Kicking the brain into addiction: a new side to the morphine story
How morphine produces that "kick" and leads to the compulsive drug-seeking behavior characteristic of addiction has been a subject of intense research over the past decades. Adding a new facet to the underlying complex neurobiology, researchers at Brown University have demonstrated that morphine can block the strengthening of inhibitory signals to a key reward area of the brain, thereby exciting it. This mechanism, write the authors, might contribute to the early stages of addiction, and could be exploited to yield effective therapies against the same.
Impulses are transmitted in the brain from one neuron (presynaptic) to another (postsynaptic) across very small gaps known as synapse, and the chemicals which transmit this message are called neurotransmitters. Sometimes, the neurotransmitter released by the presynaptic cell excites the postsynaptic cell, while at other times chemicals like GABA inhibit the postsynaptic cell. In a process called Long-Term Potentiation (LTP), there occurs an increase in the strength of a synapse; after a synapse has undergone LTP, subsequent stimuli applied to the presynaptic cell would elicit stronger responses in the postsynaptic cell. Such synaptic plasticity is thought to be critical to memory formation, as well as pathologies such as drug addiction.
Communicating in the 26th April issue of Nature, Fereshteh Nugent and colleagues at the Brown University found that morphine prevents the long-term potentiation of inhibitory GABA synapses in an area of the brain known as the Ventral Tegmental Area. The ventral tegmental area or VTA is a key reward area of the brain involved in the processing of naturally rewarding stimuli such as food and sex, as well as the rewarding effects of drugs of abuse. The VTA contains dopamine producing neurons; dopamine is that "pleasure chemical" which gets released by naturally rewarding experiences.
The inhibitory GABA neurons mentioned above probably, under normal conditions, act as a brake that would limit the release of dopamine. By blocking the LTP of these GABA signals, morphine removes these brakes, so that dopamine neurons start firing more rapidly. "That activity, combines with other brain changes caused by these drugs, could increase vulnerability to addiction. The brain may, in fact, be learning to crave drugs," said Kauer, a senior author of the study.
The researchers found that as little as a single dose of morphine blocks LTP in the rat brains and continued to do so 24 hours later-long after morphine itself is out of the system. "So it's not the residual effect of morphine, but rather a persistent change in the brain that the drug has caused," pointed Kauer.
At the molecular level, morphine acts by inhibiting an enzyme called guanyl cyclase in the presynaptic GABA neurons that is required for the synthesis of GABA. By blocking its synthesis, morphine reduces the release of GABA and hence inhibits LTP.
Possible therapies could emerge out of this scenario. One of them could be to increase the GABA signals that have fallen as a result of this inhibition by using various modulators of GABA receptors. Another possibility could be to target the enzyme guanyl cyclase and try to restore its functioning or normal levels.
"This discovery has come as an enormous surprise because of many reasons", said Kauer. "Earlier reports suggested that morphine would reduce GABA release, but it would do so only as long as it was there. When it was gone, the GABA release would come right back. The effect on a long term process is really important. And secondly, we have identified the exact molecule where morphine acts."
Nugent, F. S. et al. "Opioids block long-term potentiation of inhibitory synapses." Nature 446, 1086-1090 (2007).
- By Gurjot Singh