February 2014 – The Brain Bank North West

A tale of anxiety and reward – the role of stress and pleasure in addiction relapse

February 23, 2014February 23, 2014 by The Brain Bank North West

At the start of February we heard the horrible news that Philip Seymour Hoffman, a wonderful Academy Award winning actor, had died from a drug overdose. This followed news from last year of the death of Glee star Cory Monteith from a heroin and alcohol overdose. Perhaps the most shocking thing about these deaths was that no-one saw them coming.

From http://www.flickr.com/photos/beinggossip/ — From www.flickr.com/photos/beinggossip/

Worryingly, the reality is that drug relapses such as these are all too common, but often go unnoticed. Our understanding of the science behind these relapses has come on leaps and bounds in recent years. We have moved from understanding how a drug makes us feel pleasure, to understanding how a drug may cause addiction and subsequent relapse.

Classically, scientists have explained addiction by focusing on how a drug affects the reward systems of the brain. Drugs have the ability to make us feel good due to their actions on this pathway. The reward system of the brain is a circuit that uses the chemical dopamine to stimulate feelings of elation and euphoria. This system has a motivational role and normally encourages survival behaviours such as obtaining food, water and sex. Drugs of addiction can hijack this system to induce euphoric feelings of their own.

Cocaine, for example, is a highly addictive drug that blocks reuptake transporters of dopamine. These transporters normally soak up excess dopamine and ensure that the reward system is not overactive. Cocaine stimulates euphoria by preventing dopamine from being retrieved and increases stimulation of the reward system. Another addictive drug, nicotine directly stimulates the reward system to produce more dopamine.

These classical views work well when considering the motivation to start taking drugs and to continue taking drugs in the initial stages. The drug stimulates feelings of euphoria, ‘rewarding’ the taker. The taker learns to associate taking the drug with these feelings of euphoria and therefore the taker wants to do it more.

This theory can also explain some aspects of withdrawal. Just as activation of the reward system has a physiological role, so does shutting it down. It appears there is such a thing as ‘too much fun’. If we spent all of our time copulating and over-eating we’d be prime targets for predators. Due to this, the body has its own off-switches in our reward pathways that try to limit the amount of pleasure we feel. These normally work by desensitising the brain to dopamine, so that dopamine isn’t able to produce the effects it once could.

During drug use, when dopamine levels and subsequent pleasurable feelings are sky-high, the brain works to limit the effects of this overload of dopamine. When the drug wears off, dopamine levels fall but the desensitisation to dopamine persists. This causes withdrawal, whereby when there are no drugs to boost dopamine, one fails to gain pleasure from previous pleasurable day-to-day activities. The dopamine released when one has a nice meal for example, is no longer sufficient to cause enough activity in the reward pathways and no satisfaction is felt.

Scientists believed for a while that the reward system could tell us all we need to know about addiction and how it manifests itself throughout the brain. However, tolerance builds and the euphoric responses to these drugs begin to wane. Some users start feeling dysphoria, a horrible sombre feeling, and don’t know why they continue using these drugs as they are no longer experiencing euphoria – the reason why they took the drug in the first place.

On top of that, when doctors and therapists talk to drug addicts who relapse, the addicts often do not talk about wanting to feel pleasure, wanting to feel elation again. They talk of stress building up inside them, the release from this stress they want to feel.

When asked about why they relapsed, previously clean addicts often talk of stressful events leading to their relapse – they lost their job or they broke up with their partner. First-hand accounts suggest this stress seems to be the driver of a relapse, the driver to continued addiction.

This is depicted clearly back in the 19^th century by the eccentric American author and poet Edgar Allan Poe:

“I have absolutely no pleasure in the stimulants in which I sometimes so madly indulge. It has not been in the pursuit of pleasure that I have periled life and reputation and reason. It has been the desperate attempt to escape from torturing memories, from a sense of insupportable loneliness and a dread of some strange impending doom.”

Intrigued by this, scientists have now found many threads of evidence to suggest that stress pathways within the brain play a key role in addiction and relapse. For example, work into this so-called ‘anti-reward system’, has led to proof that stress can instigate drug-seeking behaviours in animal studies.

Our stress pathways are built around a hormone system known as the HPA axis – the hypothalamic-pituitary-adrenal axis. This axis is responsible for regulation of many biological processes but plays a crucial role in stress.

The HPA axis is the stress hormone system of the body.
*CRF = corticotrophin releasing factor; ACTH = adrenocorticotropic hormone*

Much like other drugs of addiction, drinking alcohol feels good due to its actions on the reward system. In line with addicts of other drugs, alcoholics commonly talk about the release of stress they want to feel. Evidence is building to suggest that alcoholics have increased activity through the HPA axis.

A hormone called cortisol is the final chemical involved in the HPA axis, released from the adrenal glands during times of stress. Compared to occasional drinkers, alcoholics have higher basal levels of cortisol and a higher basal heart rate – two common measures of HPA activity. This pattern has also been seen in other addictions. For example, in previously clean cocaine addicts, higher basal HPA axis activity correlates with an earlier relapse and higher levels of stress hormones (e.g. cortisol) can predict a higher usage of cocaine in the future.

A puzzling scenario surrounding addiction is how most users can enjoy occasional usage but for some, this can spiral uncontrollably into an addiction? The likelihood of different individuals having a higher propensity to addiction could well be explained by differences in how different people respond to stress.

So what begins as a behaviour driven by the reward pathways appears to have now escalated into a behaviour dominated by stress pathways. It seems it is the stress that drives the craving and relapse, not the longing for a ‘reward’.

Armed with this knowledge, work into how we can design medicines to alleviate cravings and prevent relapse has shown early potential. Blocking the first stage of the HPA axis has been able to prevent alcohol addiction in rats. Blocking a suspected link between the stress pathways and the reward pathways has shown to be able to prevent stress-induced cocaine seeking behaviour.

These compounds have yet to be tested in humans but the early promise is there. It is an intriguing theory that the susceptibility to stress of different individuals may explain the varying susceptibility to addiction. This idea provides a basis for further work to try to understand why some individuals can only occasionally use, whilst others become addicted. Relapse is a horribly common situation amongst drug addicts and with the stigma attached giving addicts substantial additional stress, it is well-worth the research to prevent more unnecessary deaths. Unfortunately, this will be too late for those we have already lost, but the future is bright with continued progress in understanding these horrible ordeals.

By Oliver Freeman @ojfreeman

A smoking revolution – What’s in a cigarette?

February 14, 2014 by The Brain Bank North West

Travel back in time to the forties and fifties. Smoking was seen by some as a fashion statement. This was before we were clued-up on the abundant chemicals and the massive impact it could have on our health. As research into cigarettes snow-balled, smoking became less fashionable. Even so, there are still many people around the world who smoke.

This week has seen a drastic change in UK laws regarding smoking.

The UK Government has decided to ban smoking in cars when children are passengers. This change has come after shed-loads of research over the last couple of decades has highlighted health risks associated with smoking that far outweigh the benefits.

But is smoking really as harmful as the Government drums into us on a daily basis?

The statistics seem to speak for themselves; almost 80,000 deaths occurred in the UK in 2011 as a direct result of smoking. What’s more, around 11,000 people die from passive smoking each year (according to Cancer Research UK), and around 9,500 children are admitted to hospital with smoking-related problems from passive inhalation.

So what exactly is in cigarettes that make them so addictive and what produces these toxic effects?

Nicotine– a plant-derived chemical in cigarettes that is responsible for the addictive nature of smoking. The chemical enters the blood stream by inhalation and absorption through the air sacs in the lungs. It is then carried by the blood into our brains, where it binds to cholinergic receptors. Usual functioning of these receptors helps to maintain some of our normal bodily processes, but when nicotine is inhaled it changes the number of these receptors and also alters their sensitivity to nicotine. This is the mechanism responsible for smoking addiction- nicotine needs to be used regularly to keep the brain ticking over.

Tar– the gunky stuff in cigarettes that is deposited mainly in the gas exchange region of the lung, and carries all the nasty chemicals that are toxic to our bodies. Apparently there are almost 4,000 of these chemicals in each cigarette smoked, many of which can cause cancer. Not surprisingly, tar can affect the proper functioning of the lungs. It also ‘clogs’ the cilia that trap bacteria and dirt, so that dangerous substances can enter our lungs.

Carbon monoxide– the chemical in cigarettes that significantly reduces the oxygen-carrying ability of our red blood cells, as it is 200 times more attractive to our blood than oxygen. As the lungs are no longer able to supply our bodies with enough oxygen, we start to have issues with our breathing as we try to take in more oxygen, and also put our heart under immense strain as it tries to supply us our organs and muscles with enough oxygen (amongst many other things!).

Arsenic– a carcinogen that affects how the body repairs DNA.

Benzene– a solvent and carcinogen used in petrol

Formaldehyde– a chemical and carcinogen most commonly used to preserve dead bodies.

Polonium – a radioactive substance

Hydrogen cyanide– poisonous gas that damages the heart and blood vessels

Yet despite these major health risks, large numbers of us are still regularly lighting up.

In 2012 approximately 20% of the UK population smoked cigarettes on a regular basis. Astonishing statistics also showed that 10% of school pupils aged 15 were regular smokers. Not only this, but the average number of cigarettes smoked per day was 12. Despite these figures, many smokers say that they wanted to give up smoking.

Based on all the frankly quite frightening research that hasn’t been brought to our attention, reducing smoking and passive inhalation is something that the Government is beginning to take seriously. Some of the changes that have already been introduced are;

Government bans smoking in public buildings and enclosed places in 2007. Having just been old enough to go to clubs and pubs before the smoking ban came into place, I really reaped the benefits when smoking was banned in public places. I was able to enjoy a night out with my friends, without coming home smelling of an ash tray. I wouldn’t have minded so much if I actually smoked myself!
Stopping promotion of tobacco products– Advertising of cigarettes is banned (2003), and supermarkets are permitted to hide tobacco displays (2012).
Tobacco tax– Tax rates on cigarettes are high, apparently with the aim to put people off smoking, and nothing to do with the revenue it makes them!
Anti-smoking campaigns– These campaigns aim to get people to quit smoking by making them aware of the health risks, dissuading young people from taking up smoking and trying to educate people on the risks of passive smoking.
E-cigarettes– These electronic imitation of cigarettes are currently a massive craze in the UK. In theory these are a great alternate to smoking; they retain all the ‘good parts’ of smoking, without all the added health risks. As these are relatively new they are not well regulated, so more research is needed to evaluate their health impact.

We know for certain that smoking is damaging to the body and has serious health implications. I have provided a (somewhat biased) summary of the health-related impact that smoking can have, from a non-smokers perspective. Another thing is also clear; the Government are taking smoking seriously. They are tackling this issue in a number of vital ways from trying to stop the ‘glamorisation’ of smoking by banning advertisements, reducing the impact on non-smokers, research and regulation into ‘better’ alternatives and in my opinion the best way possible; educating the public on the harmful effects of smoking. Next time you reach for a cigarette just cast a thought to some of the chemicals and toxins that you are putting into your body, and be aware of how this may be affecting yours, or someone else’s health.

What is a headache?

February 5, 2014 by The Brain Bank North West

We all know the feeling after a long stressful day, when the tensions of the past few hours begin to amass in your temples, perhaps starting as a dull throb before advancing in waves to a deep pounding ache. The headache is a common malady, but what mechanisms lay behind these debilitating pains and which aspects of your life may be triggering them?

The question of why and how we experience headaches is significantly harder to answer than you might imagine. Particularly since the term ‘headache’ is in itself non-specific, being a broad term used to describe a range of common head pains, each of which may stem from a different underlying cause. Interestingly, however, one thing we do know is that the pain you experience during a headache does not originate from the brain itself. Indeed, the brain lacks pain receptors (nociceptors), therefore does not have the capacity to feel pain.

But then where does the pain of a headache come from? The pain we experience during an everyday headache originates in pain-sensitive structures surrounding the skull. These include; the extracranial arteries, veins, cranial and spinal nerves, neck and pericranial muscles – all of which express pain receptors and are therefore susceptible to these sensations.

It is possible to pin down a number of simple lifestyle factors which commonly contribute to the development of headaches. These include; emotional disturbances, stress and mental tension, certain types of food, alcohol, cigarette smoke, exercise and even the way you wear your hair – hair-dos (including the tight ponytail, braids, headbands and even tight hats) can strain the connective tissue that lies across the scalp and cause headaches. So simply letting your hair down can relieve this pressure and thus the pain of the headache.

A number of the factors which lead to headaches (including certain foods, cigarette smoke and alcohol) involve the blood vessels which lie around the brain. For example, inhaling nicotine from cigarette smoke causes narrowing of blood vessels around the skull. Narrowing of these vessels can often induce extremely painful headaches. Changes in blood pressure also explain hangover and exercise headaches and why, for some people, certain foods can act as headache triggers.

The episodic tension headache (the type you may get after a long day at work) is the most commonly occurring type of headache. However despite the extensive research into the cause of migraines, this common type of headache remains one of the least investigated. As relief can normally be sought through over-the counter painkillers, most sufferers will not consult a doctor. The mechanisms underlying what specifically causes these headaches remains elusive, however, a number of theories regarding their pathophysiology have been proposed:

It appears that the occurrence of headaches are commonly linked to general problems of the musculoskeletal system. Skeletal muscle constitutes the largest muscle mass of the body, controlling movement, breathing, facial expressions and numerous other normal physiological functions. Each individual skeletal muscle is composed of hundreds of cells, arranged in muscle fibres. Each muscle fibre is connected to the nervous system via interactions with a single branch (an axon) of a nerve cell.

Each fibre of a muscle can relax or contract in response to signals sent from the brain via these nerves. These muscle fibres also contain sensory receptors which can feedback the health of the muscle to the brain. This helps tell you when the muscle is tired or overstretched for example. Abnormal activity in these nerves, perhaps as a consequence of injury, stress or poor posture, can therefore result in the relay of pain signals to the brain. For example, bad posture places abnormal pressure on the muscles of the neck which can result in heightened tension and the subsequent development of ‘tension headaches’.

Interestingly, tension headaches can also be induced by activation of so-called ‘trigger points’. A trigger point is defined as ‘a hypersensitive area of the body, associated with taut bands within a skeletal muscle’. Pressure or compression on these localized trigger points can cause the referral of pain along linked nerves to a nearby area. So, the presence of active trigger points in your head, neck and shoulder muscles can refer pain that will be subsequently experienced as a headache.

A number of studies have confirmed this, identifying an increased number of trigger points in the muscles of the head in patients prone to headaches, compared with patients who do not regularly experience headaches. What causes these trigger points to develop in the first place still remains unclear, however, some have speculated that they may be associated with past muscular injuries, fatigue, diet and even as a result of chronic repetitive strain, such as persistent typing.

Infrequent headaches, while menacing, are nothing compared to their chronic cousins. Infrequent headaches can become chronic as a result of changes that originate in the brain and spinal cord. This involves so called ‘second-order’ nerve cells which act as connectors between peripheral organs (e.g. the skin and muscles) and nerve cells in the spinal cord and brain.

A number of studies have proposed that chronic tension headaches may be triggered by changes in the sensitivity of these second order nerves, particularly those in the spinal cord and an area of the brain known as the trigeminal nucleus. This process is known as ‘central sensitization’ and can alter pain thresholds and trigger nerve cell activity. It is hypothesized that, in the presence of persistent stress or pain signals from peripheral muscles (such as that brought about through regular bad posture), nerve cells can grow forming new connections and effective contacts to low-threshold nerves that do not normally signal for pain. Furthermore, increased sensitivity can be caused by the enhanced release of chemicals that facilitate nerve cell communication. This increase in the number of pain signalling nerves and their sensitivity to strain and tension results in enhanced pain sensitivity, lower pain thresholds and the development of chronic pain states.

Chronic pain states, may be a result of prolonged stress and musculoskeletal tension, alongside central changes in the brain and spinal cord. So, if regular headaches are wearing you down you might benefit from trying to reducing your stress levels, being aware of dietary triggers, improving your posture and trying exercises to relax your muscles.

Post by: Isabelle Abbey-Vital