One of the most compelling theories about hyperactivity and attention deficit disorder is one that holds that hyperactivity is caused by a malfunction in the dopamine transporter, the molecule that takes the neurotransmitter dopamine out of circulation. The theory is hyperactive kids, and the disaffected adults they turn into, are thus essentially unable to turn their brains off.
The theory is simple and elegant, and makes a stunning prediction—that hyperactive kids will have paradoxical reactions to stimulants like Adderall, Ritalin, and cocaine. The theory is supported by the recent discovery of a pair of brothers who, thanks to an unusual genetic quirk, lack the dopamine transporter entirely and are indeed extremely hyperactive. It's also borne out by experiments with mice genetically engineered to lack the transporter ("knockout mice" that lack individual genes make for about as much fun as you can have in neurobiology, and will come up up often in this blog), who do in fact exhibit the paradoxical reactions the theory predicts.
There is only one key problem with the theory: it works for mice, but it does not, in practice, work for humans. The overwhelming weight of the evidence is that most kids (or for the matter, adults) with ADHD do not, in fact, have paradoxical reactions to drugs. This seminal paper on the effects of dextroamphetamine (substantially similar to Adderall) by Judith Rapoport, will give you an idea of the thrust of most research. But having twice experienced a rare, bona fide paradoxical reaction to Ritalin myself (it made me fall asleep instantly), however, I've been interested in this line of thinking.
I saw a recent paper involving mice and cocaine (enough work has been done along this line to make you start wondering where neuroscientists get the substantial amount of cocaine that these studies need) that starts to provide an answer to the question. The mice involved are “knockdown mice.” Unlike the “knockout mice” that lack the dopamine transporter gene, and on which similar studies have been done, the knockdown mice are not totally missing the gene; they are just bred to have an extreme shortage of transporter molecules. This actually makes them much closer to actual hyperactive kids—they are, in technical terms, “hyperdopaminergic.”
Intuitively you might assume, and pretty much everyone seems to have assumed, that the effect of cocaine on these mice would be similar to its effect on dopamine transporter knockout mice. But this is not the case. Cocaine has a paradoxically calming effect on knockout mice. But the knockdown mice are very different: knockout mice are immune to cocaine's stimulant effects, but knockdown mice are at lower doses actually hypersensitive to the drugs rewarding and especially its stimulating effects:
This is a very counterintuitive result, and it has a lot of implications. It goes a long way toward explaining how people who kids—and adults—with very similar profiles can have startlingly different reactions to the same drugs. The results from cocaine have a lot of implications for prescription drugs like Ritalin, Adderall, and Dexedrine—these are a lot more similar in action to cocaine than you might think. And they have even broader implications if you start looking at the whole range of modern psychotropic drugs, like anti-depressants, a subject I'll address in a later post.
The theory is simple and elegant, and makes a stunning prediction—that hyperactive kids will have paradoxical reactions to stimulants like Adderall, Ritalin, and cocaine. The theory is supported by the recent discovery of a pair of brothers who, thanks to an unusual genetic quirk, lack the dopamine transporter entirely and are indeed extremely hyperactive. It's also borne out by experiments with mice genetically engineered to lack the transporter ("knockout mice" that lack individual genes make for about as much fun as you can have in neurobiology, and will come up up often in this blog), who do in fact exhibit the paradoxical reactions the theory predicts.
There is only one key problem with the theory: it works for mice, but it does not, in practice, work for humans. The overwhelming weight of the evidence is that most kids (or for the matter, adults) with ADHD do not, in fact, have paradoxical reactions to drugs. This seminal paper on the effects of dextroamphetamine (substantially similar to Adderall) by Judith Rapoport, will give you an idea of the thrust of most research. But having twice experienced a rare, bona fide paradoxical reaction to Ritalin myself (it made me fall asleep instantly), however, I've been interested in this line of thinking.
I saw a recent paper involving mice and cocaine (enough work has been done along this line to make you start wondering where neuroscientists get the substantial amount of cocaine that these studies need) that starts to provide an answer to the question. The mice involved are “knockdown mice.” Unlike the “knockout mice” that lack the dopamine transporter gene, and on which similar studies have been done, the knockdown mice are not totally missing the gene; they are just bred to have an extreme shortage of transporter molecules. This actually makes them much closer to actual hyperactive kids—they are, in technical terms, “hyperdopaminergic.”
Intuitively you might assume, and pretty much everyone seems to have assumed, that the effect of cocaine on these mice would be similar to its effect on dopamine transporter knockout mice. But this is not the case. Cocaine has a paradoxically calming effect on knockout mice. But the knockdown mice are very different: knockout mice are immune to cocaine's stimulant effects, but knockdown mice are at lower doses actually hypersensitive to the drugs rewarding and especially its stimulating effects:
While cocaine was capable of increasing locomotor activity in both genotypes, there were differences in each genotype's response. For instance, both 5 and 10 mg/kg cocaine produced stronger locomotor stimulation in DAT-KD mice than it did in wild type mice.
This is a very counterintuitive result, and it has a lot of implications. It goes a long way toward explaining how people who kids—and adults—with very similar profiles can have startlingly different reactions to the same drugs. The results from cocaine have a lot of implications for prescription drugs like Ritalin, Adderall, and Dexedrine—these are a lot more similar in action to cocaine than you might think. And they have even broader implications if you start looking at the whole range of modern psychotropic drugs, like anti-depressants, a subject I'll address in a later post.
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