1. NEURO-PHARMACOLOGY OF NICOTINE
Mini-Lecture 2
Module: Tobacco and the Nervous System

2. Objectives of the Mini Lecture
Goals of Mini Lecture: Provide students with the knowledge about nicotine action on the brain and how nicotine causes craving and addiction.
Learning Objectives :
Students will be able to:
Describe the pathways of nicotine action on the brain.
Explain how nicotine causes craving and addiction.

3. Contents Core Slides: Nicotine Pathways of Nicotine Action
How Nicotine Acts in the Brain (1-4)
Optional Slides:
Nicotine and Nicotinic Receptors
Alternate Pathway: GABA

4. CORE SLIDES Neuro-Pharmacology of Nicotine Mini Lecture 2
Module: Tobacco and The Nervous System

5. Nicotine
Each cigarette contains approx. 10 milligrams of nicotine  a smoker gets approx. 1 to 2 milligrams from each cigarette.1
Nicotine is shaped like the neurotransmitter acetylcholine.2
Notes:
Nicotine is a chemical found in all tobacco products. The tobacco in manufactured cigarettes contains between 6 and 12 mg of nicotine. On average, a cigarette smoker absorbs about 1 mg of nicotine per cigarette smoked into the body. However, smokers can adjust their smoking behavior to take in the desired dose of nicotine, even from the lowest nicotine-rated cigarettes.1 For example, if a person is used to smoking a certain brand and then switches to a “light” cigarette, he usually breathes in the smoke deeper and takes puffs more rapidly to obtain the same dose of nicotine from the cigarette.
Nicotine is shaped like the neurotransmitter acetylcholine so it can fit in the same receptors and act just like acetylcholine. After repeated use of nicotine, there is more activity at the acetylcholine receptors than usual because the receptors are being activated by both acetylcholine and nicotine. This change in balance causes the brain to “think” there is too much acetylcholine and react by reducing the number of receptors and releasing less acetylcholine into the synapse. The brain now needs nicotine to maintain normal functioning. These changes in the brain cause a nicotine user to feel abnormal when not using nicotine. In order to feel normal, the user has to keep his or her body supplied with nicotine, which is termed addiction. If the person stops using nicotine, the number of receptors and their sensitivity to acetylcholine will eventually be reestablished, but only after some time.2
References:
Benowitz NL. Cotinine as a biomarker of environmental tobacco smoke exposure. Epidemiol Rev. 1996; 18:188–204.
National Institute on Drug Abuse. Brain Power! Challenge: Grades 6–9; Module 2: Legal Doesn’t Mean Harmless. Available at: (accessed: June 5, 2009).
1. Benowitz 1996; 2. National Institute on Drug Abuse.

6. Pathways of Nicotine Action1
Nicotine activates nicotinic receptors in brain → modulates immune response by a or b pathways (figure):
a → activation of the hypothalamus–pituitary–adrenal axis
b → activation of the autonomic nervous system via sympathetic and para-sympathetic innervations a b
Notes:
Nicotine from cigarette smoke enters the brain and interacts with nicotinic receptors in the brain. Activation of nicotinic receptors could modulate the immune response by either of two pathways:
a → activation of the hypothalamus–pituitary–adrenal axis, whereby corticotropin-releasing hormone (CRH) from the hypothalamus stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary gland, which, in turn, stimulates the production of glucocorticoids (CORT) by the adrenal gland — increased levels of CORT suppress the immune system.
b → activation of the autonomic nervous system, which connects the brain directly to the visceral target tissues, including lymphoid tissues, through sympathetic and parasympathetic innervations. Noradrenaline from the sympathetic nerve terminals might modulate T-cell function through adrenoceptors that are present on T cells. The role of the parasympathetic nervous system in the regulation of T-cell function is not clear.
Reference:
Sopori M. Effects of cigarette smoke on the immune system. Nat Rev Immunol. 2002; 2:372–377. Available at:
1. Figure reprinted from Sopori 2002

7. How Nicotine Acts in the Brain (1)
1) Nicotine (half-life: 40 minutes) mimics actions of acetylcholine.
2) Directly activates dopamine systems in brain → responsible for mediating pleasure response.
Notes:
Research has shown that along with directly stimulating the brain's reward system, nicotine also stimulates it indirectly by altering the balance of inputs from two types of neurons that help regulate its activity level. This additional stimulation intensifies the pleasure from smoking and makes it last longer.
Nicotine, like other addictive drugs, attaches to the core neurons of the brain's reward system situated in the ventral tegmental area (VTA), where beneficial behaviors are rewarded and reinforced. Nicotine activates dopamine systems within the brain. Dopamine is a neurotransmitter that is directly responsible for mediating the pleasure response.
Reference:
School of Chemistry, Bristol University, UK. The Metabolism of Nicotine Available at:
1. School of Chemistry, Bristol University, UK

8. How Nicotine Acts in the Brain (2)
3) Blocks reabsorption of dopamine and stimulates release of more dopamine through glutamate.
4) Prolonged nicotine exposure → excessive and chronic activation → decreased dopamine efficiency → reduced no. of available receptors .
Notes:
Nicotine increases the stimulation of nicotinic receptors and triggers off the production of dopamine in the nucleus accumbens (NAc). When nicotine attaches to these neurons they increase their activity, releasing dopamine, which produces pleasure, encouraging a repetition of the behavior. A prolonged exposure leads to excessive and chronic activation of these receptors to nicotine and reduces the efficiency of dopamine by cutting down the number of available receptors.
Reference:
School of Chemistry, Bristol University, UK The Metabolism of Nicotine. Available at:
1. School of Chemistry, Bristol University, UK

9. How Nicotine Acts in the Brain (3)
5) Reduction in no. of active receptors → decreased psychotropic effect of nicotine. 6) Leads to phenomenon of tolerance → smoker needs to smoke more cigarettes just to create normal levels of dopamine.
Notes:
The reduction of the number of active receptors reduces the psychotropic effect of nicotine. Due to the phenomenon of tolerance, the smoker needs to smoke more and more cigarettes to keep a constant pleasurable effect.
Reference:
School of Chemistry, Bristol University, UK. The Metabolism of Nicotine Available at:
1. School of Chemistry, Bristol University, UK

10. How Nicotine Acts in the Brain (4)
Notes:
After a brief period of abstinence (overnight for instance), the brain concentration of nicotine lowers and allows a part of the receptors to recover and be reactivated. On waking up, the return of all receptors to an active state raises the neurotransmission to an abnormal rate. The smoker feels uncomfortable, which induces him to smoke again. The first cigarette of the day is the most pleasant because the sensibility of the dopamine receptors is maximal. Then, the receptors are soon desensitized and the pleasure wears off. This is the vicious cycle of smoking.
Reference:
School of Chemistry, Bristol University, UK. The Metabolism of Nicotine. Available at:
7) After brief abstinence (e.g., overnight) → reduced brain nicotine → receptors partially recover → increased dopamine receptor sensitivity → increased neurotransmission rate abnormally → induces craving.
1. School of Chemistry, Bristol University, UK

11. OPTIONAL SLIDES Neuro-Pharmacology of Nicotine Mini Lecture 2
Module: Tobacco and The Nervous System

12. Nicotine and Nicotinic Receptors1
Physiological normal conditions
After the opening of the canal by binding to acethylcholine, the receptor becomes desensitized before it goes back to the state of rest or it is regenerated.
Continuous exposure to tobacco
Nicotine substitutes for acetylcholine and over-stimulates the nicotinic receptor. The receptor is long-term inactivated and its regeneration is prevented by nicotine.
Notes:
The active form of nicotine is a cation whose charge is located on the nitrogen of the pyrrole cycle. This active form is very close to acetylcholine. It has been demonstrated that nicotine interferes with acetylcholine, which is the major neurotransmitter of the brain. Acetylcholine can bind to two different kinds of receptors: nicotinic receptors, which are activated by nicotine, and muscarinic receptors, which are activated by muscarine. Nicotine and muscarine are thus specific agonists of one kind of cholinergic receptor (an agonist is a molecule that activates a receptor by reproducing the effect of the neurotransmitter.)
Nicotine competitively binds to nicotinic cholinergic receptors. The binding of the agonist to the nicotinic receptor triggers off a conformation change of the architecture of the receptor, which opens the ionic channel during a few milliseconds. This channel is selective for cations (especially sodium). Its opening thus leads to a brief depolarization. Then, the channel closes and the receptor transitionally becomes refractory to agonists. This is the state of desensitization. Then, the receptor  usually goes back to a state of rest, which means that it is closed and sensitive to the agonists. In case of continuous exposure to agonists (even in small doses), this state of desensitization will last long (long-term inactivation).
Reference:
School of Chemistry, Bristol University, UK. The Metabolism of Nicotine Available at:
1. School of Chemistry, Bristol University, UK

13. Alternate Pathway: GABA1
Nicotine also acts on neurons producing glutamate and GABA.
Leads to a combination of effects → amplifies rewarding properties of nicotine → promotes addiction.
Notes:
However, nicotine’s attachment to the dopaminergic neurons in the ventral tegmental area (VTA) accounts for only part of the drug's pleasure-producing and ultimately addictive effect. Nicotine attachment stimulates the DA neurons for only a few minutes at most, yet dopamine levels in the nucleus accumbens (NAc) remain elevated for much longer. This is explained by nicotine's impact on two other types of neurons that affect dopamine levels. These neurons produce neurotransmitters, glutamate and GABA, which act as fundamental pacemakers throughout the brain. Once released by its producing neuron, glutamate attaches to other neurons, including the DA neurons in the VTA, and stimulates them to speed up their activities. GABA, on the other hand, has the opposite effect: It slows neurons down.
According to researchers, nicotine acts on these pacemaker neurons to increase the ratio of glutamate to GABA in the VTA. If the amount of glutamate acting on DA cells were to increase while the amount of GABA remained the same or decreased, the result would favor high levels of dopamine in the NAc. In glutamate-producing cells, the brief nicotine application induced a condition known as long-term potentiation, which promotes high-level activity for an extended time, leading to elevated dopamine levels in the NAc even after nicotine stops directly affecting the dopamine-producing neurons.
The combination of effects—increasing dopamine release and decreasing the inhibitory [GABA] response—results in an amplification of the rewarding properties of nicotine, promoting addiction.
Reference:
National Institute on Drug Abuse. Nicotine's Multiple Effects on the Brain's Reward System Drive Addiction Available at:
1. National Institute on Drug Abuse

14. The most important health message a doctor can give to patients is to quit smoking.