“We knew these lipids were implicated in nicotine addiction, but until now manipulating their synthesis was not pharmacologically feasible,” said senior author Loren Parsons, professor at The Scripps Research Institute (TSRI) in US.
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 signalling in neurons and keeps the system in balance.
Previous research indicated that chronic nicotine exposure boosts the excitation of dopamine signalling while decreasing the controls on this system by GABA’s inhibitory signalling.
Nicotine exposure also leads to release of lipids called endocannabinoids, which affect dopamine-producing neurons.
Some researchers have tested potential anti-smoking therapies that block activity in the endocannabinoid receptor, where endocannabinoids bind.
Although these treatments reduced the effects of nicotine on dopamine release and tended to reduce smoking, they also produced undesirable side effects, like depression and anxiety, that limited their clinical use, said Matthew Buczynski, Research Associate at TSRI.
The team hypothesised 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 study 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.
Researchers then studied the cellular effects of chronic nicotine exposure on GABA signalling in rat brains.
These experiments showed a strong correlation between enhanced production of 2-AG by diacylglycerol lipase and decreased GABA levels.
The researchers found that in animal models with a history of nicotine exposure, GABA signalling 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. Buczynski found that treating rats with the 1,2,3-TU inhibitors reduced nicotine self-administration without changing the motivation for natural rewards.
The study was published in the journal PNAS.