Sunday, July 30, 2006

Knocking out stimulant reward   posted by rosko @ 7/30/2006 06:16:00 PM
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I just posted this on my own blog last night and thought I'd cross-post it here, as there have been a few posts lately about neurotransmitters, neurons, and behavior.

About a month ago I saw this article about the role of the dopamine transporter in cocaine reward. For those that don't know, the modified amino acids dopamine, norepinephrine, and serotonin, collectively known as monoamines, are neurotransmitters that are released by specific neurons in the brain and activate receptors on other neurons, sending a message from one cell to another. There are "pumps" in the membranes of the neurons that release these transmitters, which "clean up" the released monoamines so that they don't keep activating receptors for too long. These pumps are blocked by many psychotherapeutic and recreational drugs, producing a change in brain function. While each neurotransmitter has multiple effects in the brain, the transmitter dopamine in particular is believed to participate in the behavior-reinforcing properties of both natural (food, sex, etc.) and pharmacological (drug) stimuli. Among many scientists dopamine is still believed to be a kind of "pleasure chemical" whose concentration determines the degree of positive subjective sensation produced by the environment, regardless of the specific nature of the stimulus. This idea has been called into question especially lately, though, for a number of reasons, many of which have nothing to do with this article. For instance, the effect of drugs that directly activate dopamine receptors is not euphoric in humans.

The finding that concerns us here is one made by Sora et. al. in 1998. To understand the significance of this study, it is important to know that the stimulant cocaine blocks the transporters ("pumps") for all three monoamines. Given the assumed responsibility of dopamine for reinforcement, it has long been assumed that the block of the dopamine transporter (DAT) produces the euphoric effect of cocaine by allowing dopamine to sit around and activate its receptors longer. To test this, Sora et. al. deleted ("knocked out") the gene encoding DAT from mice, and showed that they still prefer to spend time in a chamber in which they have previously received cocaine. This so-called conditioned place preference suggests that cocaine can act as a reward even when it cannot block DAT (because DAT doesn't exist in these mice). Knocking out the serotonin transporter (SERT) also left cocaine reward intact (This SERT is the same as the 5-HTT mentioned in the Caspi and Moffitt study-geneticists seem to like the name 5-HTT and biochemists SERT, and some use the alternative SLC6A4 occasionally). A follow-up study showed that knocking out both DAT and SERT makes mice that do not prefer an environment they associate with cocaine. Sora et. al. took this to mean that blocking SERT is rewarding as well, which flies in the face of the fact that blocking SERT with drugs like fluoxetine (Prozac) does not produce signs of euphoria. An obvious caveat here is that the brains of DAT knockout mice are flooded with dopamine and the animals are very hyper even when they aren't on any drugs, so findings may not generalize to normal mice.

The new study by Chen et. al. took a different approach. They found that by mutating part of DAT, they could prevent cocaine from binding to it without breaking the pump. When this mutant DAT was added back into DAT knockout mice, cocaine no longer made the mice hyperactive like normal or DAT knockout mice (paradoxically, it even calmed them) and was not rewarding. This confirms what I--and probably many other researchers--suspected was going on: the mice with DAT knocked out only showed a response to cocaine because it slightly amplified the effect of the high baseline dopamine. Possible explanations are that increased activation of serotonin receptors overcomes some negative feedback mechanism limiting dopamine levels, or that lack of DAT induces a form of plasticity in the reward pathway such that SERT blockade becomes rewarding. This still doesn't explain other results questioning the idea of dopamine as a "pleasure chemical", but at least it shows that cocaine, and probably methylphenidate (Ritalin) and amphetamines, do produce their reinforcing effects through inhibition of dopamine reuptake.

*I just corrected the links. For some reason the first time I posted the URLs got all messed up, even though it worked perfectly fine for my own blog when I cut and pasted from the same file on my computer.