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Showing entries tagged reward.  Show all entries

December 5, 2011

Morphine: Friend or Foe for People Dealing with Long-Term Pain?


Lights reflect off of the gleaming road in the rain. The highway embankment funnels traffic into a valley where pools of black water flood the lanes. Your car suddenly hydroplanes and you veer into the other lane. The sound of metal wrinkling like tin foil ricochets in your ear. You wake up in the hospital with a horrendous pain emanating from your broken legs. Morphine is dispensed to ease the pain. Rehabilitation is slow and the pain is incessant. Tolerance develops. Withdrawal symptoms like abdominal cramps and depression begin. You want to stop taking morphine, but the pain in your legs persists and makes it difficult to walk. What do you do?

Morphine has the possibility to help those in pain, but it also has the potential to create a dangerous addiction. Morphine has been in use since Byzantine times because it's a powerful and effective painkiller. Research is now looking into morphine's mode of action in the body, to better mitigate the unfortunate side effects of tolerance and addiction for long-term pain control. In the November 30th issue of the Journal of Neuroscience, a group led by Dr. Ping Zheng in China found that chronic morphine treatment actually switches the effect of dopamine from inhibition to excitation on pyramidal cells of the basolateral amygdala. Pyramidal cells in the BLA are involved in emotion. Excitation of these cells could change the emotional response, which is especially important in withdrawal, when negative feelings can contribute to a relapse.

The researchers used rats to test the effects of chronic morphine treatment. They induced morphine tolerance in rats and then used brain slices to study excitatory postsynaptic currents (EPSC) using the whole-cell patch clamp method. Compared to the control group injected with saline, the morphine treated rats had higher amplitude EPSCs by 50%. After this observation, the team wanted to investigate the reason behind this change. They used a dopamine D1 receptor antagonist in the morphine treated rats, and the EPSC was now the same as the saline control group. Thus they concluded a change in D1 receptors is responsible for the excitatory response.

But what changed about the dopamine D1 receptors at the molecular level? The researchers determined that morphine treated rats had a higher release of glutamate from the presynaptic neuron. Looking at the expression of D1 receptors using Western blotting, they saw there was increased expression of D1 receptor, versus saline. The researchers hypothesized this increased expression might be dependent on protein kinase A (PKA) so they tested this with a PKA inhibitor. They indeed found that the increased release was due to PKA activation.

To supplement these studies, a behavioral test called conditioned place aversion (CPA) were performed on the rats. In this test, rats were placed in one section on days when they received the drug, and in another section on days when they did not receive the drug and were experiencing unpleasant withdrawal symptoms. The rats were then allowed to freely go into either section, plus a third section. Time was clocked for how long the rats spent in each section and the CPA score was determined by the difference between the time spent in the withdrawal-paired compartment divided by the time spent in the drug-paired compartment. The researchers used this to test to determine whether the increase of D1 receptors is responsible for the withdrawal induced conditioned place aversion. The morphine rats strongly avoided the withdrawal compartment, but when a D1 receptor antagonist was injected into their BLA, they no longer avoided that compartment. Therefore, D1 receptors are responsible for part of the withdrawal process.

This study could lead us to understand more about the molecular nature of morphine tolerance and addiction. Using these findings, new ways to combat the negative side effects of morphine use could be implemented.

Li, Z., Luan, W., Chen, Y., Chen, M., Dong, Y., Lai, B., Ma, L., Zheng, P. (2011). Chronic Morphine Treatment Switches the Effect of Dopamine on Excitatory Synaptic Transmission from Inhibition to Excitation in Pyramidal Cells of the Basolateral Amygdala. Journal of Neuroscience, 31(48): 17527-17536.
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December 3, 2011

Drinking on the Job: How Flies get Drunk


Thursday, Friday, and Saturday night... I know what you're thinking. No class till Monday, no work, what a great night to get ahead on studying and up to date with all the problems in the world. However, I must point out this plan is not the first thing that pops into everyone else's mind (at least those outside the world of the poor soul who is reading this neuroscience blog). Much of western society is based around the beverage/drug/poison we've come to know as alcohol. It has come to the attention of neuroscientist that our race is not the only one that takes pleasure in consuming firewater. It turns out some researchers were playing with the old 160 proof lab ethanol when they came upon an astounding discovery.

It all started when one turned to the other and croaked, "I'm drunkk frog haha." The other slurred back, "weelll thenn, gooood thing I'm not a fly huh?" That's when it hit them. "Eureka!" piped the first. "Oh my god!" yelled the second. "Let's" get the flies wasted!" the second hollered back. They quickly spun off their lab stools and bustled for the fly room stumbling and tripping the whole way. When they got to the room they immediately grabbed the first beaker of flies, ripped out the cork and filled it full of the powerful booze, instantly killing all the flies inside. Once they realized the horrendous massacre they had just committed in front of all the hundreds of thousands of other flies in the room their drunken smiles slipped off. The beaker was placed on the counter as the two somber scientists held each other with silent tears streaming down their cheeks. Then one started laughing; irritated, the other muttered, "How can you laugh at a time like this? We just killed them, in front of their families... drowned them, squashed them like flies... "Look, that one's drunk," the other researcher pointed at a fly that was clearly not adhering to the standard sober drosophila flight pattern. They watched the fly for nearly two hours, they sat on the fly room floor entranced by the fly's drunken escapades. Then as its flight pattern began to return to normal it headed back to the beaker full of booze, and began gulping down, without a thought to the dead brothers, sisters, cousins and children floating on top. Gleeful laughter burst from the researchers as they cheersed and began taking large quaffs of their own. Quickly forgetting their bloody hands they then began pulling the corks of the other beakers, filling up petri dishes with ethanol, and pipetting small volumes of ethanol in for the larvae--so no one was left out. They spent the whole night at the lab with their new found drinking buddies and had a gay old time. A few days later after their handover was gone they decided to write a paper.

It was determined drosophila liked the inebriation caused by excessive consumption of ethanol. Like us, the flies were experiencing their pleasure through the activation of the dopamine pathway. Activating this pathway induced LTP in the flies. Looking further into the flies' neural circuitry the researchers determined the rewarding memories the flies experienced (or the lack of memory if they got too plastered from not getting enough sugar before) were localized, accessed and retrieved with a distinct set of neurons in the mushroom body. With the vast number of flies they got drunk the researchers' found some flies didn't come back to drink. The experimenters were obviously offended and quickly squashed them. However, they didn't stop there; they proceeded to analyze the DNA so they could breed out the bad gene and make sure no other flies would be lame. They found mutations in scabrous were responsible. They commonly call it the party pooper gene around the lab. "This gene encodes a fibrinogen-related peptide that regulates Notch signaling, disrupted the formation of memories for ethanol reward" (Kaun, 2011). The experimenters have been thought to have had a little bit too much fun drinking with the flies, but they have felt the public pressure. Now they're looking into how this research will help their own species and we will undoubtedly be hearing more from them soon.

Hope you enjoyed the read, sincerely Charlie Stewart

"A Drosophila model for alcohol reward"
Karla R Kaun, Reza Azanchi, Zaw Maung, Jay Hirsh & Ulrike Heberlein
Nature Neuroscience April 17th 2011
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