Experimental Biology Blogging: High and Low Cocaine Responding Rats, Cocaine Abuse, and the Norepinephrine Transporter

Apr 11 2011 Published by under Experimental Biology Blogging 2011

Cocaine, and other drugs of abuse, are difficult things to predict. We know to some extent what their initial effects on the brain are, how they act, and some of the things that we can do. But what we don't know, is who will become addicted to them. It is estimated right now that 15% of people who use cocaine will become addicted. But which 15%? Being able to predict, or determine, the attributes that make a future addict is extremely important. It would allow us to target anti-drug programs, intervene with therapy, and attempt to stop the use before it escalates to addiction. Not only that, if people who are most likely to become addicted to cocaine have neurological differences (as they are very likely to), knowing what predicts their behavior would allow us to study which circuits of the brain are most involved, and help us develop therapies for addiction to cocaine and other drugs of abuse.

But how do you develop a model for this? Welcome to the world of individual differences.

Richards and Zahniser. "High cocaine locomotor responding rats have greater hippocampal norepinephrine transporter function than low cocaine locomotor responding rats after acute cocaine exposure" University of Colorado Denver, presented at Experimental Biology, 2011.

Many scientists are after one of the new buzzwords in addiction research: impulsivity. High impulsivity individuals are more likely to drink heavily, more likely to try drugs, and some think they might be more likely to become addicts. In rats, a high impulsivity rat might be a rat that more readily explores and shows high locomotor activity in a novel environment. But Zahniser's laboratory showed that high activity in a novel environment in outbred rats doesn't actually predict how they will respond to their first exposure to cocaine. What DOES predict how they will respond to cocaine is their locomotor response to a low dose of cocaine.

You might predict that rats with a high locomotor response to cocaine (HCR) might be more prone to addiction related behaviors in rats, like the tendency to spend time in a drug-paired chamber (conditioned place preference), or the willingness to press on a lever to get cocaine injections (drug self-administration). But in fact, this isn't the case. It turns out that LOW locomotor responses to cocaine (LCR) in rats are correlated with higher conditioned place preference and increased willingness to work to self-administer cocaine. Previous studies in the Zahniser lab have shown that these LCR rats have higher numbers of dopamine transporters. Dopamine is a neurotransmitter which is associated with feelings of reward/motivation and increases in response to drugs like cocaine. The dopamine transporter recycles released dopamine from the synapse back into the neuron, playing a role in keeping the levels of dopamine in the brain under control. Cocaine blocks these transporters, causing dopamine to build up, and increases dopamine signaling, which we believe results in the pleasurable rush of a "high".

The more dopamine transporters you have, the more cocaine it will take to block them (one molecule of cocaine per transporter please, no pushing). And so if you have LARGE numbers of dopamine transporters, and a low dose of cocaine, you're probably going to get a smaller behavioral effect, like the lab sees with their LCR rats. But cocaine doesn't act on dopamine alone, in fact it has a similar affinity for the norepinephrine transporter. Norepinephrine is another neurotransmitter which influences things like vigilance and attention. And the question for this poster was: if the LCR rats have high dopamine transporters, what do their norepinephrine transporters look like?

Richards took a group of rats and characterized them into low and high cocaine responding rats (the differences can be big, some of the HCRs respond 2-5 TIMES more to cocaine than the LCRs). She then looked at the norepinephrine transporter levels in the hippocampus, where there is a large amount of norepinephrine transporter, but relatively little dopamine transporter. And just like with the dopamine transporter, the LCR rats, who had little locomotor response to cocaine, showed a large increase in the numbers of norepinephrine transporters, with 41% more than HCR rats. And the number of norepinephrine transporters was negatively correlated with impulsivity measures like locomotor activity in a novel environment. This means that the MORE norepinephrine transporters they had, the less they responded to a novel environment. This could have something to do with norepinephrine's role in attention, stress, and anxiety, where the hippocampus in particular may play a role.

And so the next thing to do is look at how the LCRs and the HCRs respond to stress, and how they behave in anxiety measures. And as they characterize these animals, they may be able to tell us more about what type of brain can easily become addicted to cocaine, and it may not always be the high impulsivity people who have a big drug response after all.

References:

Nelson AM, Larson GA, Zahniser NR. "Low or high cocaine responding rats differ in striatal extracellular dopamine levels and dopamine transporter number." J Pharmacol Exp Ther. 2009

Crews FT, Boettiger CA. "Impulsivity, frontal lobes and risk for addiction." Pharmacol Biochem Behav. 2009

Nelson, A., Larson, G., & Zahniser, N. (2009). Low or High Cocaine Responding Rats Differ in Striatal Extracellular Dopamine Levels and Dopamine Transporter Number Journal of Pharmacology and Experimental Therapeutics, 331 (3), 985-997 DOI: 10.1124/jpet.109.159897

Crews, F., & Boettiger, C. (2009). Impulsivity, frontal lobes and risk for addiction Pharmacology Biochemistry and Behavior, 93 (3), 237-247 DOI: 10.1016/j.pbb.2009.04.018

3 responses so far

  • mat says:

    Between groups- I assume you don't mean an increase in NET caused by the cocaine trial bit rather a presumably constitutive group difference?

  • Noreppy says:

    Mat,

    I think the problem with the High/Low responders is that to get the groups you need the cocaine trial. So you're not looking at a difference in the animals in their naive state but in their response to the coke.

  • K says:

    Oh man, did you see the guy who was trying to cure meth addiction with antibodies?

    I talked to a dude and he said 'lol his shit is messed up, not gonna work'

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