A Small Dose of Addiction

The following is my entry for the Pembroke College Peter Clarke Science Communication prize.

What is Addiction?

Superb question! Addiction could mean lots of things to lots of people. However, I shall talk to you about addiction in the context of substance abuse, as opposed to behavioural addictions like gambling, and I shall only talk of the neurobiology behind it.

So first things first, how do we know when the use of a substance goes from ‘recreational fun’ to full-blown addiction? The Diagnostic and Statistical Manual of Mental Disorders has the answers you require. According to the manual, you are declared an addict when:

1) You have impaired control over the substance (failing to give up cigarettes every New Year).

2) Your use of the substance leads to social impairment (taking speed instead of attending your niece’s christening).

3) Your use of the substance is risky (taking your morning hit of heroin with a dirty needle before starting your job as a pilot).

4) Pharmacological effects such as tolerance, withdrawal and dependence to the substance become apparent.

In 2013, the Centre for Social Justice calculated that alcohol abuse costs UK taxpayers £21,000,000,000 a year and abuse of other substances £15,000,000,0001. They also estimated that there are 1,600,000 people dependent upon alcohol and 300,000 drug addicts in the UK alone. So addiction is a big deal (I also say this to justify my studentship).

Let’s talk about Drugs

The thing that ‘drugs’ or, to use a less ambiguous term, addictive substances have in common is that they are psychoactive. A psychoactive substance is one that can alter signalling in the brain and spinal cord to cause changes in mood, perception or consciousness. You are probably under the influence of a psychoactive substance just now: the caffeine in your coffee, the alcohol in your beer, the MDMA in your ecstasy.

Caffeine I can take or leave, but my Meth use is becoming a bit problematic

It is clear that some psychoactive substances are more prone to abuse than others. Although caffeine drinkers may develop withdrawal symptoms of headaches and agitation if their coffee is withheld, they do not put their health, friendships and jobs on the line just for another sip of Starbucks in the same way a cocaine addict is. Why some substances are addictive and others are not appears to boil down to which signals in the brain substances are acting on.

Diagram of a synapse

Neurons transmit binary (on or off) electrical impulses down their length. The impulse reaches the end of the neuron (presynaptic neuron) where there is a gap separating the neuron from, potentially thousands of, other neurons (postsynaptic neurons) it can be functionally connected to. The electrical impulse cannot jump the gap (synaptic cleft) between neurons, so the neuron instead releases a chemical (neurotransmitter), which can travel across the gap. Once on the other side, the neurotransmitter then communicates with the postsynaptic neuron(s) via receptors on the surface of their membrane. You can think of neurotransmitters as molecular postmen and receptors as letter-boxes. The combination of neurotransmitter and receptor then tells the postsynaptic neurons to either send an impulse or not to. Neurotransmitters can remain in the synaptic cleft and keep binding to their receptors, passing their message on until the neurotransmitters are removed. To remove neurotransmitters and stop impulses from being continually generated, the neurotransmitters can either be ‘hoovered’ up by a reuptake transporter, or broken down by enzymes in the synaptic cleft. You can breathe now; that’s the conceptually hard part done.

Molecular structure of dopamine

Substances with the highest potential for abuse directly or indirectly cause large increases in levels of the neurotransmitter called dopamine in the synaptic cleft. This can be done either by blocking the reuptake of dopamine from the synaptic cleft (cocaine), stopping neurons from telling dopamine-containing neurons not to release dopamine (heroin) or directly stimulating dopamine-containing neurons to release dopamine, and then competing with dopamine to be transported back into the neuron (amphetamines). This means when under the influence of an addictive substance there will be more dopamine released per presynaptic impulse and/or dopamine will hang around in the synaptic cleft longer than usual. This has the effect of amplifying every dopamine signal since the postsynaptic receptors will be activated many more times. For instance, instead of one impulse in the presynaptic neuron causing one impulse in the postsynaptic neuron, it can now trigger potentially hundreds of impulses long after the presynaptic neuron has stopped sending its signal.

What makes dopamine unique?

Other psychoactive drugs can and do boost the signals of other neurotransmitters (glutamate, acetylcholine, GABA). However, these substances carry little risk of addiction. The differences stem from which processes these neurotransmitters are involved in. Dopamine is involved in learning, memory and, perhaps, pleasure2.

Okay, but why would that be addictive?

Now you are asking the juicy questions! I have a copious number of theories from throughout history for you to deliberate on, but I’ll narrow it down to three for relevance and your reading pleasure:

1)      Moral Failure

Alternatively, “You’re an addict because you’re sinful”. This was the leading theory for a considerable amount of history3. With the discovery of dopamine and its role in signalling ‘pleasure,’ this theory morphed into “Hedonic Dysregulation”3 or less succinctly “Getting high is divine, and everything else in life pales in comparison because it doesn’t give me as big a dopamine hit in my pleasure systems.”

The emphasis in hedonic dysregulation is that the substance abuser is making rational choices about how to maximise pleasure, and therefore choosing to continue to take substances. Yet addicted individuals consistently report they no longer find their substance(s) of choice as pleasurable as when they first started. This theory also does not explain how those who want to quit can’t, one of the hallmarks of addiction4.

2)      Withdrawal-Induced Relapse

Alternatively, “This hangover is literally the worst, give me more drugs to fix this”. The essence of this theory is that the effects of a drug come-down and reduced dopamine signalling create a very unpleasant state that addicted individuals learn to avoid5. This theory argues that the addicted individuals learn that continued substance use is a much more attractive option than dealing with drug withdrawal. However, withdrawal only lasts so long, yet the tendency to relapse can last a lifetime. Clearly, something more is afoot if an abstinent alcoholic can relapse from a single sip decades after their last drink.

3)      Maladaptive Conditioning

Alternatively, “This extra dopamine has sent so many signals down my learning pathways I now take drugs on autopilot”. The  theory du jour is Maladaptive Conditioning. This theory helps move us away from thinking of substance abuse as indicative of personal failure and lack of willpower and towards one of a disease state caused by changes substances make to the brain. This diseased state impairs and, in some cases, removes the addicted individual’s abilities to make rational choices over substances6.

Go on then, tell me about Maladaptive Conditioning

I shall. Conditioning is one of the simplest forms of memory. It is the formation of associations between stimuli, behaviours and outcomes. Pavlovian conditioning is the learning of which stimuli predict an outcome (e.g. Pavlov’s bell = food), and instrumental conditioning is the learning of which actions increase the likelihood of a particular outcome (e.g. making puppy dog eyes at your owner increases the likelihood of getting food). Conditioning allows you to learn how to, or how not to, get that pleasant reward, of say, a wholesome Sunday roast or a wholesome line of coke again.

Rescorla-Wagner equation describing learning. In essence: The more wrong you are, the more you learn.

Usually, dopamine neurons in learning pathways only fire learning signals when there is something new to learn, the size of the signal indicating the discrepancy between what your brain predicts and what is actually happening. As you learn these associations, there is less and less error as the memory becomes closer to reality and thus the learning signal decreases. Substances with the highest potential for addiction reliably cause a large and rapid release of dopamine, triggering a lot more signals in learning pathways than usual. This means not only do you learn which environmental cues predict a drug high (your stoner friends, your bong) and how to get high (going to your dealer) very quickly, you continue learning with each use far past the point when you’ve already ‘got it’. All this signalling really entrenches the memories of the cues and actions associated with drug highs. This then sets the brain up for a fight with itself.

The brain fights itself?

I appreciate that this metaphor is a bit of a stretch, but essentially yes, let me explain. The brain likes to be efficient. The prefrontal cortex or ‘thinking’ part of your brain makes choices on

Diagram of human brain areas. Frontal cortex and striatum highlighted.

Diagram of human brain areas. Frontal cortex and striatum highlighted.

the best set of actions at that moment to achieve the desired outcome (getting high). This allows you to be very flexible with how you achieve the outcome and is known as an Action-Outcome association4. However, this processing takes up a lot of mental resources, which could be used for more important things like finding a mate, locating food or reciting Taylor Swift lyrics. If the prefrontal cortex notices that the Action-Outcome association is always the same, it decides there is no use in always performing the same calculations and teaches a more primitive part of the brain in which situations (stimuli) a pre-calculated set of actions (responses) should be performed. This more primitive part of the brain is known as the dorsal striatum, and is involved with habits or Stimulus-Response associations4.

A habit allows quick and easy initiation of a response but does not allow flexibility in the actions performed nor consideration of whether the outcome is still desired. Usually, the prefrontal cortex can actively veto the execution of a habit if it realises the outcome would be inappropriate, but a habit is not broken that easily.

Suppose you are on the way into town on the weekend, you get distracted thinking about dinner plans or Taylor Swift lyrics, and oops, you’ve shown up at the office – a memory of the route so often correct that it has become habitual. As this innocuous example shows, the prefrontal cortex’s veto can easily slip up if it is processing something else, and the stronger a habit is, the less sway the prefrontal cortex has over the habit’s execution7. In addition, the habitual behaviours of how to get and take drugs become so well learned, and there are so many stimuli that can trigger these habits, that the prefrontal cortex has to work constantly to veto them. This leads to massive amounts of mental resources being spent dealing with cravings, distracting from work and even impairing cognitive abilities8.

At this point, I hate to say it, but Sigmund Freud may have been partially correct with his incredibly Freudian notion encapsulated in the following quote “It has dawned on me that masturbation is the only major habit, the ‘primal’ addiction and that is only as a substitute and replacement for it that the other addictions – for alcohol, morphine, tobacco, etc – come into existence.” While orgasm is certainly a rewarding experience (a big a dopamine hit as a shot of heroin apparently), substance-related habits and self-pleasuring are independent acts (though not mutually exclusive if you partake in the pastime of ChemSex9).

But people can stop being addicted?

I think it would be more accurate to say addicted individuals can become abstinent. Addictive substances’ high-jacking of dopaminergic learning pathways mean learnt substance habits are incredibly persistent4. People attending Alcoholics Anonymous tend to do so for many years whilst sober. Through time and interventions like Cognitive Behaviour Therapy an addicted individual can learn strategies which help them avoid and stay better in control of their cravings, but there is always the risk of relapse as long as the underlying memories still exist4.  Regardless of what initiated their use, addictive substances induce a disease state that disrupts healthy choice making and execution. Prolonged abstinence requires medical as well as social intervention, and true treatment of addiction will take much further research into memory mechanisms and how to disrupt these maladaptive memories10.

References

  1. The Centre For Social Justice. No Quick Fix: Exposing the depth of Britain’s drug and alcohol problem. (2013). at <http://www.centreforsocialjustice.org.uk/UserStorage/pdf/Pdf reports/addict.pdf>
  2. Schultz, W. Predictive Reward Signal of Dopamine Neurons. J. Neurophysiol. 80, 1–27 (1998).
  3. Crocq, M.-A. Historical and cultural aspects of man’s relationship with addictive drugs. Dialogues Clin. Neurosci. 9, 355–61 (2007).
  4. Milton, A. L. & Everitt, B. J. The persistence of maladaptive memory: Addiction, drug memories and anti-relapse treatments. Neurosci. Biobehav. Rev. 36, 1119–1139 (2012).
  5. Koob, G. F. & Moal, M. Le. Drug Abuse: Hedonic Homeostatic Dysregulation. Science (80-. ). 278, 52–58 (1997).
  6. Everitt, B. J. & Robbins, T. W. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat. Neurosci. 8, 1481–1489 (2005).
  7. Everitt, B. J. Neural and psychological mechanisms underlying compulsive drug seeking habits and drug memories–indications for novel treatments of addiction. Eur. J. Neurosci. 40, 2163–82 (2014).
  8. Merlo, E., Milton, A. L. & Everitt, B. J. Enhancing cognition by affecting memory reconsolidation. Curr. Opin. Behav. Sci. 4, 41–47 (2015).
  9. Bourne, A. et al. ‘Chemsex’ and harm reduction need among gay men in South London. Int. J. Drug Policy 26, 1171–6 (2015).
  10. Milton, A. Drink, drugs and disruption: memory manipulation for the treatment of addiction. Curr. Opin. Neurobiol. 23, 706–712 (2013).

 

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