The straight dope on rational drug addicts

Crack, dope, ice…One hit, and you’re hooked for life.

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Meth: one strike you’re out? Source: http://heisenbergchronicles.tumblr.com/

That’s what the war on drugs has been telling us for years. And for a while neuroscience seemed to back it up. Drugs of abuse stimulate our dopaminergic reward centers, causing a surge of dopamine efflux that changes synaptic transmission, “rewiring” the brain to create intense feelings of craving and drug-seeking behaviours. Lab rats hooked on cocaine will keep pressing a lever for another hit, eschewing food and rest until they die. Addicts beg and steal, enslaved to their drug of choice with a relapse rate as high as 97%.

But 80-90% of people who use methamphetamine and heroin don’t get addicted; not all ex-addicts relapse. In an unpopular series of studies, collectively called “Rat Park”, rats turned their noses at free-for-all morphine, preferring instead to socialize with their rat buddies in an enriched environment.

“Drugs have the power to rob us of our free will” – is this scientific fact, or social-politically construed caricature?

Hart, CL (2000) Alternative reinforcers differentially modify cocaine self-administration by humans. Behavioural Pharmacology. 2000; 11:87-91

The authors recruited 6 experienced crack cocaine smokers, and watched how they responded when offered a choice of between pharmaceutical grade cocaine versus a $5 monetary voucher, or a $5 merchandise voucher which can be used at local stores. In other words, they were offered drugs or an alternative award.

The volunteers were invited to stay at a Clinical Research Facility with TVs, radio and movies for entertainment. They had free access to cigarettes when not in session, but weren’t allowed “extra-curricular” doses of cocaine. At the start of each experimental session, researchers presented the addicts with a voucher indicating what the alternative award is. Addicts then pressed the spacebar a keyboard to “work” for a hit of cocaine, while blindfolded so that they couldn’t tell the dose.

In the subsequent trials, addicts had the freedom to choose to get the same dose of cocaine as the sample trial. But they were also offered an alternative reward: in the first four sessions, it was 5 bucks hard cash; in the last four, a voucher worth 5 bucks which they could trade for merchandise.

As you can see below, at lower cocaine doses (0 and 12mg), addicts choose to receive the voucher (black) or the money (white) more than half of the time. At higher doses though, addicts lusted after the cocaine hit 4-5 times out of the 5 trials.

Screen Shot 2013-09-18 at 9.13.48 PMWhen researchers pool all the data at various cocaine doses together, they found that out of the available 20 doses of cocaine, the addicts requested to smoke 2 doses LESS when cash was available compared to when merchandise vouchers were available. In other words, cash is a more competitive alternative reward. However, because the study did not include a condition where the participants smoked cocaine without the availability of either voucher, it’s impossible to say in absolute terms how much either the $5 or voucher decreased cocaine self-administration.

All the users in the study were kept abstinent except during the trial, except for that one tease at the start of each session. According to popular beliefs, that should have triggered insane cocaine cravings and driven them to choose the drug in subsequent trials regardless of dosage. When given an alternate to cocaine, the addicts were capable of deciding that a low dose wasn’t “worth it”. They made a rational choice. Presumably the effect size would’ve been larger if the monetary reward was higher  – this was indeed the case in a follow-up study with meth addicts, when the monetary reward was upped to $20.

The study is not without its faults. First, it suffers all the problems of small sample size, especially generalizability. Second, the addicts had to work for cocaine, while the alternative reward was readily available (albeit one can argue whether pressing a space bar several times can be counted as “work”). I would’ve loved to know what would’ve happened if they were offered the money first, then given the choice to keep it or spend it on a hit in the lab? And what did the addicts DO with the money after the study – did they use it to buy more drugs?

Nonetheless, the author of this study stresses that neuroscience has a lot to loose by caricaturizing addiction as the “one-hit you’re done” boogeyman – it essentially takes out all social-economic factors, and solely focuses on the drug’s pharmacology. This is understandable in one sense – studying drugs in a sterile lab out of context is simple – but perhaps a more useful approach is to understand why some, but not others, get hooked for life. The personal traits and environmental influences that bias someone towards drug addiction are mainly still unknown, though individual differences in cognitive control and early-life stressors definitely play a role.

As Mind Hacks eloquently puts it:

“Nonetheless the research does demonstrate that the standard ‘exposure model’ of addiction is woefully incomplete. It takes far more than the simple experience of a drug – even drugs as powerful as cocaine and heroin – to make you an addict. The alternatives you have to drug use, which will be influenced by your social and physical environment, play important roles as well as the brute pleasure delivered via the chemical assault on your reward circuits.”

Head over there if you’d like to read more about Rat Park and the complexity of addiction.

Hat tip to @Scicurious for news on the lead author of this study, Dr. Carl Hart, who has a book out on the topic – looks like an interesting read.

ResearchBlogging.org
Hart CL, Haney M, Foltin RW, & Fischman MW (2000). Alternative reinforcers differentially modify cocaine self-administration by humans. Behavioural pharmacology, 11 (1), 87-91 PMID: 10821213

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Dopamine crescendo marks the path to reward

You’re navigating the convoluted aisles of an ethnic market, heart pounding, hoping that it’s there. Suddenly, you see it – that beautiful bag of rare, powerful, soul-shakingly delicious coffee beans that you’ve been craving for years.

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Source: Niv Y 2013 Nature  doi:10.1038/500533a

While you grab the bag weeping in joy, your brain is busy learning. Striatal dopamine-secreting neurons fire in unison, forming a single clear-cut message that is broadcasted across reward-related circuits to signal “pleasant surprise (score!)”. In technical terms, “surprise” is just a reward prediction error, or the difference between the reward we expect and the one we actually get. Since the action of going to the market INCREASED the future expected reward (sipping on a cuppa joe), phasic dopamine firing signal a positive reward prediction error that strengthens this action, telling you to return for more. You learn.

However, life’s not always so straightforward. From bean to coffee, we navigate many steps – grinding, measuring, heating, brewing – before we finally cup the reward in our hands. Herein lies the conundrum: which one of these (often) inseparable actions do we attribute the reward to? How can spurts of dopamine – which signals the unexpected – teach us that EVERY step is crucial? How do we know that we’re getting close to the final goal?

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How do we attribute reward to each step? Can you guess? Source: Niv 2013 Nature doi:10.1038/500533a

Mark W. Howe (2013) Prolonged dopamine signalling in striatum signals proximity and value of distant rewards. Nature. 500; 575-579.

The answer may lie in a couple of chocolate-craving rats. Researchers measured dopamine levels in the striatum of rats, as they navigated a simple left-or-right choice T-maze to hunt down their reward – chocolate milk. Some trials started with a clicking sound, signaling to the rats that the reward is available. As standard dopamine-dependent learning theory would predict, the authors should see a dopamine spike at the click (“cue”) or at the delivery of reward – this is indeed what they saw. But something more intriguing also showed up. As you can see below, dopamine levels gradually crept up as the rats set off, increasing steadily until they reached their prize. Dopamine levels didn’t differ between right and wrong choices BEFORE rats got their award, but diverged after they got the treat.

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Dopamine spikes right after the cue (click), then gradually ramps up as the rat navigates the maze, terminating when they reach their goal. Source: Extended Fig 4

What is this ramp encoding for? Perhaps it acts like a stopwatch, tracking how much time had elapsed since the start of the trial? Or maybe it tells the rat how close the reward is, like hikers urging themselves on just before the summit? Or it could simply be the sum of countless transient dopamine spikes reflecting fixed “checkpoints” in the maze, letting the rat know that it’s on the right path.

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Left: Peak dopamine levels are the same regardless of trial length. Right: But it did correlate with how close the rats were to the goal. Source: Fig 2

To tease out the answer, researchers looked at how ramps changed with elapsed time, distance and the magnitude of the reward. As shown above, peak dopamine levels didn’t change with trial length, nor did it correlate with how fast the rat accelerated or their running speed. However, it DID predict how spatially close the rat was to the reward, relative to the total length of the run. For example, although rats had to run further to get to their treat in the M-maze as compared to T-maze, their final dopamine levels were the same, with the ramp in the M-maze stretched out to cover the entire running trial (it’s almost as if dopamine is shouting “you’re at the half-way point!” regardless if you’re running 1km or 1 marathon). In other words, the ramp may be interpreted as reward anticipation or expectation – “hey I’m close!” Indeed, when the rat paused to think and rest, the signal showed a transient dip, which picked up when the rat once again took off.

Just like transient spikes, the SLOPE of dopamine ramps also reflected the value of the anticipated reward – the bigger the reward, the larger the slope. When researchers teasingly swapped the location of two rewards of different values in the T-maze (left arm in the bottom graph first, then right arm), the ramps also shifted, so that the slope was still larger for the bigger reward, even though it was in the opposite position.

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Red= more dopamine, blue= less. Reward was first in the left arm (left two graphs) but switched to the right arm (right three graphs). See how there’s more dopamine in the right arm after the shift?

Even more surprisingly, the ramps didn’t disappear as the rats became well versed in the task, hinting that they weren’t encoding for reward prediction errors, as the element of surprise would surely have disappeared with repeated trials.

So in sum, ramping dopamine signals seem to be tracking how well you are doing in a lengthy task. How does this fit into the theory of dopamine-mediated reward learning? Well, it doesn’t. The ramps are highly consistent and predictable, hence according to the theory they should disappear – but they remained observable even after rats learned to predict the reward. They also didn’t correspond to another way of dopamine signalling – background “tonic” dopamine – which is thought to dictate how vigorously one should pursue their goal.

Instead, the authors hypothesized that these dopamine ramps may work “behind the scenes”, actively directing motivation and attention to a previously correct choice when multiple options are available (“should I go left or right?”). This way, they may maintain and promote long-term actions that will eventually lead to predicted rewards (“go right, that’s what I did last time to get the chocolate”). Without sufficient sustained dopamine ramping, we may be easily distracted and venture off the beaten track, wobbling away from the ultimate reward.

It’s a very believable theory, albeit just that. There’s no causative evidence in the data to support the hypothesis – that’s left for future studies. I find it incredible that dopamine ramping has never been seen in previous studies involving tasks requiring a series of actions. Is it because other studies directly recorded dopaminergic cell responses, while this study measured dopamine with fast-scan cyclic voltammetry? Or are dopamine ramps only observable for spatial navigation? Does it generalize to any type of extended work? What is the mechanism that’s generating the dopamine ramp? How does it relate to the “classical” tonic and phasic dopamine firing, ie can changes in one influence any of the others? Does it exist outside the striatum? Can it be manipulated to influence stimulus-reward learning?

And a naïve one for the computer scientists out there: does the discovery of dopamine ramping help with the problem of credit assignment in reinforcement learning algorithms?

ResearchBlogging.org
Mark W Howe (2013). Prolonged dopamine signalling in striatum signals proximity and value of distant rewards. Nature, 500, 575-579 DOI: 10.1038/nature12475

Is the taste of beer dangerously intoxicating?

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Me adhering to Asian stereotypes after pouring my first pint of beer bartending.
It looks pretty pathetic, I know 😛

Last Friday around lunch break, sweating profusely on the way back to lab, I was suddenly struck by an irresistible urge to chug a cold fizzy beer. Crisp! Grassy! Bubbly! The punchline? Due to a genetic inability to metabolize alcohol, I stick to the extra lights (I know, I know). To me, beer is intoxicating even without apparent alcohol intoxication.

And the culprit that triggers this lust for a sip –or keg- of beer? A new study points to dopamine, a neurotransmitter involved in reward prediction and motivation. In the early stages of drug use, cocaine, meth and amphetamines all trigger a dopamine rush in the brain’s reward system, which induces a sense of high-flying pleasure, power and jazzed-up ENERGY. But the “feel good” molecule has a dangerous side: it also encodes for triggers that lead to the expectation for reward. Hence the theory goes, with each increased pint of beer, the sight, smell and taste of it starts becoming sufficient to trigger a dopamine rush, signalling to us that reward is coming long before the beverage touches our lips. One camp of thought stipulates that these beer-related cues may eventually trigger feelings of wanting and craving, leading to alcoholism in the vulnerable.

Is it possible that the taste of beer, instead of the alcohol it carries, can act as a cue and kick-start the cycle of use, reuse and abuse?

Brandon G Oberlin et al (2013). Beer Flavor Provokes Striatal Dopamine Release in Male Drinkers: Mediation by Family History of Alcoholism. Neuropsychopharmacology 38: 1617-1624

To answer this question, researchers recruited 49 male beer lovers, ranging from the occasional social drinker to the potentially problematic binger. The volunteers were separated into three groups: those with or without a family history of alcoholism, and those who don’t know. Researchers then teased their taste buds (and brain) with a tiny squirt of either their favourite beer or Gatorade – an amount way too small to cause intoxication – while monitoring their brains’ responses to the flavours with Positron Emission Topography (PET) and the radioactive tracer RAC. RAC competes with dopamine released in the brain for binding spots on the dopamine receptor – hence low RAC binding tells us that there’s MORE dopamine around, and vice-versa.

The findings were remarkable straightforward: a taste of beer, but not Gatorade, elicited a desire to drink more beer in all volunteers, regardless of family history. Pooling all of the volunteer’s data together, RAC binding dropped significantly in the right ventral striatum during beer tasting compared to Gatorade tasting, indicating more dopamine release. Unfortunately, the magnitude of dopamine release was NOT related to subjective feelings of wanting to drink beer, how much beer the volunteers drank previously or how much more they preferred beer to Gatorade.

However, as you can see below, the taste of beer did induce larger dopamine release in those with a family history of alcoholism (black bar) compared to those who didn’t (white) or those who didn’t know (grey). The authors hence concluded that the taste of beer (“intraoral sensory properties”, gotta love jargon sometimes), in cahoots with its alcohol properties, might together induce dopamine responses that in turn promote and maintain booze-craving and seeking behaviour.

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Yellow spots indicate areas where dopamine levels changes.

My first non-scientific reaction: has anyone ever become an alcoholic from drinking light beers? How much, if any, does the taste of alcohol contribute to addiction, even in those with bad/vulnerable genetics? Based on this study, I’d say very little. If you look closely at the graph above, the effect size is incredibly small. So small that, when researchers looked at each group separately (not pooled like described above), only people with a history of alcoholism (Family History Positive) showed significant dopamine release after tasting beer.

Next, even though FHP volunteers had larger dopamine release in response to beer, it did not correlate with how much pleasure they felt nor how much they wanted beer afterwards; the neurobiological response did not translate to behaviour. The magnitude of dopamine response also didn’t correlate with how much the volunteers drank on average. Together, the results show that dopamine release in response to a taste of beer CANNOT predict a person’s potential of alcoholism, regardless of family history.

The one solid conclusion from the study is that beer-related cues make you want more beer if you already like beer. (Do we really need science to tell us that?) In some people this is paralleled in time to dopamine release – which we already know from previous studies that used pictures of alcoholic beverages. In fact, the same dopamine response is seen for most rewarding things, such as food and drugs (and maybe even Gatorade!).

Maybe someone should study whether reading about beer-related studies triggers dopamine release in the beer-lovers’ brains.

ResearchBlogging.org
Oberlin BG, Dzemidzic M, Tran SM, Soeurt CM, Albrecht DS, Yoder KK, & Kareken DA (2013). Beer flavor provokes striatal dopamine release in male drinkers: mediation by family history of alcoholism. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 38 (9), 1617-24 PMID: 23588036