Addicted to Nicotine
A National Research Forum

Section IV: Biology of Nicotine Addiction
Neil E. Grunberg, Ph.D., Chair

NEUROPHARMACOLOGY AND BIOLOGY OF NEURONAL NICOTINIC RECEPTORS

Kenneth J. Kellar, Ph.D.
Department of Pharmacology
Georgetown University School of Medicine

What We Know

Nicotine's important effects on the brain, spinal cord, and autonomic nervous system are mediated by nicotinic cholinergic receptors. These receptors, which normally respond to the neurotransmitter acetylcholine, exist as several subtypes that differ in the details of their exact structure and characteristics, but each forms an ion channel through the cell membrane that allows sodium, potassium, and calcium ions to flow into or out of the cell when the receptor is activated by nicotine. This in turn typically leads to depolarization of the cell and an excitatory response. For example, nicotine stimulates cells in the adrenal gland to secrete epinephrine (adrenaline) into the blood, and thus it activates a number of systems collectively involved in the body's "fight or flight" responses.

Nicotinic receptors are found on neurons throughout the brain, including the cerebral cortex, thalamus, hypothalamus, hippocampus, basal ganglia, midbrain, and hindbrain. They are often associated with the cell bodies and axons of major neurotransmitter systems, and they appear to influence the release of several different neurotransmitters, including catecholamines, acetylcholine, GABA, and glutamate. Nicotine, in fact, stimulates the release of dopamine and norepinephrine in specific neuronal circuits thought to be closely involved in so-called reward functions. This action may underlie the addictive liability of nicotine; in fact, its action to stimulate dopamine neurotransmission in these specific reward circuits is consistent with the actions of other well-known drugs of abuse, such as cocaine and amphetamine.

In addition to its actions in the brain's reward circuits, nicotine stimulates the release of certain pituitary gland hormones, such as prolactin and ACTH. Measurement of nicotine's effects on these hormones offers a window on its in vivo pharmacological actions and can be used to assess how acute and chronic exposure to nicotine affect its receptors. For example, in rats a single injection of nicotine stimulates prolactin release, but a second injection given any time up to several hours after the first is ineffective, indicating that the nicotinic receptors are desensitized. This desensitization is reversible, and within about 12 hours after the first nicotine injection, receptor function is restored.

In contrast, after chronic exposure to nicotine (for 10 days), a single injection does not stimulate prolactin release even up to 8 days after chronic exposure has ended. This suggests that the function of these receptors is lost permanently - the receptors are inactivated as opposed to desensitized. Nicotine-stimulated prolactin release does return about 14 days after the last exposure to nicotine, time enough for new nicotinic receptors to be synthesized by the neurons involved.

One of the interesting and more unusual aspects of nicotine's effects on brain nicotinic receptors is that chronic exposure to nicotine in rats, mice, and humans actually increases the density (number) of these receptors. Thus, in rats or mice exposed to nicotine for 7 to 21 days, the density of these receptors is increased by 30 to 100 percent in many areas of the brain. In the brains of smokers, the density of the nicotinic receptors is 100 to 300 percent higher than in nonsmokers. The higher density of receptors, however, may not necessarily translate into an increased level of functions mediated by these receptors. Quite the opposite may be the case, as demonstrated by the prolactin studies described above. On the other hand, recent studies that examined nicotine-stimulated dopamine and norepinephrine release in vivo found that administration of low doses of nicotine could actually increase the release of these neurotransmitters in some brain areas.

What We Need To Know More About

This difference in how chronic administration of nicotine affects nicotine-stimulated prolactin release and dopamine release in vivo probably reflects fundamental differences in the regulation of the subtypes of nicotinic receptors that mediate each of these responses. Thus, a critical task is to identify the receptor subtypes that are associated with the pharmacological actions of nicotine in altering neurotransmission and ultimately behavior. The means to accomplish this task are beginning to emerge in the form of new methods and tools to localize and identify the specific receptor subtypes in specific areas of the brain and spinal cord and in peripheral nervous tissue. These include new high-affinity ligands to label the receptors, subunit-specific antibodies that allow determination of the subunit composition of the receptor subtypes, patch-clamp measurements of the conductance, and rapid regulation of the receptors' ion channels. In addition, new approaches to studying the characteristics of the receptor subtypes and to determining their roles in vivo have been developed using the methods of recombinant molecular biology, including the production of stably transfected cell lines that express a single subtype of nicotinic receptor (which allows precise characterization of that receptor's properties) and knockout mice lacking a specific subunit of the receptors.

A fundamental question is, Which subtype(s) of nicotinic receptors are involved in the rewarding aspects of nicotine's actions? Is it the receptor that is inactivated by chronic nicotine and thus does not fully function after chronic exposure to nicotine? Is it the receptor whose function is actually increased during chronic exposure? Or is it a combination of receptor subtypes? And beyond the neurobiology of nicotine's actions on its receptors is an even more intriguing question: How do nicotine's effects on neurotransmission lead to alterations in the fundamental drives and behaviors associated with addiction? The means are available to begin to address these questions, and the answers are likely to have relevance to more than just nicotine addiction.

Recommended Reading

Benwell, E.M., and Balfour, D.J.K. Regional variation in the effects of nicotine on catecholamine overflow in rat brain. Eur J Pharmacol 325:13-20, 1997.

Hulihan-Giblin, B.A.; Lumpkin, M.D.; and Kellar, K.J. Acute effects of nicotine on prolactin release in the rat: Agonist and antagonist effects of a single injection of nicotine. J Pharmacol Exp Ther 252:15-20, 1990.

Hulihan-Giblin, B.A.; Lumpkin, M.D.; and Kellar, K.J. Effects of chronic administration of nicotine on prolactin release in the rat: Inactivation of prolactin release by repeated injections of nicotine. J Pharmacol Exp Ther 252:21-25, 1990.

Marshall, D.L.; Redfern, P.H.; and Wonnacott, S. Presynaptic nicotinic modulation of dopamine release in the three ascending pathways studied by in vivo microdialysis: Comparison of naive and chronic nicotine-treated rats. J Neurochem 68:1511-1519, 1997.

Wonnacott, S. Presynaptic nicotinic ACh receptors. Trends Neurosci 20:92-98, 1997.