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June 26, 2016

Drug addiction: the paradox of evolution

Marie-Catherine Mousseau explores drug addiction and the underlying neurophysiological mechanisms responsible for its hold on our behaviour

According to the World Health Organization (WHO), the essence of drug addiction is repeated and out-of-control use of a psychoactive substance. The person who is addicted compulsively seeks and uses the drug at the expense of other activities, finds it impossible to relinquish that drug-seeking/drug-taking habit, and exhibits determination to obtain the substance by almost any means.
What physiological mechanisms are capable of such a powerful hold on our will and behaviour? For many years, research in drug addiction sought to answer this perplexing question.
Direct CNS effect
Not all drugs are addictive. The physiological mechanism underlying a drug’s effect on the central nervous system (CNS) varies, giving rise to different classifications. The most used classification, adopted by the United Nations Office on Drugs and Crime (UNODC), divide addictive drugs into three categories: depressants of the CNS, CNS stimulants and CNS modulators.
CNS depressants include opioids (e.g. morphine, heroin), ethanol and sedative-hypnotic drugs (e.g. benzodiazepines, barbiturates). Commonly abu-sed stimulants are nicotine, cocaine and drugs of the amphetamine family, while modulators of the CNS include hallucinogens — LSD, psilocybine, mescaline and cannabis.
So, all drugs vary in their CNS effect and mechanism of action. However, interestingly, in each drug category, regardless of its effect, a well-known chemical messenger in the brain called dopamine (DA), and a specific neuronal pathway, namely the reward system, have been implicated (see Figure).
The mechanisms of stimulants are the best known. Roughly, cocaine blocks the recapture of dopamine while amphetamine stimulates its liberation. Nicotine has been shown to activate dopaminergic transmissions in the prefrontal cortex. The mechanism underlying the dopaminergic effect of the other classes of drugs is not so clear. However, some believe that opioids activate dopaminergic ascending neurons by binding to mu receptors on interneurons in the VTA.
Alcohol might influence the DA system in several ways; in particular it has been shown to increase DA levels by directly raising the firing rate of isolated DA neurons.
And cannabinoids, via CB1 receptors, are thought to locally desinhibit DA neuron activity in the accumbens nucleus. Thus, virtually all drugs causing drug addiction increase the dopamine release in the reward (mesolimbic) pathway in the brain, even though they do so in different ways. And the result is a rewarding feeling, a more or less intense sensation of pleasure.
Why such a biochemical convergence? The assumption is that during evolution, dopaminergic pathways have evolved to mediate the pleasure of life survival activities such as eating, drinking and sex. Taking addictive drugs short circuits the system that has evolved to reward these natural behaviours.
However, while the liberation of dopamine triggered by drugs may explain their rewarding effect, it does not explain the progression to a compulsive form of drug use – this overwhelming drive where all self-control has virtually disappeared.
Tolerance and dependence
Two other candidates, key features of drug addiction, are called tolerance and physical dependence. Both refer to the adaptation of the organism to chronic use.
Tolerance occurs when the body becomes accustomed to a drug and requires ever-increasing amounts of it to achieve the same pharmacological effects. When use of the drug is stopped, the evidence of the brain’s adaptation then becomes even more obvious and may result in drug withdrawal symptoms. These reflect the physical dependence.
The severity of drug withdrawal symptoms varies depending on the drug involved. All depressants (including opioids, alcohol, benzodiazepines, barbiturates), as well as nicotine, generate tolerance and physical dependence.
Take alcohol, for instance. Scientists believe that following chronic alcohol use, the brain increases the number of dopamine transporters – i.e. transporters in charge of carrying away DA released in the synapses – in order to compensate for the increased DA release caused by alcohol.
When the alcohol stops, so does its increased DA production. But the extra number of transporters remains, clearing away what little dopamine there is. The result of this low DA level seen in abstinent alcoholics is a feeling of depression and the inability to feel any normal pleasure.
The strongest and most obvious withdrawal symptoms are actually seen with heroin, and include insomnia, sweating, cramps, vomiting, diarrhoea, and fever. In this case, these are due to a decreased production of enkephalins (naturally occurring opiates in the brain) with repeated heroin use.
A major theory of addiction says that individuals keep using heroin not so much to get the positive effects of the drug, but to stop feeling so bad when they are in a state of withdrawal. However, contradicting this theory, many addicts will use heroin over a long period of time without ever undergoing withdrawal. In fact, it seems that tolerance and physical dependence are normal reactions that are neither necessary nor sufficient for addiction.
Stimulants such as cocaine and amphetamine, or CNS modulators such as cannabis, are not associated with withdrawal symptoms when stopped. And repeated use of cocaine and cannabis do not even trigger the development of tolerance.
In spite of this, the craving is still there. Understanding the basis of this psychological dependence would be critical to understanding drug addiction.
Long-term CNS effects
What is more, even after detoxification and long periods of abstinence, relapse frequently occurs – the most difficult aspect of drug addiction treatment is actually the prevention of relapse. This proneness to relapse suggests a long-term CNS effect of drug use. Repeated intake seems to leave a trace in the brain lasting for months or years after the last use of the drug.
In particular, in a large number of human neuroimaging studies, intense craving has been associated with activation of the limbic system (brain structures including the hippocampus and the amygdala that are implicated in long-term memory and emotions). Such studies also indicate reductions in frontal lobe metabolism with stimulant, opioid and alcohol dependence. While not fully understood, these long-term changes might explain deficiencies in behavioural inhibition among addicts and vulnerability to fall back into self-destructive drug use after long periods of abstinence.
More generally, there has been a growing theory that CNS changes occurring during addiction are somewhat akin to those that occur with learning and memory – that is, strengthening of synapses in the dopaminergic parts of the brain that subserve addiction. The original purpose is to reinforce natural rewarding stimuli important for survival such as food or sex. However, changes in synaptic strength that occurs with drug abuse may be beyond what should normally happen – with the pathological consequences that we know.
Until recently, theories on drug-addiction mechanisms — based mainly on animal models — assumed that all individuals were alike in their responses to drugs. In reality, only a relatively small percentage of those humans exposed will develop an addiction (9 per cent to 32 per cent depending on the drug, see Table). This observation is critical. It means that additional factors alter short-term and long-term physiological mechanisms highlighted above.
A first obvious factor is genetic vulnerability. Minor genetic variations might account for alcoholism tendencies in rats. It has been shown that when exposed to alcohol, around half of the rats of the same strain will be alcohol drinkers, while the other half will not develop addiction. In humans, the most convincing evidence comes from twin studies: inheritability for addiction ranges from 40 per cent to 60 per cent, depending on the type of drugs.
What are the physiological mechanisms underlying genetic predisposition to drug addiction? We do not know yet, but many genes are thought to be involved, including genes with a direct impact on personality. According to recent research, an impulsive personality is more prone to take drugs and escalate drug intake. And subordinate but not dominant monkeys use cocaine as a reinforcer. A new study actually suggests that brain dopamine receptor density in the striatum correlates with social status.
But of course environmental conditions may also have an impact in the development of behavioural traits leading to drug addiction. Environmental factors interact with genes to construct personality.
Changes in brain function have been shown to be linked with social stress (e.g. subordinate position, dysfunctional family) and situational triggers (e.g. environmental cues associated with drug use). In particular, stressful situations in early development can predispose an individual to drug addiction. On a molecular level, corticosterone has been shown to interact with the DA system.
Evolutionary paradox
Some of the common physiological basis of drug addiction, including drug rewarding effect, tolerance and physical dependence, are now becoming clearer. However, psychological dependence, the complex mechanisms associated with long-lasting changes in brain function and relapse, as well as the huge variability between drugs and individuals, are far from being fully understood. This variability suggests that the progression from use to abuse to addiction is the result of a complex interaction between the type of drug, the host and the environment.
In any case, the fact remains that special characteristics of dopaminergic neurons, packed in a small area of the midbrain, give them a central role in the development of addiction. Based on its plasticity in response to stress and situational changes, a possible main role of the dopaminergic system is to ensure an optimal behavioural response to environmental triggers. Driven by pleasure, this response happens to be shunted by certain drugs in a pathological, non-adaptive way.
Many of our most addictive drugs, from nicotine to opioids and cocaine, come from plant toxins. Ironically, plants originally developed these toxins to deter predators from eating them, not to make us crave them. So where did evolution get it wrong?
Maybe it did not, and this is a paradox of evolution. Thanks to their recreational and medicinal properties, these toxins have ensured the survival of the species that created them, as we humans will take care of these plants for ever.
References on request.
l Marie-Catherine Mousseau holds a PhD in Neurosciences and is
Editor of MIMS Ireland.
l The views expressed above are those solely of the author(s) and in no way may be deemed to reflect the views or policy of either MSD Science Centre or MSD.