Everyone knows that smoking is a terribly harmful habit. But this is not about smoking, this is about nicotine and nicotinic receptors.

Nicotine has numerous effects: it decreases the appetite, it improves mood and has some anti-depressant properties, it increases heart rate and blood pressure and it stimulates memory, alertness, and focus, for example. The addictive nature of nicotine relies on its stimulant actions and on the activation of reward pathways, inducing feelings of pleasure.

Dopamine is the key neurotransmitter in this circuitry and nicotine is known to increase the levels of dopamine in reward pathways. Nicotine’s pharmacokinetic properties also potentiate its abuse potential: smoking delivers nicotine to the brain within 10 seconds of inhalation but its acute effects dissipate quickly, along with the feelings of reward, which causes the continued smoking to maintain the drug’s pleasurable effects and prevent withdrawal.

Nicotine acts on the cholinergic system; it is a nicotinic acetylcholine receptor agonist, hence the name of these receptors. The endogenous agonist of nicotinic receptors is acetylcholine, the main neurotransmitter of the parasympathetic nervous system (part of the autonomic nervous system). Nicotinic receptors are widely distributed throughout the nervous system and participate in a variety of physiological responses, including anxiety, pain processing, feeding behavior and cognitive functions. Dysfunctions of neuronal nicotinic receptors have been associated with many neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, as well as autism spectrum disorders and schizophrenia.

Cholinergic deficits are observed in early stages of Alzheimer’s disease and it is thought to be associated with Alzheimer’s cognitive symptoms such as memory loss, confusion, and impaired thinking and reasoning. Brain regions associated with attention, spatial and episodic memory are those where the biggest cholinergic losses are observed in early Alzheimer’s disease. Therefore, due to its ability to increase cholinergic activity via nicotinic receptors, nicotine and nicotine analogs have been considered as possible therapeutic tools for Alzheimer’s; importantly, they could be helpful at early stages of the disease, which would be the best therapeutic strategy for Alzheimer’s.

Cholinergic dysfunction also may contribute to the neurotransmitter imbalance underlying Parkinson’s disease. Studies reveal that cholinergic and dopaminergic systems work together to fine tune the control of motor and cognitive functions that become impaired in Parkinson’s disease. Activation of certain subtypes of nicotinic receptors can stimulate anti-inflammatory signaling pathways and promote neuronal survival. The activation of these receptors can potentially prevent neuroinflammation and promote neuronal survival in the brain regions affected by Parkinson’s disease. Nicotinic receptors subunits have thus been proposed as therapeutic targets against Parkinson’s disease.

Interestingly, many epidemiological studies have shown that tobacco users have a lower incidence or severity of PD, with an estimated 40% decrease of risk of developing Parkinson’s disease for smokers when compared to never smokers. It has also been shown that smoking may prevent motor complications in Parkinson’s disease patients. Obviously, this is not due to cigarette smoking, but to nicotine intake.

Abnormalities in the cholinergic system have also been linked to autism. The study of adult post-mortem autistic brains has shown a marked decrease in the expression of different nicotinic receptor subunits in the cerebral cortex, with the reduced expression of some of these subunits being a major feature of the neurochemical pathology of autism. Due to this loss of cholinergic activity in the autistic brain, nicotinic receptor ligands may restore or at least improve cholinergic transmission, thereby compensating such loss and, hopefully, significant decreasing cognitive changes associated with autism.

Schizophrenia has been genetically linked to dysfunction in the hippocampal cholinergic system. Interestingly, schizophrenia patients exhibit a much higher prevalence for smoking than the general population. This has been regarded as a form of self-medication and nicotine intake actually appears to improve or normalize some of the cognitive and sensory deficits. However, due to the adverse health effects of smoking, an alternative approach to action on nicotine receptors would obviously be desirable. Partial nicotinic agonists have in fact shown cognitive improvements in schizophrenic patients.

Nicotine is intuitively associated to smoking, but as a drug per se, it may actually have interesting therapeutic applications that are worth pursuing.

References

Barreto GE, Iarkov A, & Moran VE (2014). Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson’s disease. Frontiers in aging neuroscience, 6 PMID: 25620929

de Leon J, & Diaz FJ (2012). Genetics of schizophrenia and smoking: an approach to studying their comorbidity based on epidemiological findings. Human genetics, 131 (6), 877-901 PMID: 22190153

De Reuck J, De Weweire M, Van Maele G, & Santens P (2005). Comparison of age of onset and development of motor complications between smokers and non-smokers in Parkinson’s disease. Journal of the neurological sciences, 231 (1-2), 35-9 PMID: 15792818

Dineley KT, Pandya AA, & Yakel JL (2015). Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends in pharmacological sciences, 36 (2), 96-108 PMID: 25639674

Hernán MA, Takkouche B, Caamaño-Isorna F, & Gestal-Otero JJ (2002). A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson’s disease. Annals of neurology, 52 (3), 276-84 PMID: 12205639

Martin-Ruiz CM, Lee M, Perry RH, Baumann M, Court JA, & Perry EK (2004). Molecular analysis of nicotinic receptor expression in autism. Brain research. Molecular brain research, 123 (1-2), 81-90 PMID: 15046869

Perry EK, Lee ML, Martin-Ruiz CM, Court JA, Volsen SG, Merrit J, Folly E, Iversen PE, Bauman ML, Perry RH, & Wenk GL (2001). Cholinergic activity in autism: abnormalities in the cerebral cortex and basal forebrain. The American journal of psychiatry, 158 (7), 1058-66 PMID: 11431227

Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, Mantua V, Mecocci P, Pani L, Winblad B, & Kivipelto M (2014). Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. Journal of internal medicine, 275 (3), 251-83 PMID: 24605808

Winterer G (2010). Why do patients with schizophrenia smoke? Current opinion in psychiatry, 23 (2), 112-9 PMID: 20051860

Image via Aleksminyayalo1 / Shutterstock.