Until 1903, a bottle of Coca-Cola contained around 60 mg of cocaine — enough, it has now been shown, to trigger long-lasting changes in brain activity. According to a report in today’s issue of Nature, giving a single dose of cocaine to mice changes the way that nerve connections transmit signals in a part of the brain thought to be crucial to the development of addiction. Such changes may predispose the brain to subsequent addiction, say the researchers.
Cocaine — made from the leaves of the South American plant Erythroxylon coca — produces its powerful psychostimulant effect by blocking the reuptake of dopamine in the brain. Dopamine is a neurotransmitter affecting brain processes that control movement, emotional response and the ability to feel pleasure and pain — people with Parkinson’s disease, for example, have almost no dopamine. Cocaine changes the flow of dopamine by preventing it from returning to storage in the neurons in the midbrain. Nerve impulses in the pleasure centers of the brain are therefore repeated, producing a “high.”
Until 1916, cocaine could be bought over the counter at Harrods: Many Victorians, it seems, had brains altered like the mice in the new study. Now, despite its illegality, use of the drug remains widespread. In 1997, 1.5 million people in the United States aged 12 and above were chronic cocaine users, and in Britain cheap prices have meant the drug has become popular with students and other groups besides the traditional wealthy users.
The new work should help research into the problem of addiction, and not just cocaine addiction. The strong effect that scientists found cocaine had on the brain will probably be similar with that of other drugs, such as nicotine, alcohol, morphine and amphetamines, since all these drugs affect the same family of receptors in the brain.
“When you learn something, you might expect to see a change in very few synaptic connections — the junctions between communicating neurons,” said Mark Ungless, lead author of the paper, of the Department of Neurology, University of California, San Francisco. “What’s so amazing [with the new work] is that nearly all dopamine neurons are affected by this single cocaine exposure. This kind of response is extremely rare, and would have a profound effect throughout the brain, particularly other areas involved in addiction.”
The neurons’ response is also likely to be at the root of the changes that occur during drug relapse. Relapse occurs when a single exposure to a drug, even after prolonged abstinence, can induce renewed drug-seeking behavior. It’s why an alcoholic who’s on the wagon can never have another drink again, even a sip.
Alan Leshner, director of the National Institute on Drug Abuse in Bethesda, Md., said it is a myth that drug addiction is a character flaw. “Drug addiction is a brain disease,” he said.
Some kinds of memories are formed and stored by what is called long-term potentiation, which occurs when interlinked neurons in the brain become more strongly connected. This means recalling the memory will always involve the firing of certain neuronal pathways.
With addictive drugs, this phenomenon of memory formation is hijacked. The mice given a single dose of cocaine underwent a surge in activity in the memory/addiction region of the brain — a surge that lasted a week. This could effectively prime the brain, presenting a “window” for addiction, said the researchers.
The psychological effects of cocaine are well-known — the euphoric high, the boosted self-confidence, the apparent leap in conversational prowess. Similarly, the effects of withdrawal have been exhaustively documented, not least by novelists — the craving, the compulsive patterns of behavior, the paranoia. Perhaps the most chilling is “formication” — a tactile hallucination often described as feeling like insects are crawling beneath the skin.
But how cocaine works at a molecular level has not been well understood. Last month, scientists at NIDA’s Intramural Research Program used genetically engineered mice to show that the serotonin system, as well as the dopamine system, is critical in mediating the cocaine high. Serotonin is another neurotransmitter, affecting sensory perception and mood. The results explained why manipulating dopamine had failed to fully explain cocaine’s effects — serotonin is involved, too.
Antonello Bonci, another of the UCSF authors on the Nature paper, hopes that the mechanisms of addiction will now become clearer, but he is well aware that it will involve tinkering with processes at the root of the human experience. “The question,” he said, “is how to develop drugs that interfere with these cocaine-induced changes but not with normal memory formation. This is something we plan to explore.”
Grandmaster Flash had it right in 1983 when he sang “White lines (blowin’ through my mind)” — now the researchers are catching up.