New understanding of how nicotine causes addiction has emerged, according to research published in eLife.
Although smoking rates are declining, a consistent portion of the population continues to smoke, making continued research into tobacco addiction important.
One reason people find it hard to quit smoking is that each time they have a cigarette, feelings of craving, irritability and anxiety melt away.
This is known as negative reward and is partly controlled by a region of the brain called the habenula.
The neurotransmitters acetylcholine and glutamate are thought to influence nicotine dependence in the habenula, but the molecular details of this regulation are unclear.
Neurotransmitters are the chemical messengers of the brain. They are packaged into spherical structures at the ends of neurons, called vesicles. On receiving certain signals, neurons release their vesicle contents into the synapse, sending the signal on to the next neuron.
Neurons can recycle neurotransmitters by reabsorbing them through reuptake, a process that allows them to control the exact number of neurotransmitters in the synapse.
Even a small upset in the balance of neurotransmitters can affect behavior. In the case of acetylcholine, it can influence our ability to cope with addiction.
Ines Ibanez-Tallon, and colleagues from Rockefeller University in New York, knew that acetylcholine and glutamate played important roles in the neurons in the habenula - but not how they might interact to reinforce addiction.
Acetylcholine controls glutamate release
The researchers created a mouse model where a key gene involved in acetylcholine processing was missing; this prevented acetylcholine production in habenular neurons. The elimination of acetylcholine affected glutamate in the habenula in two ways. First, the amount of glutamate released by neurons was reduced; second, the reuptake of glutamate back into vesicles was impaired.
Both of these mechanisms disrupt normal signaling, thus affecting the excitability of neurons.
Based on these findings, the researchers suggest that acetylcholine regulates how much glutamate is released into the synapse, and at what frequency. It also facilitates the packaging of glutamate into vesicles.
Studies using electron microscopy confirmed that the neurotransmitters are in the same place at the same time and are able to affect one another.
Removing acetylcholine decreases sense of reward
When the researchers removed acetylcholine from the habenula of the mice, the mice became insensitive to the rewards of nicotine. They did not develop a tolerance to continued nicotine exposure, nor did they experience withdrawal symptoms, such as body shakes and scratching.
The findings suggest that without acetylcholine, nicotine addiction would not occur.
They also reveal new clues about the brain circuitry involved in nicotine dependence, which is relevant to opioid and cannabinoid addiction.
In future, the researchers hope to examine how the interaction between acetylcholine and glutamate might work in other areas of the brain.