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. Dopamine transmission from the VTA is critical for controlling both rewarding and aversive behaviours. The degree to which the reward system can be activated is normally tightly controlled by a neurotransmitter called GABA which inhibits excitatory signaling in neurons and keeps the system in balance.
Chronic nicotine exposure results in long-term homeostatic regulation of nicotinic receptors that play a key role in the adaptive cellular processes leading to addiction. However, the relative contribution of the different nicotinic receptors subunits in this process is unclear. Now, a study from researchers at The Scripps Research Institute (TSRI) has identified a fat molecule in brain cells that acts as a switch to increase or decrease the motivation to consume nicotine. The team state that their findings in animal models point to a way that a drug might someday return this lipid to normal levels, making it easier for smokers to quit. The study is published the journal Proceedings of the National Academy of Sciences.
Previous studies show that chronic nicotine exposure boosts the excitation of dopamine signaling while decreasing the controls on this system by GABA’s inhibitory signaling. This is thought to contribute in part to the motivation for continued nicotine use. 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. However, they also produced undesirable side effects, like depression and anxiety, that limited their clinical use. Earlier studies from 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 current study shows that compounds called 1,2,3-triazole urea (TU) inhibitors can block the production of a specific endocannabinoid called 2-arachidonoylglycerol (2-AG).
The current study identified the potency and selectivity of these inhibitors in rats in vitro via the rat brain proteome, ex vivo in brain slices, and in vivo from intracerebroventricular administration, using activity-based protein profiling and targeted metabolomics analyses. Results show 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.
Data findings show that blocking 2-AG production also affected the motivation to consume nicotine with 1,2,3-TU inhibitor rats reducing nicotine self-administration. The group state that their findings suggest that 2-AG acts as a molecular switch for turning an important inhibitory control of dopamine neurons on and off. They go on to add that 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 team surmise that their study opens a door to new basic research and because endocannabinoids influence many aspects of behaviour, inhibitors similar to 1,2,3-TU compounds may be the key to investigating normal brain function. For the future, the researchers state that the findings could guide therapies, perhaps enabling scientists to design therapeutics that prevent aberrant 2-AG activity without affecting other healthy activity at the endocannabinoid receptor.
Michelle is a health industry veteran who taught and worked in the field before training as a science journalist.
Featured by numerous prestigious brands and publishers, she specializes in clinical trial innovation--expertise she gained while working in multiple positions within the private sector, the NHS, and Oxford University.