Methamphetamine Toxicity in the Striatum

The striatum is a crucial part of the brain. This part of the brain plays very important roles but it can be adversely affected by the use of stimulants and other drugs of leisure. Substances such as cocaine and methamphetamine produce their primary effects inside the brain by boosting the presence of dopamine which is a neurotransmitting chemical that activates the pleasure-producing neurons contained within the limbic system. As stated above the limbic system includes the hippocampus, along with several other brain structures. According to the results of two separate studies published in 2008 in the Journal of Neuroscience and Biological Psychiatry, the presence of either cocaine or methamphetamine alters normal adult neurogenesis inside the hippocampus and damages this region’s ability replenish its neuron supply.  It is no longer news that methamphetamine intoxication causes long-lasting damage to dopamine nerve endings in the striatum. However the mechanisms underlying this neurotoxicity are not yet known but oxidative stress has been linked to it.

Microglia are the major antigen-presenting cells in brain and when activated, they secrete an array of factors that cause neuronal damage. Astoundingly, very little work has been directed at the study of microglial activation as part of the methamphetamine neurotoxic cascade. It has been report that methamphetamine activates microglia in a dose-related manner and along a time course that is coincident with dopamine nerve ending damage. Through tests done on mice scientists have discovered that prevention of methamphetamine toxicity by maintaining treated mice at low ambient temperature prevents drug-induced microglial activation. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) not only damages dopamine nerve endings and cell bodies but also  causes extensive microglial activation in striatum as well as in the substantia nigra. Contrastingly, methamphetamine causes neither microglial activation in the substantia nigra nor dopamine cell body damage.

Dopamine transporter antagonists do not mimic the effect of methamphetamine on microglia. Hyperthermia, a prominent and dangerous clinical response to methamphetamine intoxication, has been also ruled out as the cause of microglial activation. Together, these data suggest that microglial activation represents an early step in methamphetamine-induced neurotoxicity. Other neurochemical effects resulting from methamphetamine-induced overflow of dopamine into the synapse, but which are not neurotoxic, do not play a role in this response.

Methamphetamine use on the rise despite effects

The use of methamphetamine has been on the rise despite the fact that it is a powerful stimulant drug that has adverse effects when abused as most people do. According to the UN Office on Drugs and Crime reported recently that abuse of amphetamines, including designer drugs such as methamphetamine and 3, 4-methylenedioxymethamphetamine, now exceeds that of cocaine and heroin on a global scale. This presents no sign that its use will decline any soon. Past researchers were able to establish a fact that methamphetamine causes persistent reductions of function in dopamine nerve endings of animals and humans. Methamphetamine neurotoxicity has been under intense study for over 20 years, but still there is much that still remains to be learned about how this dangerous drug causes damage to dopamine nerve endings. The theory that revolves around oxidative stress has been at the top of the speculations. Drug-induced oxidative stress is an attractive construct that can account for many of the effects of methamphetamine on the dopamine nerve ending such as inhibition of tyrosine hydroxylase activity as well as reductions in the dopamine transporter and the vesicle monoamine transporter. This may even be an early event that leads eventually to methamphetamine-induced apoptosis. However, the source of the reactant species that mediate methamphetamine-induced damage is not known.

Due to their crucial roles they play in mediating the mediating damage to the nervous system, Microglia has attracted considerable attention. Immune like in many ways  these interesting cells become activated by damage and then transmigrate to sites of injury where they can secrete an array of factors  like cytokines, prostaglandins, nitric oxide, and superoxide that are known to have detrimental effects on neurons. However, the role of microglia in methamphetamine-induced damage to the dopamine system has received little attention. In 1994 a researcher, Bowyer and his colleagues noted for the first time that methamphetamine resulted in activation of microglia in striatum of treated rats. These investigators concluded that microglia were increased in response to nerve ending damage and were not apparently a cause of it.  Recently, another research was conducted to give an in-depth analysis of the effect of methamphetamine on striatal gene expression. Numerous genes linked to microglia were activated significantly within hours of methamphetamine intoxication, suggesting the possibility that microglial activation occurs earlier in the methamphetamine toxic cascade than previously thought.

Today there are researchers who are building on the initial analysis of methamphetamine and report the pharmacological characterization of microglial activation by methamphetamine in striatum. As mentioned before, striatum is an area dense in dopamine nerve endings and is known to be targeted for damage by methamphetamine. Microglial activation coincides with the onset of methamphetamine-induced damage in striatum and the extent of this effect is related to the degree of damage to dopamine nerve endings. Numerous nontoxic effects exerted by methamphetamine, such as inhibition of the DAT, increases in synaptic levels of dopamine, activation of D1 and/or D2 DA receptors, and hyperthermia, cannot explain methamphetamine-induced microglial activation.

Finally, this is still a dark area and there is need for more literature so as to establish the mechanism of methamphetamine toxicity on the striatum. Needless to say, Drug abuse, addiction and independence are problems that people grapple with every day. These problems need to be treated effectively through integrative medicine. Dr. Dalal Akoury (MD) is an expert at this.  Call her on (843) 213-1480 for help.

Methamphetamine Toxicity in the Striatum

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