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Tests correlate biochemical abnormality with deficits in rats' responses to sounds.

April 01, 2009

Some children of women who smoked during pregnancy experience subtle difficulties processing auditory information; for example, they may have more than average problems recognizing slightly garbled words or understanding speech in a noisy environment. A recent series of animal experiments indicates that the cause of the problem is not in the ear but in the brain: Nicotine exposure during development damages a set of receptors in the brain's auditory processing center.

line graphs showing reduction in auditory response as described in caption  Nicotine Exposure During Development Alters Auditory Response: Normal rats rely on nicotinic acetylcholine receptors in the auditory cortex to process auditory information. Rats exposed to nicotine shortly after birth have damaged nicotinic acetylcholine receptors and develop compensatory sound-processing mechanisms. As a result, blocking the receptors with mecamylamine reduces auditory cortex responsiveness dramatically in normal rats, but only slightly in rats exposed to the drug as pups.

Hearing Versus Heeding

The NIDA-funded experiments first demonstrated a deficit in sound processing in rats that had been exposed to nicotine at a developmental stage corresponding to that of a human fetus in the third trimester of gestation. Dr. Raju Metherate and colleagues at the University of California, Irvine, began by injecting rat pups with nicotine twice daily for 5 days (postnatal days 8 to 12). The injections produced nicotine blood levels approximating those of smokers, and presumably of pregnant smokers' fetuses. A group of same-aged control rats received injections of saline.

When the rats were 2 months old, a researcher trained them to escape an electrical shock by crossing from one chamber of an experimental box to another. The next day, a 5-second tone preceded each shock. All the animals immediately turned their heads toward the tone, indicating that they had heard it. Over 4 days, the rats had the opportunity to learn that the tone signaled an impending shock.

By the end of the training, all but one of the 12 control animals had learned the lesson well enough to routinely avoid the shock by crossing into the safe chamber during the tone. These animals moved to the safe chamber more rapidly as time went on, and eventually, many went into the safe chamber as soon as the tone began. Just 6 of the 11 rats exposed to nicotine, however, learned to associate the tone with the shock, and they responded more slowly than the control animals. The remaining 5 nicotine-exposed rats moved to the safe chamber only after receiving the shock.

A Less Responsive Cortex

The UC-Irvine researchers' next experiment linked the nicotine-exposed rats' poorer responses to warning tones to a difference in the animals' brains.

The auditory cortex is the brain's primary area for interpreting sounds. Normally, nicotine amplifies the cortex's responsiveness to auditory inputs. Researchers measure this effect by comparing electrical activity levels in the cortex before and after an injection of the drug.

Using this protocol when their rats were 2 to 3 months of age, Dr. Metherate's team documented smaller increases in cortical activity levels, on average, in the animals with early exposure to nicotine than in the control animals. Among adult rats not exposed to nicotine as pups, a stronger auditory cortex response to nicotine at 2 to 3 months of age correlated with faster and more accurate learning to associate sound with electrical shocks. These observations may provide a hint why rats' early nicotine exposure leads to later difficulty using warning tones.

Underdeveloped Receptors

The researchers next investigated the underlying mechanism for their nicotine-exposed rats' diminished cortical responsiveness. The findings indicated that nicotine exposure during early development prevents a key receptor in the brain's acetylcholine signaling system from achieving full functionality.

Nicotine binds to the same receptors as acetylcholine, a chemical that neurons in the auditory cortex and elsewhere use to transmit electrical excitation to neighboring neurons. "When nicotine or acetylcholine binds to a receptor on the surface of a nerve cell, the binding process sets off chemical reactions inside the cell that help the cell function properly and fulfill its special physiological role," Dr. Metherate says.

The researchers measured electrical activity in the auditory cortex before and after injecting 2- to 3-month-old rats with mecamylamine, a compound that shuts down the nicotinic acetylcholine (nACh) receptors. The injection markedly reduced electrical activity in normal rats but made little difference in the rats that had been exposed to nicotine shortly after birth. This finding indicates that their nACh receptors were ineffective.

"Somehow, early nicotine exposure disconnects the receptors from the inside of the cell," Dr. Metherate says. "Acetylcholine and nicotine bind to the cell surface, but no chemical reactions take place in the interior."

New Role for a Neurotransmitter and Its Receptor

Researchers have discovered a novel function of the nicotinic acetylcholine (nACh) receptor: It influences the propagation of signals along an axon.

Previous research had revealed nACh receptors along the myelinated axons that carry signals from the thalamus—a sensory processing center—to the auditory cortex. The new work, by Dr. Raju Metherate and colleagues Drs. Hideki Kawai and Ronit Lazar, at the University of California, Irvine, indicates that both nicotine and normally occurring acetylcholine activate nACh receptors along these axons, thereby increasing the effectiveness of a signal. This influence is distinct from the known mechanisms of acetylcholine activity at synapses.

"The regulation of axon excitability offers a powerful mechanism to control signal propagation," says Dr. Metherate. This action, he notes, might underlie nicotine's effect on the response of the auditory cortex to sound. However, that effect seems to be specialized. The team has recently found evidence that nACh receptors are not present along many other axons in the nervous system.


Kawai, H.; Lazar, R.; and Metherate, R. Nicotinic control of axon excitability regulates thalamocortical transmission. Nature Neuroscience 10(9):1168-1175, 2007. [Abstract]

A Clue and a Caution

Because human and rat brains process sounds similarly, the UC-Irvine findings may relate to the problems that people prenatally exposed to nicotine have interpreting sounds, and the experimental results may provide a clue to effective treatments as well. "If we can figure out how to reconnect the receptors to the activity inside the cells, we may be able to reverse these auditory-cognitive deficits in children, adolescents, or even adults," Dr. Metherate says.

He adds that nACh receptors also play a role in the development of other parts of the brain, including cortical areas that process vision and touch. So, prenatal nicotine exposure may undermine brain activity in those areas as well.

"Even though Dr. Metherate's rats were exposed to nicotine for only 5 days, the damage to their brains was long-lasting," says Dr. Thomas Aigner of NIDA's Division of Basic Neuroscience and Behavioral Research. "This is important information for women who think that smoking only intermittently during pregnancy is safe for the fetus. If they smoke during a critical period of brain development, in this case a few days into the third trimester, it looks as though the nicotine exposure can produce serious and long-lasting damage."


Liang, K., et al. Neonatal nicotine exposure impairs nicotinic enhancement of central auditory processing and auditory learning in adult rats. European Journal of Neuroscience 24(3):857-866, 2006. [Abstract]

Liang, K., et al. Nicotinic modulation of tone-evoked responses in auditory cortex reflects the strength of prior auditory learning. Neurobiology of Learning and Memory 90(1):138-146, 2008. [Abstract]