Bad Brake Leads to Addiction
15 May, 2007 12:36 pm
Two weeks ago, lying on a hospital bed after surgery, I was hooked up to a morphine pump so I could self-administer morphine whenever I had pain. Every now and then I had to press a button to get some morphine to manage the intense post-surgical pain that I was experiencing. As morphine was flowing into my brain, making me calm and sleepy, I kept thinking of what our recent work indicates about what morphine was doing in my brain at that very moment, and how this may play a role in initiating opiate addiction.
Neurons communicate with each other at special places called synapses, which are minute gaps that exist between the neurons. One neuron communicates with another by releasing a chemical messenger called a neurotransmitter into the synapse. Based on the nature of neurotransmitter released by a neuron, the other neuron can be excited or inhibited and in this way the activity of the second neuron can be changed. Synapses are said to exhibit plasticity, meaning that they can change in strength, getting stronger which is referred to as long-term potentiation or LTP, or weaken, which is called long-term depression or LTD. In fact, when we learn something new it is believed that the brain synapses undergo changes in strength (synaptic plasticity) to store the memories. With regard to addiction the question is does the brain develop addictive behavior by learning and building up bad "memories"? We believe that our research supports the theory of addiction as a disease of learning and memory.
The pleasurable feelings after eating good food or watching a favorite movie, as well as the rush caused by an injection into a heroin user, is mediated through the activation of dopaminergic neurons in a region of the brain called the ventral tegmental area (VTA). The end result of this is the release of the "pleasure" neurotransmitter, dopamine. Boosting the brain’s reward response through activation of the VTA dopaminergic system is a common action of all drugs of abuse. The activity of these dopaminergic neurons is under the control of other neurons which secrete different chemicals into their synapses to excite or inhibit these neurons. We found that the inhibitory synapses on these neurons also exhibit plasticity, similar to what we see with excitatory neurons, and they also show LTP. The LTP of inhibitory synapses would shut down the signal that causes dopamine to be released from dopaminergic neurons. In another words, this inhibitory brake on dopaminergic neurons works to keep the neurons in the normal range of their activity. We demonstrated that morphine removes this brake, therefore causing excessive dopaminergic cell activity which results in an increase in dopamine release. This activity, combined with other brain changes caused by morphine, could increase vulnerability to addiction. The brain may, in fact, be learning to crave drugs. Morphine’s primary target of activity appears to be at an enzyme called guanylate cyclase; morphine’s ability to block a cascade of neuronal LTP appears to be tied to this enzyme. It’s believed that drugs that target guanylate cyclase might be of potential therapeutic value in treating or preventing opiate addiction.
Fereshteh S. Nugent, et al, Opioids block long-term potentiation of inhibitory synapses, Nature, 2007 Apr 26; 446(7139):1086-90.