The motivation for natural rewards such as food, sex and exercise -- and also of drugs such as nicotine --relies on neurons in the brain's reward system, based in a brain region called the ventral tegmental area (VTA). Obtaining a reward leads to excitation of these neurons and the release of a neurotransmitter called dopamine, which acts on other neurons to trigger positive emotions.
The degree to which the reward system can be activated is normally tightly controlled. A neurotransmitter called GABA (gamma aminobutyric acid) inhibits excitatory signaling in neurons and keeps the system in balance.
Chronic nicotine exposure sabotages this carefully balanced system. Previous research indicated that chronic nicotine exposure boosts the excitation of dopamine signaling while decreasing the controls on this system by GABA's inhibitory signaling.
Dopamine doesn't act alone. Nicotine exposure also leads to the release of lipids called endocannabinoids, which affect dopamine-producing neurons. Because of this, some researchers have tested potential anti-smoking therapies that block activity in the endocannabinoid receptor, where endocannabinoids bind. These treatments reduced the effects of nicotine on dopamine release and tended to reduce smoking.
"Unfortunately these treatments also produced undesirable side effects, like depression and anxiety, that limited their clinical use," said the co-first author of the study.
The team hypothesized that instead of blocking endocannabinoid receptors throughout the brain, it would be more effective to specifically target the endocannabinoid mechanism that appears to be dysregulated by chronic nicotine.
The new study published in Proceedings of the National Academy of Sciences suggests compounds called 1,2,3-triazole urea (TU) inhibitors can block the production of a specific endocannabinoid called 2-arachidonoylglycerol (2-AG).
These inhibitors were selected for their potential to inhibit the source of 2-AG itself: an enzyme called diacylglycerol lipase. The experiments revealed a strong correlation between enhanced production of 2-AG by diacylglycerol lipase and decreased GABA levels. The team then targeted the 2-AG pathway using the 1,2,3-TU inhibitors.
The researchers found that in animal models with a history of nicotine exposure, GABA signaling returned to normal when the effects of nicotine on 2-AG production were prevented with the 1,2,3-TU inhibitors. Blocking 2-AG production also affected the motivation to consume nicotine. Treating rats with the 1,2,3-TU inhibitors reduced voluntary nicotine self-administration without changing the motivation for natural rewards (for example, water self-administration by thirsty rats).
"This suggests 2-AG acts as a molecular switch for turning an important inhibitory control of dopamine neurons on and off," said the author. If this switch is turned off, as in those with chronic nicotine exposure, the excitation of dopamine neurons by nicotine is less controlled, and the drug is more rewarding.
The findings could guide future therapies, perhaps enabling scientists to design therapeutics that prevent aberrant 2-AG activity without affecting other healthy activity at the endocannabinoid receptor.