Introducing the brain: drug addiction factors in DNA (Introduction)

by David Turell , Monday, June 24, 2024, 18:10 (96 days ago) @ David Turell

New studies:

https://www.chemistryworld.com/features/the-proteins-that-drive-drug-addiction/4019683....

"Nestler explains that while ΔFosB increases an animal’s interest in consuming rewards like food and drugs and produces a positive emotional state, Creb mediates a more aversive emotional condition – but one that ultimately also drives drug-seeking behaviour. ‘ΔFosB causes an animal to take more drugs because it feels good, it wants the positive experience – it’s called positive reinforcement. Whereas Creb would cause an animal to take more drug because it wants to treat this negative emotional state – so-called negative reinforcement,’ he says. ‘And we know that in people with addiction syndromes, both of those factors are at play.’

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"Interestingly, while ΔFosB and Creb are implicated in the actions of many drug types, Nestler’s lab has recently identified subtle differences in how these changes occur in response to different drugs. 95% of the nerve cells in the nucleus accumbens are a type called medium spiny neurons. These are divided into two subtypes based on the type of dopamine receptor that they express – half of the cells express a D1 receptor, while the other half express the D2 receptor. The two cell types differ with respect to the inputs they receive and the outputs that they send to other parts of the brain.

"While all addictive drugs induce ΔFosB in the D1 medium spiny neurons, certain drug classes differ in their effects on the D2 subtype. ‘Opioids converge a lot in producing many of the same effects as cocaine on D1 cells, but in addition, produce a whole additional set of long-term changes in the D2 cells,’ explains Nestler.

"While studying this phenomenon, Nestler’s lab discovered that a gene called Rheb, which is involved in many cell processes, is correlated with Fos expression brought on by exposure to both cocaine and morphine.

"'... ΔFosB and Creb are really just two of a relatively large number, perhaps 10 or so, key transcription factors that are driving the same types of changes in the nucleus accumbens and other brain regions,’ he adds. ‘And that, in turn, has led us to study many other transcriptional mechanisms, and ultimately to look at the various transcriptional mechanisms for possible therapeutics.’

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"In 2021, Heller’s team showed that one specific histone modification caused by cocaine exposure shifts the ratio of isoforms of a protein called SRSF11 that are produced in nucleus accumbens neurons.

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"Heller’s team showed that administering a compound called cytosporone-B, which activates NR4A1, inhibits drug reward behaviour in mice. The team are now investigating other small molecules as well as the epigenetics of CartPT to try to gain new insights into ways of treating addiction-linked behaviours.

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"One difficulty when designing drugs that alter dopamine regulation is that dopamine is involved in all sorts of biological processes. ‘We call it the reward molecule or the pleasure molecule. But … it’s really not a reward molecule at all – it just helps us learn really important information,’ explains Calipari. ‘And so if you put your hand on a hot stove dopamine goes up just as much as it does when you have something pleasurable.’ (my bold)

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‘'So I think that the feasibility for epigenetic editing for psychiatric disorders is stronger now, because epigenetic editing in general is moving into the clinical space,’ she adds. ‘The challenge is the targets affect so many different genes. So how do we make it specific? If we target one gene, will that be sufficient? If we target a gene that affects other genes, will that be too much – will we get undesirable side effects?’ Despite the complexity of this challenge, Heller is optimistic. ‘I think we’re going to figure it out,’ she says. ‘And maybe now is the time in the next 10 years with these epi tools.'’

Comment: our God-given brain is amazing. We can tinker with the genome and determine which factors are involved in addiction and work toward treatment. Our natural pleasure centers are captured by drugs and subverted.