Every new experience leaves a mark on our brain, from a fleeting burst of electricity and neurotransmitters to a longer-lasting architectural shift. When we meet a new person, learn a new fact, or visit a new place, connections in our brains strengthen and weaken accordingly to store a memory for minutes, days, months, or years. But there are other ways to produce long-term changes in brain structures, forming “memories” that may drive behavior in subconscious ways. A recent strain of research has discovered that the drugs humans use – from alcohol to cocaine to heroin – all produce long-lasting changes in the brain, hijacking the mechanisms of memory with sometimes dangerous results.
The laboratory of Daniel McGehee, a neuroscientist and associate professor in the Department of Anesthesia & Critical Care, studies how one of the world’s most popular drugs, nicotine, can dramatically alter regions of the brain involved in reward. Normally, these brain areas (which include the ventral tegmental area and nucleus accumbens) help motivate animals to pursue natural rewards such as food and sex that are necessary for life and reproduction. But for centuries, humans have been drawn to substances that produce those same rewarding sensations despite being inessential for life – cigarettes, alcoholic drinks, or harder stuff. When these rewarding drugs are used often enough, people can become dependent or addictive upon their effects, suggesting that their brain reward system has been somehow re-tuned to pursue the drug despite significant personal cost.
In 2000 and 2002, McGehee and former post-doc Huibert Mansvelder published two papers that characterized how nicotine can produce memory-like long-term changes in the ventral tegmental area (VTA). The excitability of neurons that release the neurotransmitter dopamine is known to be related to reward – loosely put, when the neurons are more active and release more dopamine in the nucleus accumbens, the feeling of reward is stronger. McGehee and Mansvelder took slices of rat brain that can be kept “alive” in solution for a few hours after dissection, and measured the activity of dopamine neurons before and after exposing the slices to nicotine. The effects mirrored a well-studied process of memory formation called long-term potentiation (LTP) – the excitatory drive to dopamine neurons increased, while the inhibitory drive decreased, producing a lasting increase, a sort of nicotine-induced “memory” in the reward system.
“When we’re learning things consciously, we repeat things, and that apparently reinforces the memories,” McGehee said. “We believe that cells are working in a similar way: the stronger the activation, the more repetition of excitation of that synapse, the stronger it becomes. That is a sort of memory, as it lasts for extended periods of time.”
In a new paper, published last week in The Journal of Neuroscience, McGehee and post-doc Danyan Mao looked at the longer-term effects of nicotine in VTA. In the Mansvelder experiments, changes in dopamine neuron excitability was observed in the minutes following nicotine exposure. In Mao’s experiments, she exposed the slices to the amount of nicotine the brain encounters after a single cigarette, then waited as much as 5 hours after drug to measure the electrical activity of the neurons. Once again, VTA dopamine neurons were more excitable, even long after the nicotine was removed. But the way those long-term changes are formed were found to be subtly different in Mao’s study, bringing the effects of nicotine in line with another commonly-abused drug.
“We found that nicotine and cocaine employ similar mechanisms to induce synaptic plasticity in dopamine neurons in VTA,” Mao said.
The overlap comes down to a specific type of dopamine receptor, the molecule on the cell surface that dopamine attaches to like a key to a lock, called D5. When a blocker of D5 receptors was applied alongside nicotine to the brain slice, the active ingredient in tobacco no longer could produce its long-term effects, suggesting that D5 plays a critical role in the “memory-making” process. Cocaine, which can also cause long-term excitability in dopamine neurons, utilizes the same receptor, suggesting that nicotine and cocaine share effects upon the brain reward pathway.
“We know without question that there are big differences in the way these drugs affect people,” McGehee said. “But the idea that nicotine is working on the same circuitry as cocaine does point to why so many people have a hard time quitting tobacco, and why so many who experiment with the drug end up becoming addicted.”
A common effect for the two drugs could also point the way to a common treatment for those who struggle with dependence. The D5 receptor would seem a promising target for building an intervention, but it’s also a tricky one – drugs that block D5 also block another dopamine receptor, D1, involved in movement and normal, healthy motivation.
“This dopamine receptor is attractive as a potential target,” McGehee said. “The real challenge is to tweak the addictive effect of drugs like nicotine or other psychostimulants without totally crushing the person’s desire to pursue healthy behavior.”
Future experiments will also try to more closely replicate what happens to reward systems when a person smokes regularly, rather than the effects after the first taste of nicotine. But while nobody becomes addicted after their first cigarette (in fact, it can be a profoundly negative experience), that doesn’t meant that there isn’t a neurobiological legacy of those first, tentative puffs.
“Of course, for smoking it’s a very long-term behavioral change, but everything starts from the first exposure,” Mao said. “That’s what we’re trying to tackle here: when a person first is exposed to a cigarette, what happens in the brain that might lead to a second cigarette?”
Mao D, Gallagher K, & McGehee DS (2011). Nicotine potentiation of excitatory inputs to ventral tegmental area dopamine neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (18), 6710-20 PMID: 21543600