Friday, January 25, 2013

Isolation and drug addiction

We all know that adverse, early life experiences can affect normal development and the ability to lead a happy and healthy adult life.  A number of recent studies have shown that rodents which are mistreated as pups have long lasting changes to their gene expression (i.e. epigenetics).  They are more anxious and have a harder time forming new memories.  A paper this week in Neuron builds upon these results, by studying the effects of social isolation on the “reward pathway” in the brain.

Reward pathway
What is a reward pathway?  Deep in the brain is a region known as the ventral tegmental area (VTA), which makes connections to the nucleus accumbens and prefrontal cortex.  When we do something that is naturally good, like eating or sex, the neurons in the VTA release dopamine onto the nucleus accumbens and we interpret that as “feeling good”.  This is our reward for doing something that will help us survive and procreate. 

The Reward Pathway in a brain cross section (from

Many drugs of abuse like cocaine, amphetamines and alcohol increase the amount of dopamine signaling in this pathway; this is one reason why drugs produce a “high”.  When this pathway gets overstimulated by increased drug use, the brain will try to compensate by making the pathway less efficient.  This is why drug users feel depressed when not on drugs and why higher and higher concentrations of drugs are necessary to produce the same high feeling.  This is a neurological explanation for drug addiction.  Drug abusers also start to make connections in their lives, and in their brains, between environments (a certain room, certain people, etc) and the feeling of reward.  Getting sober is so difficult because the brain has to unlearn these connections and the reward system has to recover back to its normal level of activity.

Before we talk about the paper, I need to introduce one more concept.  Neurons become activated when channels in their membranes open and positive ions rush in.  They can then pass on this signal to another neuron by releasing neurotransmitters (like dopamine) onto the next neuron.  The activity in the neuron and the amount of transmitter it releases into the synapse can change over time, based on that neuron’s previous experiences.  This is known as synaptic plasticity.  There are short-term changes, like facilitation, and longer-term changes (we’re talking hours and days here).  One of the more famous types of long-term plasticity is called long term potentiation (LTP) and is thought to underlie learning and memory.  When drug users start to become addicted, these types of long term changes to neuronal activity are occurring throughout the reward pathway.

Social isolation and VTA neurons
The experiment begins when young male rats were either housed together in groups of 3 or alone.  The researchers then recorded neuronal activity of VTA neurons under various conditions.  They found that rats that were isolated for more than 3 weeks, specifically during the equivalent of the rats’ early adolescence, can more easily induce LTP in the VTA neurons.  In other words, rats that had no social interactions during a critical period had more sensitive VTA neurons.  That is to say, their reward pathway is primed to be overstimulated, just like during repeated drug use.

What are the behavioral manifestations of having a sensitive reward pathway?

The next set of experiments they did is called conditioned place preference.  The rats were placed in a cage that had two different compartments, with different wall colors and floor textures.  The rats were then injected with amphetamine in one of those particular compartments, so they learned to associate the drug high with that environment.  The rats were then given a choice between the two compartments and inevitably they went to the room that was associated with the drug.  The researchers found that isolated rats had a greater preference for the drug room and developed the preference sooner than the control rats.  Social isolation as an adolescent causes an increased rate of learning an association between drugs and environment.  This could make these rats more vulnerable to drug addiction. 

What about unlearning the drug association?

After the drug testing, the rats were exposed repeatedly to the drug room, but this time they didn’t receive any drugs.  This is called extinction of a memory and it is measured by the rats losing their preference for the former drug compartment.   Socially isolated animals had a significantly slower rate of unlearning the preference.  Their memory was more resistant to extinction.  If their VTA neurons are overly sensitive, then it may be harder to rewrite that connection in the brain between environment and reward.

In the context of drug addiction, these findings are big.  An adverse early adolescence can prime the brain to develop addiction more easily and make it harder to sober up.  If the VTA neurons start firing every time you go through an environment associated with drugs, you’re going to want to take a hit again.  The authors bring up an interesting point that social isolation generally causes a depression of neuronal activity in places like the hippocampus (the site of learning), so maybe the increased activity in the VTA is the way for the brain to maintain some sort of homeostasis – some areas increase, some decrease, but overall the brain may have normal amounts of activity.  This is an interesting way of looking at this problem.  I suspect that social isolation offers little in the way of rewards, so the reward pathway is trying to compensate by getting more sensitive.  It will be interesting to see if there is also a connection with changes in gene expression.  The authors explain how the VTA neurons get overactive, from a cellular point of view, but what actually initiates those changes?  And how can social interactions feed into the biology of the cell? 

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