There is truth in the testimony by smokers that the nicotine in tobaccoimproves their memory and enhances their learning ability. Thesefindings, however truthful, are of course anecdotal.

To test the molecular basis of nicotine's cognitive effects, Frenchneuroscientists have created a mutant mouse model, minus one of thekey receptors in the brain that specifically activate nicotine, inhaledor injected .

Today's Nature carries their report, titled "Abnormal avoidancelearning in mice lacking functional high-affinity nicotine receptor inthe brain." Its first author is Marina Picciotto, a post-doctoralmolecular neurobiologist at the Pasteur Institute in Paris.

By gene-knockout methods, she and her co-authors raised apopulation of rodents unable to synthesize neuronal nicotinicacetylcholine receptor a2. This high-affinity molecule, Picciottoexplained to BioWorld Today, is the one of nine known receptorsubunits "that we thought would cause the greatest deficit in thenicotinic system."

She and her co-authors sent their a2-minus knockout mice to memoryand learning school, along with cohorts of normal animals.

Spatial Memory 101 consisted of a mouse-size swimming pool, filledwith milky water, and deep enough to require that the animals swimto keep their snouts above water. Below the opaque surface was aledge or platform on which a mouse could relax and breathe easy _if he found it.

Remembering How To Find The Toe-Hold

Along the walls of the pool, in plain view, were 3-D cues pointing tothe location of this invisible foothold. The quiz consisted ofmeasuring how long it took each category of mouse to memorizethese signposts.

"In fact," Picciotto reported, "our mutant knockout animals provedcompletely normal on that test. They learned just as fast as their wild-type brothers and sisters did."

Once the murine models passed Spatial Memory, they graduated toPassive Avoidance. This consisted of a two-compartment box, oneilluminated, the other dark. "When we put a mouse in the lightchamber," Picciotto explained, "being a nocturnal animal, it doesn'treally like the light, so it runs into the dark compartment."

There, it promptly gets a mild but memorable electric shock to thefeet. "Then" she continued, "we take it out and immediately inject adose of nicotine."

Now came the final exam, grading the performance of four mousecohorts: Two normal wild-type groups, (i.e., with intact a2receptors), one of which got a post-shock bolus of nicotine, and twoa2-minus knockout groups, of which one received the nicotine fix.Here is their report card:

Twenty-four hours later, when all four groups of mice were returnedto the light-dark testing set-up to see what they had learned, thosewho got nicotine avoided the dark chamber longer than animals notinjected with nicotine.

"The normal untreated animal will have learned," Picciottoexplained: "`Uh-oh. It's not good to go into the dark. I have to avoidthe foot-shock.'" She added, "If we inject that normal animal withnicotine, it will avoid the shock area even longer. Let's say itsmemory of that event improved."

A a2-minus knockout mouse injected with nicotine will show noeffect at all. It avoids the shock for the same amount of time as itsnon-nicotine litter mate.

"That's an important finding," Picciotto underlined, "because now wesee that the effect of nicotine on this cognitive test is passing througha receptor, namely, nicotine's a2."

"Even more surprising," she observed, "was that mutant mice givenno nicotine avoid the shock longer than a wild-type animal." As theknockouts have exactly the same pain thresholds as normals, thebottom line "does seem to be a difference in memory."

These preliminary behavioral results suggest to the Pasteurneuroscientists "that the nicotinic receptor has a role in events such asmemory and cognitive processes." This means, Picciotto pointed out,"that we now have a model system where we can test the role of thehigh-affinity receptor in various behavioral trials."

What does the nicotine receptor in the brain do for non-smokers?

"That's exactly what we're trying to find out." Picciotto replied."One thing that's very clear now is that its primary role is tomodulate other systems. With nicotine we can modify how much ofanother neurotransmitter _ such as dopamine, or GABA [g-aminobutyric acid] or glutamate _ is released by a neuron."

Short-Run Gain, Long-Run Loss?

She hypothesized, "if you can up-regulate and down-regulate thenicotinic system, that's how you would modify a synapse, andperhaps get learning."

Her behavioral experiments suggest that nicotine does enhancememory, at least in the short term. "It's not clear that smokers over along term are increasing their memory," she observed. "It may in factbe decreasing the over-all function of the system, and therefore youneed more nicotine each time to get it back to normal levels. That's abig debate."

Besides behavioral testing, Pasteur's nicotine-receptor knockoutmutants may prove useful in discovering drugs to treat memory lossin senile dementias, including Alzheimer's disease.

"In these dementias," Picciotto pointed out, "there is a reduction ofabout 50 percent in high-affinity nicotinic binding sites. And wedon't know what role this plays in those disorders.

"Now we have a system with 100 percent reduction, in which perhapswe can test pharmaceutical agents that might be used to compensatefor that lack of nicotine binding in humans," she said. n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.