Good News for Rat Psychiatry

"Nicotine Exposure During Adolescence Induces a Depression-like State in Adulthood" is the title of a study published by Bolanos et al (the fruity looking guy to the right, 1).

The summary over at Sciencedaily is titled "Teen Smoking Could Lead To Adult Depression, Study Says" (2).

As you can see in the picture, Ms..err..Mr. Bolanos is pictured with a group of rats and not with Jonas Brothers. However, the title of his study, plus the conclusions he and his colleagues draw, lead you to believe that they are referring to actual people.

"Carlos Bolanos and a team of researchers found that nicotine given to adolescent rats induced a depression-like state characterized by a lack of pleasure and heightened sensitivity to stress in their adult lives. The findings suggest that the same may be true for humans." Actually, nothing in this study suggests that same may be true for humans.

Why is that? Because they studied rats.

You mean Harry Reid and Nancy Pelosi?

No, I mean members of the genus Rattus; Reid and Pelosi are members of Desmodus rotundus (3).

The rats were injected with "either nicotine or saline for 15 days. After the treatment period ended, they subjected the rats to several experiments designed to find out how they would react to stressful situations as well as how they would respond to the offering of rewards."

The said stressful situations included: running in an open field, running in a maze, and forced swimming. The reward paradigm was the administration of sucrose. Clearly, this screams ecological validity.

"The rats that were exposed to nicotine engaged in behaviors symptomatic of depression and anxiety."

Adding, "the researchers were able to alleviate the rats' symptoms with antidepressant drugs or, ironically, more nicotine." Okay, that last sentence was just plain stupid. Perhaps these people need a primer on the neurobiology of nicotine.

The average cigarette contains approximately 6-11mg of nicotine. However, when smoked, only 1-3mg reaches the circulation (the rats were given .32mg/kg twice-a-day, which seems excessive for an animal that weighs 250g. Studies I have read usually dose rats with 10 μg/kg). The half-life (amount of time it takes for half of the drug to be excreted) is typically around 2 hours. Because of the short-half life, a characteristic withdrawal syndrome (e.g., anxiety) begins rather quickly.

Here's the rub, when nicotine is re-administered, those symptoms disappear. There is nothing ironic about it. Secondly, the antidepressnat used in the study (bupropion) is a dopamine (DA) reuptake inhibitor. As fate would have it, nicotine leads to a transient increase in DA. I think these researchers were treating withdrawal, not a "depression-like state."

I know the withdrawal syndrome can be characterized as a "depression-like state," but they are passing this off as if its actual depression, which it's not.

Why isn't it? Two words: animal model.

Here's the problem with animal models of depression (or any other psychiatric disorder). Whereas many diseases can be considered at a molecular level, mental illnesses lack such pathophysiological understanding and are reliant upon lame and nonspecific syndromal classifications (e.g., DSM-IV-TR), which renders animal models as less valid.

For those not in the know, construct validity (as it relates to animal models) is "the accuracy with which the model replicates the key abnormalities or phenomena under study within the clinical condition" (4). Another important aspect of depression animal models is its predictive validity, the "given model's ability to correctly identify effective antidepressant treatments, usually drugs." Clearly, that hasn't happened yet (4, 5, 6).

As it relates to our good ol' friend agent 296.3 ( AKA Major Depressive Disorder), "there are no symptoms, nor any other clinical features, that are pathognomonic for depression. Assumed 'core' psychopathological phenomena such as a blunting, or absence of the capacity to experience pleasure (anhedonia), can also present as a common clinical feature in substance misuse and schizophrenia" (4).

Here is what the "depression-like state" in those rats looked like, "repetitive grooming, decreased consumption of rewards offered in the form of sugary drinks (supposedly an analogue to anhedonia), and becoming immobile in stressful situations instead of engaging in typical escape-like behaviors."

It's very similar to human depression as you can see. Also, the authors admitted that "the effect size of nicotine on sucrose preference (the anhedonia analogue), though statistically significant, is small, and that nicotine did not influence total sucrose intake" (1).

As should be obvious, many of the symptoms of depression are quite difficult to model in animals (e.g., suicidal ideation). What is suppose to be science is actually an exercise in logic, "arguments for the validity of animal models rely on Causal Analogical Models (CAMs)" (4).

What!?

"These CAMs are underpinned by Casual Analogical Reasoning."

WTF!?

I have no idea either; but I think I made my point.

The reasoning goes like this: 1) Animal A is similar to animal B, with regards to properties 1, 2, and 3; 2) Animal A has property 4; 3) Therefore, animal B has property 4.

As it relates to depression, part 1 assumes that rats and humans are identical, which we are not, therefore assumptions 2 and 3 don't hold.

So why did Ms. Bolanos conclude his interview with this, "The message to young people of course is don't smoke and don't even try it, if they do smoke, they need to be aware of the potentially long-term effects that recreational or even occasional cigarette smoking can have on their systems."

Answer: He's an idiot.

By "long-term", he means one month, which is apparently how long it takes an adolescent rat to become an adult rat? (not my area of expertise). What I do know is this: Smoking cigarettes actually acts as an inhibitor monoamine oxidase A and B (7). This effect is not produced by the administration of pure nicotine, it's caused by other compounds in cigarette smoke. This means that cigarettes are actually MAOI's, which can be used to treat depression. If nicotine causes a "depression-like state," then cigarettes can counteract that "depression-like state."

So my message to young people of course is do smoke or at least try it. And while you're at it, blow smoke in a baby's face (8).



Sergio D Iñiguez, Brandon L Warren, Eric M Parise, Lyonna F Alcantara, Brittney Schuh, Melissa L Maffeo, Zarko Manojlovic, Carlos A Bolaños-Guzmán (2008). Nicotine Exposure During Adolescence Induces a Depression-Like State in Adulthood Neuropsychopharmacology DOI: 10.1038/npp.2008.220