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Neurobiochemical Effects of Nicotine

Nicotine is the main alkaloid in tobacco and the addictive compound of tobacco (Le Houezec, 1998). Nicotine is a weak base that is readily absorbed by membranes because of its lipophilic nature. Nicotine is a cholinergic agonist with sympathomimetic properties (Parrott, 1999). It is a tertiary amine composed of a pyridine and pyrrolidine ring (Hampl & Betts, 1999).

Nicotine may play a role in modulating the release of neurotransmitters such as acetylcholine, norepinephrine, dopamine, serotonin, GABA, and glutamate through presynaptic nicotinic receptors (Le Houezec, 1998). The effects of nicotine on the dopaminergic system appear to be central to its reinforcing properties. Nicotine acts on the brain in ways that are similar to other drugs of abuse, such as cocaine.

The area of the brain known as the medial forebrain bundle is the reward system of the brain (Gold & Herkov, 1998). This brain structure includes the frontal cortex, the nucleus accumbens and the ventral tegmental area. Nerve fibers run from the ventral tegmental area to the nucleus accumbens and are known as the mesolimbic dopaminergic pathway. These nerves release dopamine in the nucleus accumbens.

Nicotine has been shown to increase extracellular dopamine in the nucleus accumbens as the result of specific activation of the mesolimbic dopaminergic neurons projecting to the shell (Gold & Herkov, 1998). Nicotine interacts with the brain’s dopamine system through nicotinic cholinoceptors located on both the cell bodies and terminals of dopamine neurons.

Dopamine is a neurotransmitter that excites neurons in the nucleus accumbens, which generates the drive to repeat the brain reward through whatever engendered the release. Natural drives, to include eating, drinking, and copulation, produce this positive reward response in the brain and through this reinforcement promote continuation of the behavior (Gold & Hakone, 1998). Drugs of abuse also stimulate dopamine transmission in the nucleus accumbens and sustain self-administration.

There are also some theoretical and animal data that suggest that endogenous opioid peptides play a role in nicotine dependence and withdrawal (Gold & Herkov, 1998). Nicotine increases plasma beta-endorphin-like immunoreactivity in smokers. The plasma levels of enkephalins are also increased by nicotine.

Nicotine binds to nicotinic receptors that are located both on cell bodies and nerve terminals (Le Houezec, 1998). The peripheral nicotinic cholinergic receptor has been characterized as a ligand-gated ion channel composed of five subunits. Neuronal nicotinic receptors are distributed widely in the brain and ganglia and are made up of alpha and beta subunits only. Sodium, potassium, and calcium ions can permeate nicotinic receptors.

Nicotine receptors in the brain are heterogeneous in nature with different molecular structures and pharmacologies (Balfour, 1994). Chronic administration of nicotine results in an up-regulation of these receptors. It seems likely that the increased receptor density is a consequence of the prolonged or repetitive receptor desensitization. In the desensitized state, the receptor is able to bind to cholinergic agonists but the molecule cannot activate the receptor mechanisms involved in the production of the biological response (Ochoa, 1994). Both acute and chronic densensitization of neuronal nicotine receptors have been used to explain the effects of nicotine on the smoker’s brain. This desensitization of nicotinic receptor function modifies synaptic transmission at specific brain synapses.

Nicotine also causes changes in the electroencephalogram. In a study by Lindgren, Molander, Verbaan, Lunell and Rose (1999) clear relations were established between nicotine dose and power in the delta, theta, and alpha2 bands. Delta and theta power decreased with nicotine dose, consistent with increased arousal. Alpha2 power increased markedly at the higher nicotine doses as did the dominant alpha frequency. Alpha1, beta and P300 parameters were unaffected. In this study the arousing effects of nicotine were quite significant. However, the findings were made in monotonous non-task conditions and a fuller understanding of nicotine use as an arousing drug in daily situations would require systematic mapping of individual nicotine use under varying task loads.

Smokers tend to smoke in two broad categories (Balfour, 1994). "Peak seekers" smoke in such a way that after each cigarette there is a substantial peak in the plasma nicotine. "Trough maintainers" smoke more frequently so that the plasma nicotine concentration remains fairly constant and does not exhibit marked peaks and troughs. Peak seekers behavior stimulates central nicotinic receptors, whereas trough maintainers cause a prolonged blockade of the receptors.

Nicotine receptors are up-regulated in the brains of most people who smoke cigarettes, even those who smoke relatively few cigarettes daily (Balfour, 1994). Therefore, it is not certain that "peak seekers" smoke in such a way to repetitively stimulate the mesolimbic dopamine system. Nicotine is thought to exert its effects in the brain by interacting with a family of nicotine cholinoceptors with different physiological and pharmacological properties. It is possible that each smoker adjusts the way in which he/she smokes to achieve the appropriate combination of nicotinic receptor stimulation and desensitization which is most rewarding.

Nicotine has a number of reinforcing actions in smokers to include reduced anxiety and irritability, enhanced attention, and diminished appetite and weight (Rose & Levin, 1991). The strength of the addiction is out of proportion to the subtle rewarding and psychological effects. The repetition of the smoking act thousands of times per year by moderate to heavy smokers leads to a strong conditioned association between the sensory aspects of smoking (a conditioned stimulus) and the pharmacological effects of nicotine (the unconditioned stimulus).

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