Drugs, Reward and the Brain

©

Leandro Castelluccio

(Image taken from: link)

It is often thought that people, in the simplest terms, act to seek pleasure and avoid pain. But this is not really so simple and not necessarily true. In my book “Proposiciones” (see the section on “Book Publications” on this site – note that the book is currently only in Spanish language), I argue that the fundamental criterion of human actions is not the pursuit of pleasure or avoidance of pain, in fact I directly argue that avoiding suffering is just an apparent fact in disguising what is behind, which is the achievement of an action linked to reward, that is the criterion or fundamental reason for our behavior. But it is not a reward in the usual sense of the term, and is not necessarily associated with the concept of pleasure, but refers to a spectrum of subjective states, each of which is a state of reward. A state of peace and relaxation is a state of reward as well as one of enthusiasm or positive exaltation. And we can observe a hint of this in the consumption of psychoactive substances, since there is great difficulty in explaining addictions to such substances in terms of unique patterns at the brain level, for example, the classic idea that drugs act and the addiction is generated based on the activation of the dopaminergic circuit seems to be wrong. That is why I believe we should expand our concept of what reward means.

Why people initiate the use of drugs, taste, like or become addicted to substances is a very profound and difficult question. Unless we say that drugs are something with a different and alternative nature to all other things, then we must agree that the answer lies within our notions of motivation, of why we do or engage in all sorts of activities in general. We can say that taking drugs is different from things like playing football, but still the dimension we are talking about is motivation, of why we do what we do. In the imaginary situation in which we were to found that some drug is being taken without any motivation because now it’s something automatic or unconscious, we would still need to explain why the drug was taken in the first place, what motivated an individual to do so. In a more real scenario, we can find people addicted to drugs who are very motivated to stop taking them, but who nevertheless can’t and fail to do so. Why do they keep taking them? I think the different models of drug addiction can only take us so far in the question of why we use drugs unless we expand our notion of reward, as I have stated, the essential motivational element of our behavior.

There are different concepts of motivation within Behavioural Neuroscience, they help us understand what limbic brain systems are chiefly evolved to do. Such concepts include the idea of homeostasis, set-points and settling points, intervening variables, hydraulic drives, drive reduction, appetitive and consummatory behaviour, opponent processes, hedonic reactions, incentive motivation, drive centers, dedicated drive neurons, neural hierarchies, and new concepts such as allostasis, cognitive incentives, and reward “liking” vs “wanting”, for example (Berridge, 2004).

But let’s consider now the different models of addiction. Aberrant-learning theories of addiction, for example, state that repeated exposure to addictive drugs heightens Pavlovian and instrumental responsiveness to cues that are associated to drug taking, this is believed to happen due to actions on neurons that control normal responses to non-drug conditioned cues. The ventral and dorsal striatum in the brain would be involved in this. An interesting point of these theories is the notion of insensitisation to outcome devaluation of the heightened responsiveness to drug cues, which means that a person would present this heightened response regardless of punishment, for example. Frontostriatal-dysfunction theories of addiction on the other hand propose that repeated exposure to addictive drugs causes deficits in top-down executive control over behaviour (Badiani, Belin, Epstein, Calu & Shaham, 2011). This is related to the idea that drug addiction does not involve voluntary choice. As Kalivas and Volkow (2005) state, cellular adaptations in prefrontal glutamatergic innervation of the accumbens causes diminishing cognitive control, i.e. lack of choice. At the same time, these changes in the brain decrease the value of natural rewards and enhance glutamatergic drive in response to drug-associated stimuli. If we were to focus just on this, we would say that human usage of drugs might have nothing to do with motivation or reward (at certain levels at least), but with a wanting and craving where there is no voluntary control and where choice is lacking. But still, we would not be explaining why people star taking the drug in the fist place, and not everyone reaches this point of craving and addiction. In this sense, according to Ahmed, Lenoir and Guillem (2013), addiction as a psychiatric disorder is defined as resulting from brain dysfunctions that affect normal choice-making. So at least in the first place, choice is there regarding the usage of drugs, this implies alternatives and reasons people might be weighing when deciding to take a drug.

On the other hand, the hedonic-allostasis theory of addiction proposes that initial drug use is primarily controlled by the drug’s rewarding effects, but that chronic drug use leads to decreases in its rewarding effects and recruitment of stress-related systems (Badiani et al. 2011). This introduces an interesting idea, which could tell us a lot about motivation and why we might use drugs, which is the avoidance of negative states, in simple terms, the avoidance of suffering or displeasure.

If we link this idea to the notion of motivation in general, how accurate is it really? Do we truly act to avoid painful states? We think the answer is “yes” in a very obvious way, but I would challenge this idea and say that what we really do in almost every case is to seek a state that it is rewarding to a certain extent. Let’s take into account that many of the things we do, do not seem to truly have a state of suffering associated to it as a motivational cause of the behaviour, on the contrary, the state of suffering comes later as result of not getting what we intended with our actions, which has a goal that is associated to reward instead. Let’s consider, for example, our appetite or desire for food, this is not really a state of suffering, it is a rewarding state, when we feel appetite, just thinking about food can excite us and generate feelings of pleasure, tasting food is more rewarding, we might think is better or more tasteful than when we are full or with no desire to eat, food is in that last case no longer a rewarding thing. This would go against the notion that what we do when we have appetite is to avoid a negative state, that in which we are not consuming food. Hunger is though a negative state, but it comes after an extended period of time without consuming food, and might be psychologically exacerbated if we have no possibility of getting any food. So, when we have appetite food is rewarding, and the whole state is rewarding: now we have something that makes us feel enthusiastic, makes us think about a pleasurable moment. I think this can be extended to almost any example, when we do things, unless it is a fast, automatic response, like when we take our hand off quickly if we accidentally touched a hot surface, we are not escaping or avoiding negative states, but seeking a rewarding one. Again, I think the problem is that we have a restricted concept of reward, I would say for example that a state of relaxation and quietness can be considered a rewarding state. In this light we could consider something such as the need to consume drugs when feeling anxious or in distress, like when having withdrawal symptoms for example, not as an avoidance of pain but an active pursuit of a rewarding state (considering an expanded distinction of it). We can think of a state of relaxation and decrease arousal in this case after taking the drug.

If we go back to the models of drug addiction, we also have the incentive-sensitization theory of addiction, which indicates that drugs increase mesocorticolimbic dopamine neurotransmission and that attribution of incentive salience to context, cues and other events that are associated with activation of this dopaminergic system, and this is one of the psychological function of this system in the brain, in which long-lasting adaptations are generated by repeated exposure to addictive drugs, making the system hypersensitive to drugs and drug-associated cues. It has also been stated that sensitization of neural systems that mediate incentive salience occurs independently of changes in neural systems that control pleasurable effects of drugs. This is a dichotomy of wanting a drug vs liking a drug (Badiani et al. 2011). This might be a factor that can help us explain why people addicted to certain drugs seem not to experience any more pleasure, nevertheless they keep craving the drug. What can this tell us about motivation and why we use drugs? Again, I think it is very hard to separate behaviour from rewarding states, the problem is that rewarding as a motivation is now a very restrictive concept, I believe, and we should expand on this, if we say for example that cocaine and heroine do not produce the same effects, this does not mean that one is rewarding and the other not. As it is stated, “liking” of rewards would be a determinant of future incentive salience “wanting”. It is also argued that hedonic experience and memories of reward are the chief input to cognitive incentive valuation mechanisms (Berridge, 2004). But how do we code the memory of something being rewarding? And how does this affect the wanting of a drug in case of addiction when it is being said that there might be no liking of it? Would not this be contradictory? If a drug no longer generates pleasure, and even more, it can lead to displeasure, would not the person relearn and change the association between the liking and the drug as to not wanting it anymore? I think we must experience reward. Wanting must have a feeling of reward, though mild, and may not even be of the same specific nature, but there would be such feeling in order to guide behaviour. The reward would be associated to the drug and this would be the case if we accept a general notion of reward as the main motivational system. I believe people who crave for a drug when addicted to it are not detached from a feeling of reward they associate to the drug or to the expected outcome of taking it. The thing is, we must differentiate between the feeling of reward that might motivate behaviour to the rewarding feedback we might obtain from an experience, the person could experience reward but not have the feedback.

Finally, we have the pschomotor-stimulant theory of addiction, which proposes that a common denominator of addictive drugs is their ability to cause psychomotor activation. This relates to the idea that positive reinforcers activate a common biological mechanism that is associated with approach behaviours (Badiani et al. 2011). About this concept, the association between dopamine and creativity is very interesting. According to Mayseless, Shamay-Tsoory, Uzefovsky, Ebstein and Shalev (2013), dopamine and creativity are strongly linked. Divergent thinking (DT) has been proposed as a way to assess creativity and DT involves generating multiple novel and meaningful responses to open-ended questions, which has been related to dopaminergic activity. For example, individuals carrying the DRD4 7R allele of the human dopamine receptor scored significantly lower on tests of DT when compared to non carriers (Mayseless et al. 2013), which would imply an association between dopaminergic activity and DT at this biological level. According to Zabelina, Colzato, Beeman and Hommel (2016) however, results of past studies are mixed about this issue. These authors worked on this relation by considering the mediofrontal and the nigrostriatal dopaminergic pathways, uniquely and in combination, and how they relate to different measures of creativity. They state that creativity can be predicted from interactions between genetic polymorphisms related to frontal these pathways. Specifically, successful performance on the Torrance test (that measures certain aspects of creativity) is linked with dopaminergic polymorphisms associated with good cognitive flexibility and medium top-down control. Differently, real-world creative achievement, assessed by the Creative Achievement Questionnaire, is linked with dopaminergic polymorphisms associated with weak cognitive flexibility and weak top-down control (Zabelina et al. 2016). All these give us a picture of what dopamine might be doing in certain pathways, and how it relates to motivation. If we think about it, this might be a useful system that helps us engage with the world in novel ways, we feel motivated to act and do things for their rewarding properties to engage with the world and maybe find novel, creative ways, of dealings with problems, therefore it is easy to see how the two being related in the brain would be efficient. It would be useful then when we do things and encounter problems in the world to find novel ways of dealing with that, which aids our survival chances. This tells us a lot about motivation in general, and why some people might use certain drugs, like psychoestimulants, if they are trying to solve a particular problem, or just because they want to be more creative at something, for example. This link goes with the idea of drugs high jacking relevant circuits that aid our survival. The self-perceived survival ability and reproductive fitness theory (SPFit), for example, represent a human psychobiological construct that prioritizes and organizes behaviour, in which a cortico–mesolimbic dopamine system and its modulating interconnections are viewed as the biological substrate of this system, that is also considered as highly vulnerable to temporary artificial activation by drugs of abuse (Newlin, 2002). Although the system is proposed to be a survival and reproductive motivation system rather than a reward centre or reward pathway in itself, we can see that reward, motivation and fitness or adaptation to the environment seem to go together.

According to Badiani et al. (2011), it has been found that opiates and psychostimulants, although they have very different pharmacodynamics profiles, they share the ability to increase dopamine levels in the nucleus accumbens, which is one of the terminal regions of the mesocorticolimbic dopamine system. This increase appears to play an important role in the rewarding effects of drugs and non-drug stimuli. However, when neural activity was assessed using multiple-channel single-unit recordings in rats that consecutively self-administered heroin and cocaine, it was found that only a small number of drug-responsive neurons in the medial prefrontal cortex and nucleus accumbens showed similar responses to both drugs. According to these authors, the literature does not support the general conclusion that dopamine projections from the ventral tegmental area to the nucleus accumbens are essential to the rewarding effects of opiates. There are also differences in the way these drugs are taken. According to Badiani (2013) the setting of drug use can exert a powerful modulatory influence on drug reward and this influence is substance specific. In the case of heroin, it is used preferentially at home while cocaine is used preferentially outside the home. We could say that this is relevant to incentive-sensitization theory. Clues, for example, reinforce drug taking, but this still it does not explain why we take the drug in the first place, although it can gives an idea about how context influence why we take a drug, in this case we want to get active when we go out, but we want to relax and disconnect when we stay at home.

And so, all these models mentioned try to explain the addictive behaviours related to drugs, in a way, they are an account of why we use drugs, but in a special case, where motivations might not seem the same as in an earlier stage, when a person starts to use the drug. We cannot fully apply these concepts to the general, non-addictive, usage of drugs, but they help us understand why we take them in general. We find that dopamine pathways play a key role, this makes us think about the idea of reward again, and yet opium addiction does not seem to involve completely the same dopamine mechanism. But as I have stated before, maybe we need to expand the concept of what is really a rewarding state, and as such we can ask whether a good state of mood, with reduced anxiety that might relate to serotonin levels (Albert, Vahid-Ansari & Luckhart, 2014) be considered a state of reward.

These models can address the issue of repetitive drug intake, to a certain extent, the evidence is not fully clear, but even then they don’t explain apparently the prevalence of drug use among countries either, which varies considerably (Lopez-Quintero et al. 2011). Clearly there must be cultural modulators that are affecting the issue of why and how we use drugs. It is considered, for example, that environmental experiences unique to the person determine to a great extent whether predisposed individuals will use or misuse one class of psychoactive substances instead of another (Kendler, Jacobson, Prescott and Neale, 2003). And even if we argue that neurotransmitter-analog plant chemicals were exploited as substitutes for costly, nutritionally constrained endogenous neurotransmitters, as it is proposed to explain why we used drugs in the past (Sullivan & Hagen, 2002), and can be used to say why we might use them now, i.e. to mimic the effects of naturally current chemicals in the brain, we still don’t explain, unless we talk about motivation, why would someone do that in the first place. Someone might take caffeine to be awake and active, because that is a rewarding state specific for the person and for certain task, that itself is rewarding for example. So we must take into account multiple variables that modulate how rewarding something is.

So I would argue for a more general mechanism of reward that drugs would interact with. Dopamine is important, buy apparently the dopamine system is not equally affected by drugs like heroin, as we’ve mentioned. The role of dopamine in the subjective experience of heroin in opioid addicts is questioned, given the fact that a dopamine response to opioid agonists contrasts that found with stimulant drugs, which would suggest that dopamine may not play the same role in addiction to opioids (Daglish et al. 2008). But motivation wouldn’t reduce itself to the dopamine system if we amplify the concept of reward.

In this framework we might ask why certain drug might be more rewarding in certain context than other, it all depends on how rewarding it is, based on many factors. Let’s consider psychological addiction, for example. Apparently addiction is not constrained to certain drugs, there is a similar phenomenon associated to other things. It is considered that addiction is a condition that results when a person ingests a substance like alcohol or cocaine but also when the person engages in an activity like gambling or shopping that can be pleasurable but that it becomes compulsive and interferes with ordinary life (see in Psychology Today, n.d. for further information). At the moment, gamlbing disorder is recognized by the DSM-5 as a persistent and recurrent problematic gambling behavior, which leads to clinically significant impairment or distress (American Psychiatric Association, 2013). There is a new category concerning behavioural addictions within the DSM-IV (see in Substance-Related and Addictive Disorders, n.d. for more information), which lists pathological gambling. This change reflects findings that gambling disorder is similar to substance-related disorders in clinical expression, brain origin, comorbidity, physiology and treatment. Other behavioural addictions, such as Internet gaming disorder could be included in the future as well (Substance-Related and Addictive Disorders, n.d.)

I would say that more evidence is needed, but apparently the existence of such behavioural addictions imply that more than a substance-brain interaction is needed to explain addiction in general and also the general use of drugs. I think this involves our notion of motivation, which as I mentioned, would imply this general concept of reward, which is modulated by many factors. Let’s consider also the notion of what is call psychological addiction to a substance, this would indicate that there is more to why we engage in a compulsive and almost unavoidable consumption of a substance than the physical dependence that is often portrayed as necessary for drug addiction. What could explain this kind of addiction? People often talk about how such psychological dependence of a drug is a mechanism to cope with different problems one might be facing, if that is the case, then the drug would become rewarding because of that factor, if we consider reward as a broad concept and the key element of motivation for doing something.

If I would have to answer why do people use drugs, I would say because it is rewarding, not necessarily saying that it generates a particular feeling of reward, I am saying that, for example, if someone is anxious and the drugs helps the person cope with that, then it becomes rewarding for that person, and so it is more likely to be used.

References

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing.

Ahmed, Serge H, Lenoir, Magalie, & Guillem, Karine. (2013). Neurobiology of addiction versus drug use driven by lack of choice. Current Opinion in Neurobiology, 23(4), 581-587.

Albert, P., Vahid-Ansari, F., & Luckhart, C. (2014). Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: Pivotal role of pre- and post-synaptic 5-HT1A receptor expression. Frontiers In Behavioral Neuroscience, 8, Frontiers In Behavioral Neuroscience, 2014 Jun 6, Vol.8.

Aldo Badiani, David Belin, David Epstein, Donna Calu, & Yavin Shaham. (2011). Opiate versus psychostimulant addiction: The differences do matter. Nature Reviews Neuroscience, 12(11), 685.

Badiani, A. (2013). Substance-specific environmental influences on drug use and drug preference in animals and humans. Current Opinion in Neurobiology, 23(4), 588-596.

Berridge, K. (2004). Motivation concepts in behavioral neuroscience. Physiology & Behavior, 81(2), 179-209.

Daglish, M., Wilson, T., Taylor, S., Lingford-Hughes, L., Williams, C., Brooks, D., . . . Nutt. (2008). Brain dopamine response in human opioid addiction. British Journal of Psychiatry, 193(1), 65-72.

Kalivas, P., & Volkow, N. (2005). The neural basis of addiction: A pathology of motivation and choice. The American Journal of Psychiatry, 162(8), 1403-13.

Kendler, K. S., Jacobson, K. C., Prescott, C. A., & Neale, M. (2003). Specificity of genetic and environmental risk factors for use and abuse/dependence of cannabis, cocaine, hallucinogens, sedatives, stimulants, and opiates in male twins. American Journal of Psychiatry, 160(4), 687-695.

Lopez-Quintero, Catalina, Cobos, José Pérez de los, Hasin, Deborah S., Okuda, Mayumi, Wang, Shuai, Grant, Bridget F., & Blanco, Carlos. (2011). Probability and predictors of transition from first use to dependence on nicotine, alcohol, cannabis, and cocaine: Results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Drug and Alcohol Dependence, 115(1-2), 120-130.

Mayseless, N. G., Shamay-Tsoory, S. P., Uzefovsky, F., Ebstein, R., & Shalev, I. (2013). The association between creativity and 7R polymorphism in the dopamine receptor D4 gene (DRD4). Frontiers in Human Neuroscience, Frontiers in Human Neuroscience, 26 August 2013.

Newlin, D. B. (2002). The self-perceived survival ability and reproductive fitness (SPFit) theory of substance use disorders. Addiction, 97(4), 427-445.

Psychology Today. (n.d.). Retrieved April 20, 2016, from https://www.psychologytoday.com/basics/addiction

Substance-Related and Addictive Disorders (n.d.). Retrieved April 20, 2016, from http://www.dsm5.org/

Sullivan, R., & Hagen, E. (2002). Psychotropic substance‐seeking: Evolutionary pathology or adaptation? Addiction, 97(4), 389-400.

Zabelina, D., Colzato, L., Beeman, M., & Hommel, B. (2016). Dopamine and the Creative Mind: Individual Differences in Creativity Are Predicted by Interactions between Dopamine Genes DAT and COMT. PloS One, 11(1), E0146768.