Monkeying Around... on Morphine

Last week, Dr. Stephan Steidl presented at Loyola University Chicago concerning the reward system and drug use. His talk focused on morphine and its effects to dopamine neurons and locomotion in mice. The mesolimbic dopamine pathway and nucleus accumbens (NAc) have been identified as critical substrates reinforcing the effects of morphine. Mice that have their M5 muscarinic receptor knocked out show reduced locomotion under the effects of morphine when compared to wild-type mice. I believe that his finding show huge potential in further understanding the science behind addictions and furthering research into treatment options in severe cases. His study provided evidence that M5 receptors and critical to morphine-induced locomotion by mediating the cholinergic input to the VTA in the release of dopamine. Cholinergic neurons of the pedunculopontine tegmental nucleus (PPT) and laterodorsal tegmental nucleus (LDT) provide a major source of excitatory cholinergic and glutamatergic input to the VTA. The lesioning of the LDT provided a decrease of self-administration in rats and decrease of cholinergic neurons. Rats experience an increase in latency of self-administration after lesioning; also, longer interfusion intervals are observed after initiating self-administration. Both M5 receptor deficiency and lesioning of the PPT showed to decrease opiate usage, but researchers and doctors cannot just cut parts of brains of addicts to help them abstain from drug use. Also, the effects that this would have in dopamine function from naturally rewarding activities was not discussed, however I am sure it would impede the well-being of people. Up to now, the best scientific method in approaching addiction has been the administration of pharmaceuticals, so let us further our findings.

Bu etc. have done another study this past year examining morphine dependence and withdrawal intervention in rhesus monkeys. This study focuses on examining proteins affected by morphine usage, primarily those associated with withdrawal symptoms and ways we can help further alleviate them. Forty-six proteins were differentially expressed in six classes between morphine usage and pharmacological treatment: metabolism and mitochondrial function, synaptic transmission, cytoskeletal proteins, oxidative stress, signal transduction and protein synthesis and degradation. The study uses pharmacotherapeutic approaches for opiate withdrawal, such as methadone and clonidine. Methadone prevents cravings and severe withdrawal symptoms while clonidine can lessen signs of withdrawal and soothe the negative phases. Both medications significantly decrease morphine-induced withdrawal symptoms and provide to be extremely effective.

The protein modifications observed from both methadone and clonidine indicate that they exert similar neurochemical effects on the NAc in morphine dependent monkeys. Expression of α-synuclein and β-synuclein were upregulated with morphine usage, which can lead to synaptic degeneration and cell death. It negatively regulates dopaminergic neurotransmission by slowing synaptic vesicle refilling. Both drugs decrease levels of both proteins and therefore help alleviate withdrawal symptoms and any further brain dysfunction. Actin regulatory proteins were affected and can be connected to differences in behavior, learning, memory, and synaptic plasticity. Calmodulin also plays a critical role in the development of morphine dependence and tolerance. Many other protein regulations were affected by morphine usage, withdrawal, and pharmacological treatments. These findings demonstrate that fast transcriptional and post-transcriptional responses occur in the NAc with response to pharmacological treatments. Both studies may further enhance current treatments for drug addiction and better understand the reward pathway and proteins regulating its effects.