity changes in the mesolimbic dopamine system mediate cocaine psychomotor sensitization and cocaine-seeking behaviours, as assessed in animal models of drug addiction. Finally, we speculate on how these factors may interact to initiate and sustain cocaine psychomotor sensitization and cocaine seeking.
The premise that cocaine has a neuroadaptation effect to the chemical composition of certain parts of the brain has motivated various studies on the part of cellular actions and signaling forces that altogether causes neuro-synaptic plasticity. Effects of long-term exposure to cocaine on signaling forces, growth elements, psychosocial and physiological processes of reward transmission initially linked to neuroplasticity as a cause of mental recovery are a substantial number. They include extracellular-controlled kinase, distortion of normal neuron pathways and other neurotrophic factors, neuro-synaptic plasticity, and glutamate factors.
Neuroplasticity in Mesolimbic Dopamine System
Neuroplasticity is the brain’s ability to adjust to new environments or needs by developing new nerve cells throughout the body. It is the brain’s way of recovery. Neuroplasticity allows the cells to compensate for any injuries or diseases in the nerve system. It also allows the neurons reorganize themselves to perform new functions of the brain depending on changes in their working environment, also involves recovery from drug addiction such as that of cocaine.
Cocaine-induced neurochemical changes in glutamate transmissions and synaptic plasticity in the mesolimbic dopamine system facilitates cocaine psychomotor high sensitivity, compulsion, self-injection, and reinstatement, being interesting aspects of study in shedding light into cocaine addiction menace has been reviewed time and again.
A key consideration in the above reviews has been what experimental evidence are needed to derive a conclusion of the particular effects of long-term exposure to cocaine on neuroplasticity and how those effects facilitate the learned behavioral symptoms associated with that.
Given this objective, researchers made a strict condition that if so cocaine-induced neuroplasticity causes certain attributer learned behavior then a reversal of the physiological processes that led to that state should, therefore, guarantee a reduced exhibition of such behavior.
After further intense studies on the same, the condition is continuously being met. This has led to yet another attempt to evaluate the role of cocaine-induced neurochemical alterations in glutamate transmissions, synaptic plasticity in VTA, accumbens and amyglada in as earlier mentioned psychomotor hypersensitivity and compulsive behavioral characteristic of the drug.
Many of those studies found out repeated cocaine administration amplified the rate of activity of ERK in the development areas of the mesolimbic dopamine system, which includes the accumbens, amygdala and the prefrontal cortex of the brain.
ERK Phosphorylation in Mesolimbic Dopamine System
Triggers of increased ERK phosphorylation includes D1 dopamine receptors, (PKA) the dependent protein kinase and methyl-D-aspartic acid (NMDA). On the other hand it was observed triggers of reduced ERK phosphorylation include CREB the transcription factor, mitogen-and stress-activated protein kinase-1 (MSK-1), and immediate early genes Fos and Zif268.
Extracellular signal-controlled kinase activity and the subsequent ERK-mediated reduced gene transcription are crucial for increased cocaine-induced psych as a result of exposure to the drug. On the other hand increased cocaine-induced ERK activity in the mesolimbic dopamine system does not facilitate the development of psych after a considerable time of withdrawal. Injection of either SL327 or VTA therefore before cocaine administration lessens sensitized the drug-induced movement during experimental tests for expression of psychomotor sensitization if done some time after withdrawal.
More recent reports indicated psychomotor cocaine sensitization after several weeks of withdrawal from the drug increased ERK2 activity. This was linked to increased acumen α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and the receptor’s (AMPAR’s) surface appearance. However, no increases in ERK2 activity nor AMPAR surface expressions were observed in the specimens that did not exhibit psychomotor cocaine sensitization even after repeated non-dependent cocaine exposure and after some time of withdrawal.
Acumen’s ERK rate of activity possibly serves two specific roles in facilitating rewarding effects of the psychostimulant in a CPP procedure. During CPP training, the accumben’s rate of activity mediates consolidation of the learned behavior between the drug’s unconditioned rewarding effects and the drug’s related context during the CPP testing, ERK movement mediates serious expression of cocaine’s other habituated responses.
Systemic SL327 inoculations before cocaine CPP training prevented cocaine-induced accumbens, ERK phosphorylation and the subsequent expression of cocaine CPP. PD98059 accumben injections are given either before or after CPP training sessions blocked subsequent amphetamine CPP expression.
The relevance of the above fascinating correlational findings of cocaine’s compulsive characteristic, its’ psychomotor sensitization, and the ERK phosphorylation in the mesolimbic dopamine system is, however, a subject for further scientific, clinical research. Please sign up for this year’s August Integrative Addiction Medicine Conference to learn more about the same. Click the following link to get your chance to participate in the event: http://www.integrativeaddiction2015.com.