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Make mine a triple

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In response to a couple of questions about the implications of long-term caffeine intake, I’d thought I’d throw out a couple of findings.

I recently wrote about a study that localized the receptors underlying the arousing effects of caffeine. (A2a receptors, in cells located in the shell of the nucleus accumbens). It’s only natural then to wonder what effect chronic caffeine intake might have on these receptors (and elsehwere in the brain).

That study didn’t look at chronic effects. But back in 1996, Glass et al. found that chronic caffeine consumption increased the global expression of adenosine receptors in the brain , suggesting that this increase was to compensate for caffeine’s antagonistic effects. Withdrawal from caffeine is, at least in part, likley related to a hypersensitivity to adenosine due to this increased number of adenosine receptors. The headaches that accompany caffeine withdrawal are thought to be related to the fact that adenosine is a known vasodilator and the increased receptor density + withdrawal of caffeine from the system leads to a significant drop in blood pressure.

A couple other interesting notes in regards to long-term effects of caffeine:

The Good News
Some case control studies have shown lower incidents of Parkinson’s disease in coffee drinkers vs. non-coffee drinkers, although this finding has not always been replicated. The correlation, when it has been found, was strongest in heavy consumers. (This is certainly a finding I would love to be true!) More evidence in support of these findings come from mouse studies showing that physiological doses of caffeine were able to reduce one of the major toxic factors associated with Parkinsons (MPTP-induced dopaminergic toxicity). It’s been suggested that caffeine may offer neuroprotective effects in the brain via action occurring at A2a receptors, which are the same receptors responsible for the arousing effect of caffeine (and which are also co-localized with dopamine D2 receptors). Additional support for this idea comes from studies in which mice who had their A2a receptors knocked out showed reduced MPTP-induced injury compared to wild types. How this all might be happening on a mechanistic level, however, is not well known.

The less good (but not totally bad) news:
Unfortunately, it seems that acute doses of caffeine often cause a rise in systolic and diastolic blood pressure, increase in catecholamine release and vasodilation (wideneing of blood vessels). However, some studies have shown this effect occurs primarily in non-regular consumers of caffeine. Many studies have shown either slight increases or no difference in blood pressure for regular users of caffeine. In fact, several large scale studies have found that heavy, regular use is protective against heart disease. (yes!) The findings are quite contradictory.

So what to make of all this? Is heavy coffee drinking bad or good for you?
There’s no simple answer to that question. But the paradoxical findings suggest that different individuals have varying levels of risk. And it’s likely that genetics play a significant role.

If one thinks of coffee as a drug, then the notion that the benefits of heavy coffee consumption might outweigh the risks seems very counterintuitive. That is, due to the brain’s propensity to maintain homeostasis, drug taking, either legal or illegal, usually involves some significant cost/benefit analysis, a trade off between the good (the high, buzz, relief from psychic or physical pain) and the bad (side effects, withdrawal, expense, long-term effects on health). Yet, the evidence on long-term caffeine intake seems to put it in a distinctive class of its own.

I once chatted with an extremely energetic and sprightly 93-year old Italian man from the old country, curious to know the the secret to his longevity and good health. “Five espressos a day,” he said.  Anecdotes aren’t very informative in an empirical sense, of course, but, nonetheless, the old codger may have been on to something.*

* In addition to the  espressos, he’d also claimed that he smoked a pack a day of American Winstons and was convinced that brand loyalty was one of the other secrets to his good health.

Why caffeine jacks you up

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Have you ever wondered why, and exactly where in the brain, coffee (or any caffeinated product, for that matter) is able to exert its arousing effects? Well, wonder no longer, because an international team of researchers from Japan, China and the US, have located the primary neurons upon which caffeine works its magic (Lazarus 2011).

It was previously known that caffeine wakes you up through inhibiting activity at adenosine A2a receptors (adenosine is an inhibitory neuromodulator involved in regulating the sleep-wake cycle). However, it was not known exactly where in the brain the receptors that exerted this effect are located.

How did they do it?
The researchers utilized a method whereby the gene that codes for A2a receptors (A2aRs) is marked such that they can be deleted, but only in a specific regions of the brain. Using a rat model, the team utilized these gene deletion strategies and found that when they knocked out A2aRs in the shell of the nucleus accumbens, rats no longer experienced the arousing effects of caffeine.

How does this work?
Adenosine activates A2a receptors in the nucleus accumbens shell, activation of which receptors inhibit the arousal system. That is, the more adenosine activation there is, the sleepier an organism becomes. Caffeine, which binds to these same receptors and blocks adenosine from exerting its activity there, essentially disinhibits the arousal system, promoting wakefulness. (Amazingly, based on similarities between the brains of mice and men, the area of the human brain in which caffeine acts to counteract fatigue is approximately the size of a pea.)

What does this mean in practical terms? (or, in other words, why should we find this so cool?)

Well, for one, it gives us a more specific mechanistic explanation for the arousing effects of caffeine. It says that in order for caffeine to work, it not only has to be effective as an A2aR antagonist, but that excitatory A2aRs on nucleus accumbens shell neurons must be tonically activated by endogenous adenosine. This is especially important in consideration of individual differences in the subjective effects of caffeine.

What if A2aRs are more densely packed in the shell of your nucleus accumbens than in mine? Might you be more sensitive to the effects of caffeine than me? That certainly seems likely. And the reason that one person might over or underexpress these receptors vs. another seems to be related to variation in the gene that produces those receptors (the gene knocked out in the rat study described above). In fact, we’ve already have evidence that this is the case. Past studies have shown genetic variations in genes coding for A2aRs were associated with greater sensitivity to caffeine and sleep impairment (Retey 2007), and greater anxiety after caffeine (Childs 2008). This study refines the existing model and should inspire, and lead to more accurate interpretation of, future genetics studies.*

*Other significant genes that underly individual differences in the subjective effects of caffeine include CYP1A2, or cytochrome enzyme P-450 1A2, which is associated with caffeine metabolism, and those coding for dopamine D2 receptors.

References
Lazarus M, Shen HY, Cherasse Y, Qu WM, Huang ZL, Bass CE, Winsky-Sommerer R, Semba K, Fredholm BB, Boison D, Hayaishi O, Urade Y, & Chen JF (2011). Arousal Effect of Caffeine Depends on Adenosine A2A Receptors in the Shell of the Nucleus Accumbens. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (27), 10067-10075 PMID: 21734299

Childs E, Hohoff C, Deckert J, Xu K, Badner J, de Wit H (2008) Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology. 33:2791– 2800

Retey JV, Adam M, Khatami R, Luhmann UF, Jung HH, Berger W, Landolt HP (2007) A genetic variation in the adenosine A2A receptor gene (ADORA2A) contributes to individual sensitivity
to caffeine effects on sleep. Clin Pharmacol Ther. 81:692–698

ResearchBlogging.org

Google crosses the web/brain barrier?

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Google, are you reading my mind?

One interesting aspect of having a blog is checking out the search terms that people used to land at one’s site. It’s often difficult to figure out why a particular and seemingly unrelated term might bring someone this way.

But one recent search seems to have transcended the blog and gone straight into my brain-o-sphere, into the existential recess where some of my darker thoughts about grad school are stored:

“PhD meaninglessness”

Google, you know me so well. Now stop it, you’re freaking me out.

Name games

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Research has shown that people’s names influence what professions they choose to enter; for example, men named Dennis are overrepresented among dentists and men named Raymond are overrepresented among doctors who specialize in radiology.

I wonder if guilt about his name is what drove the third author below to study the ill effects of cigarette smoking …


Love in the time of oxytocin research

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Often referred to as the “love drug” or “love hormone”, oxytocin has attracted increasing interest from researchers in recent years. It was originally shown to modulate aspects of social attachment and pair bonding in animals such as the female prairie vole, whose monogamous nature is dependent on oxytocin. Recent research in humans has shown that oxytocin increases trust behavior in economic exchanges and increases perception of trustworthiness in human faces, as well as promoting emotion recognition and altruism. This evidence inspired hopes among some, particularly in the mainstream media, that science might have found a possible pharmacological target for humans who show deficits in prosocial behavior.

But recent evidence has complicated the narrative a bit.

Research has shown that oxytocin plays a role in increased emotional reactivity to both positive and negative social cues. For example, one study from 2009 (Shamay-Tsoory et al) had participants engage in a game of chance with another player (the actor). In one condition, the actor was made to win more than the participant, evoking feelings of envy in the participant. In another condition, the actor was made to lose more than the participant, evoking feelings of “schaudenfrude” or gloating. Participants who were administered oxytocin before playing showed increases in both envy and schaudenfrude (if oxytocin was involved only in enhancing prosocial behavior, we would expect to see the opposite result.) Other research has shown oxytocin increased approach behavior or affiliative drive rather than regulating positive or negative responding per se. And one recent study showed that oxycotin led humans to self-sacrifice for their own group while showing increased aggression toward out-group members. The gist of this set of findings is that oxytocin doesn’t seem to bias individuals toward the positive, but rather can magnify whatever “stimuli” happens to be in someone’s attentional spotlight, be it bad or good, thereby generating an increase in corresponding positive or negative emotional responses.

Jennifer Bartz and colleagues (2010) were curious to explore whether oxytocin could “correct” deficits in pro-social behavior in individuals with borderline personality disorder (BPD), a population famous for emotional instability, extreme impulsive behavior and identity confusion. People with BPD tend to be involved in intense, emotionally volatile relationships characterized by frequent arguing, repeated breakups and extreme aggression. This behavior often extends beyond their romantic relationships, as BPD individuals have also been shown to have difficulty cooperating with strangers. The existing body of research, Bartz et al suggested, offers up contrary predictions. On the one hand, oxytocin could be helpful in reducing the negative behaviors normally associated with BPD in favor of kinder, gentler behavior towards others. Alternatively, oxytocin might have increasingly negative effects for people with BPD, who are chronically concerned with (lack of) trust and abandonment and have difficulty cooperating with others. They’re essentially fixed in a constitutively negative state when it comes to social interactions and increased oxytocin could decrease prosocial behavior even further. Additionally (or alternatively), the oxytocin system might be dysregulated in BPD and could produce different responses (vs. control) to oxytocin as a result.

Bartz and company designed an experiment in which the participant was paired with a partner (in reality, a virtual “computer” partner) to engage in an economic game. In this game, the participant was to make one of two choices that involved financial rewards. The catch was that the amount of the reward was also dependent upon the choice that their “partner” made.

Both players clearly make the most money if they both choose strategy A. But because the player has to make the choice before the partner, the decision involves an element of trust (if your partner defects, you get nothing. If your partner trusts you and you defect, you get $4 and she gets nothing.)

So, what did they find?

Results showed the following:

1. BPD people trusted their partners in an economic game less after they received oxycotin than when they received a placebo.
2. Additionally, when asked if they would be more likely to make a hypothetical decision that would punish their partner, even when they knew their partner had extended trust toward them, they were more likely to punish after Oxytocin than placebo.

Administration of oxytocin to BPD individuals actually decreased pro-social behavior (and increased antisocial behavior). As the experimenters suggest, increasing the salience of a social cue that makes trust issues salient may have caused BPD participants to rely on their normal strategy for trust-dependent social interactions; that is, defect and punish the partner. Or it might have motivated approach/affiliative behaviors which triggered memory of past experiences gone awry and set off chronic and ever-present concerns about trust and rejection (e.g. “reject and punish them before they can do the same to me.”). Finally, the experimenters suggest the possibility that the oxytocin system itself may be dysregulated.

In short, the evidence doesn’t offer overwhelming support for the notion that exogenously-administered oxytocin will be a useful clinical treatment for people with pro-social deficits, such as those with BPD. Additionally, it’s difficult to imagine long-term benefits of oxytocin given that it’s half life when administered intranasally is only about three minutes. It’s been said that the most of the real action with regards to oxytocin is on the receptor end.

References:
Bartz, J., Simeon, D., Hamilton, H., Kim, S. Crystal, S., Braun, A., Vincens, V., & Hollander, E. Oxytocin can hinder trust and cooperation in borderline personality disorder. (2010). Social Cognitive & Affective Neuroscience

Shamay-Tsoory SG, Fischer M, Dvash J, Harari H, Perach-Bloom N, Levkovitz Y (November 2009). “Intranasal administration of oxytocin increases envy and schadenfreude (gloating)”. Biological Psychiatry 66 (9): 864–70.