A plethora of experiments throughout the 1950s and 60s on rats (4), pigeons (5) and monkeys (6) seemingly proved, by administering various drugs of abuse to the animals often using an operant conditioning model, that the animals would self-administer the drugs compulsively, often resulting in addiction, overdose and/or death. However, the studies, especially on rats, all shared a common flaw – the animals were kept in solitary confinement in small cages with the option of either drugs or saline. They were placed in stressful conditions and given a choice between a pleasurable / reinforcing reward or no reward. Unsurprisingly, in almost all cases they continually self-administered the drugs. These experiments therefore better represent a model of high-risk human groups, rather than the general population (7). A researcher named Prof. Bruce Alexander noticed this and carried out the experiments differently. He repeated the experiments using the same methodology, except that post-weaning, some of the rats were moved to luxurious, spacious cages filled with obstacle courses and, crucially, other rats to form social bonds with; an ideal, stress-free environment. A further group of rats were weaned entirely in the “colony housing” environment. In these experiments, all the rats in the colony housing did not compulsively self-administer morphine, whereas the rats kept in isolation self-administered up to sixteen times as much (8,9); subsequent research also indicated a role of social isolation in morphine self-administration (10). Furthermore, there are multiple studies showing that (isolated) rats preferentially choose sweetened water over cocaine (11,12), and rats with sectioned glossopharyngeal nerves reject morphine solution (13). Alexander thus proposed a shift from exposure orientation – that an individual who uses addictive drugs more than once will inevitably become addicted – to adaptive orientation – the notion that addiction is likely only under certain circumstances, such as when concomitantly faced with severe distress and rewarding drugs (14). Indeed, despite many Vietnam war veterans becoming addicted to heroin while at war – an extremely stressful environment – very few relapsed into addiction once returning home to their families (14), and many recreational opiate users never fall into addiction (15).
Haney et al. (16) examined the effect of a social stressor – repeated exposure to aggressive attack by a same-sex opponent – and found that rats which had experienced the social stressor self-administered more cocaine than controls, with this effect becoming more pronounced over time. Another study found that rats exposed to a mild stressor (a foot-shock) prior to each drug session self-administered significantly more heroin than controls, implicating that exposure to stress appears to enhance the reinforcing effects of heroin (17). This finding is strongly corroborated in humans.
Stressful life events play an “integral role” in theories of drug addiction (18). Interestingly, studies as far back as the 1980’s have shown that minor, daily stressors have a greater negative impact on an individual’s overall well-being than major stressful life events (19,20), and that negative affective states such as anxiety are closely correlated with higher rates of cravings and relapse in alcoholism (21). In fact, the number of minor stressors and the perceived severity of these seems to predict the rate of cravings experienced by an individual undergoing addiction treatment (18). Recent findings show that opium addicts experience a higher rate of psychosocial stressors, and make significantly less use of problem-focused coping methods (restraint coping, seeking social support etc) and significantly more use of less useful coping methods including venting and mental disengagement, in comparison to normal subjects (22). It has previously been shown that individuals who experience higher levels of negative effect are more likely to use drugs or alcohol as coping mechanisms to provide distraction from unpleasant emotions (23). Furthermore, the negative reinforcement model of addiction – one of the most widely studied – posits that once an individual experiences physical dependence, their drug use is primarily motivated by the desire to avoid the negative affective states associated with withdrawal (24). However, alternative theories propose that individuals who report experiencing more stressful events are more likely to experience cravings because they have a heightened attention to stressors, including cravings (18). Regardless, research has proposed that some of the most effective ways to reduce the impact of stress on cravings and relapse is by providing effective social support, combating high levels of stress – through healthy, problem-focused coping methods – as well as addressing stressful environmental factors such as unemployment (18,25). This is again an example of a shift from the view that addictive drugs cause addiction, to the view that the individuals own biochemistry – which in turn is highly dictated by personal circumstance/stress – is responsible for the formation of addictive behaviours, and that effective treatments for drug addiction should therefore focus on correcting both the individuals stressful circumstances and teaching healthier, more effective coping mechanisms to manage stress throughout (and beyond) the addicts’ recovery.
So why is it that some individuals appear to be naturally more vulnerable to addiction than others? As well as obvious environmental factors – such as stressful environments and availability of drugs as opposed to other, non-drug rewards (7) – there appear to be numerous biochemical differences between individuals who show a predisposition towards ineffective, harmful mechanisms of dealing with stress (e.g. drugs), and those who are less susceptible to drug addiction and more likely to utilise healthy coping mechanisms. Indeed, in both humans and animals, the propensity to develop compulsive self-administration of rewarding drugs under stable laboratory conditions varies among individuals with equal access to the drugs (26). It has even been shown that pre-natal stress can play a role in the likelihood of developing drug addiction. Individuals predisposed to addiction show a higher behavioural locomotor reactivity to both novelty and psychostimulant drugs (27,28) (in contrast, individuals which show a low behavioural and hormonal reactivity to novelty will self-administer amphetamine initially, but will not maintain this behaviour and become addicted (29)), and prenatal stress is correlated with both an increased locomotor reactivity to drugs and novelty compared to controls, and an increased level of amphetamine self-administration in rats (30). However, the predisposed animals also show a greater release of corticosterone under these conditions (27), an apparently innate biochemical variance between predisposed individuals and those not predisposed to addiction. Corticosterone is the primary corticosteroid hormone produced in the adrenal cortex of rats, analogous to cortisol in humans (although corticosterone is present in human cerebrospinal fluid, it only has significant effects on neuroendocrine function in supraphysiological concentrations (31)).
Increased levels and duration of corticosterone secretion, either intrinsically or induced by stress has been shown to not only increase the predisposition of rats to develop drug addiction (26), but to predict individual vulnerability (29). Furthermore, corticosterone administration in non-predisposed rats (low responders, LR) was directly correlated with increased amphetamine self-administration in those individuals, and even re-established self-administration in LR rats which had previously ceased self-administration (29), strongly suggesting a role of the hypothalamic-pituitary-adrenal (HPA) axis in the pathogenesis of addiction. Additionally, Lewis rats appear to show a greater vulnerability to compulsive self-administration of reinforcing drugs (32,33), and also exhibit lower basal corticosterone levels (34).
It is hypothesised that this association between higher levels of corticosterone and a greater vulnerability to drug addiction is due to an interaction between corticosterone and the dopaminergic (DA) system. There are three main pillars for this argument: (i) many rewarding drugs of abuse, especially psychostimulants, act on the DA system to exert their reinforcing effects (35,36) – this is the foundation of the extensively studied dopaminergic hypothesis of addiction which garnered a great deal of support over the last few decades (37) – and rats which show a high vulnerability to addiction exhibit a 250% higher basal dopamine concentration in the nucleus accumbens (NAc) than LR rats (38); (ii) DA neurons express corticosterone receptors (39) and (iii) corticosterone – both secreted endogenously in response to stress or administered exogenously, mimicking the intrinsic stress response – appears to directly stimulate DA neurons (40), and furthermore is necessary for the sensitisation of the DA system induced by amphetamine to occur (41), and subsequently modify the functioning of the HPA axis (42). Further evidence of the involvement of the HPA axis in addiction is afforded by a series of studies in which adrenalectomy – the removal or inhibition of the adrenal glands – significantly reduced the response to cocaine in rats (26) and induced a reduction in self-administration of the drug (43). A bilateral adrenalectomy completely abolished self-administration and, significantly, this effect was reversed when corticosterone was administered to the rats via their drinking water (43). This effect was also observed in ethanol addicted rats (44), as well as morphine dependent rats (45), confirming that this is not a phenomenon unique to cocaine. Furthermore, chronic ethanol exposure leads to significant alterations in corticosterone levels and dysregulation of the HPA axis (46). These findings are significant because it is known that chronic exposure to stress can also lead to alterations in the homeostatic functioning of glucocorticoids, thus leading to alterations in DA neuronal function (47), which itself is strongly implicated in the pathogenesis of addiction (37).
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| Figure 1: Major components of the stress response mediated by the hypothalamic–pituitary–adrenal (HPA) axis. From Stephens & Wand, 2012. |
The HPA axis refers to a neuroendocrine system composed of three components which together mediate the primary physiological response to stress – the paraventricular nucleus (PVN) of the hypothalamus, the anterior lobe of the pituitary gland, and the adrenal gland, together forming the hypothalamic-pituitary-adrenal (HPA) axis. In response to stress, the hypothalamus releases corticotrophin-releasing factor (CRF), which on binding to receptors in the pituitary, induce the release of adrenocorticotropic hormone (ACTH), which in turn binds to receptors in the adrenal cortex ultimately stimulating the release of glucocorticoids, primarily cortisol in humans or corticosterone in rats (48). It is known that cortisol, like corticosterone, can influence a individuals cognitive processes, promoting reward learning, which may play a role in relapse in addiction (48). Cortisol has been reported as an indicator of DA sensitivity and a predictor of the amount of craving for nicotine (49) and is implicated in the rewarding effects of other reinforcing substances including psychostimulants (50). Furthermore, stress-induced CRF is also considered a predictor of relapse, and is thought to be responsible for some of the stressful effects of withdrawal, including an increase in anxiety (51). CRF is known to play a crucial role in smoking addiction – along with Neuropeptide Y, the orexins, and norepinephrine – by briefly decreasing subjective stress levels but over time leading to a dysregulation of brain systems underlying stress (52), similar to findings with chronic alcohol exposure (46).
The hypothalamus component of the HPA axis is modulated by both diurnal and metabolic signals, as well as by the limbic system and prefrontal cortex. Chronic alcohol and nicotine use is known to induce modifications in these frontal–limbic interactions which may account for the HPA response differences observed in chronic users (53), and nicotine withdrawal is associated with a dramatic decrease in cortisol levels (54). Thus, it appears that glucocorticoids including cortisol / corticosterone – the primary mediators of the stress response – are functionally linked with the DA system, and that their functioning is altered by chronic use of addictive substances, which may be important in the pathophysiology of drug addiction.
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| Figure 2: Dysregulation of brain systems underlying stress by smoking addiction. From Bruijnzeel, 2012. |
This has been proposed in the literature over a decade ago by Piazza & Le Moal (26). In addition to observations that animals showing a high vulnerability to addiction exhibit a 250% higher basal dopamine concentration in the NAc than non-predisposed animals (38), suppression of corticosterone by adrenalectomy almost halved the NAc extracellular dopamine concentration, as measured by microdialysis (55). Furthermore, restoring the basal levels of the hormone completely reversed this effect. Various mechanisms have been proposed regarding the biochemical pathways by which glucocorticoids modulate (up-regulate) the DA system. Firstly, corticosterone appears to up-regulate the synthesis of dopamine via interactions with tyrosine hydroxylase, an enzyme which converts the amino acid L-Tyrosine to L-DOPA, the precursor to dopamine (56,57). Second, glucocorticoids have been shown to decrease monoamine-oxidase activity (58,59), the key enzyme which catalyses the oxidative break-down of dopamine. Thirdly, glucocorticoids may decrease dopamine reuptake at the synaptic cleft (60), thus enhancing the effects of dopamine. Drugs of abuse with different mechanisms of action, as well as stress, all act to increase the strength of excitatory synapses in midbrain DA neurons; however drugs with little or no abuse potential do not. Moreover, the effects of stress on these synaptic changes are blocked by the glucocorticoid antagonist RU486, while the effects of cocaine on these changes are not (61). This suggests a role of synaptic plasticity at midbrain excitatory DA neurons induced by rewarding drugs as a possible mechanism underlying their reinforcing effects. Furthermore, serotonin, endogenous opioids, glutamate and y-aminobutyric acid (GABA), which all modulate the DA-dependent effects of psychostimulants (62), are themselves modulated by glucocorticoid pathways (63). Thus, increased levels of corticosterone secretion, or cortisol in humans, whether intrinsically or induced by stress, appears to up-regulate the DA system, acting to enhance the reinforcing effects of drugs and increase the vulnerability to addiction. Pharmacological manipulations of corticosterone secretion have been examined as therapeutic targets for the treatment of addiction. Rats placed under stress (food restriction) which showed higher corticosterone levels were injected with metyrapone, a corticosterone synthesis inhibitor, which abolished the increased locomotor response to cocaine – a hallmark of increased vulnerability to addiction – induced by stress, as compared to controls injected with saline (64). However, despite the apparent strength of these findings, there have been remarkably few recent studies following this avenue of research.
As aforementioned, the consensus in the scientific literature is that the best way to treat addiction is to replace the addicts’ bond with the drug with healthy bonds, and to teach more effective ways of coping with stress – such as by the communication skills training approach (65,66). Recent research by Tops et al (2014) provides a model for the neurobiological basis of this, proposing that stress coping and social attachment share overlapping neurobiological systems (67). Responding to a novel stressor requires initial novelty processing and activation of learning mechanisms which enable habituation to the stressor. Similarly, forming attachments to novel individuals involves a similar process of novelty processing and habituation to their rewarding – or stressful – properties as the person becomes familiarised with the novel individual. The authors propose that “oxytocin facilitates social attachment and protects against addiction by stimulating the shift from novelty seeking to preference of familiarity”, and discuss findings in humans which support the notion that oxytocin facilitates this shift in part due to alterations in corticostriatal loops which mediate the derogation of alternatives. This serves to decrease novelty seeking and favour social attachment over the use of drugs as alternatives to healthy social connections. It is proposed that oxytocin exerts these effects in part via downstream modulation of dopaminergic, serotonergic and endogenous opioid systems – the latter two of which have been implicated in the drive to withdraw and seek pleasure (68). The authors conclude that this role of oxytocin supports the favouring of social bonds over drug use and serves to “increase resilience in the face of stress and addiction” (67).
Finally, orexins – a family of neuropeptides which regulate numerous processes including wakefulness (69), appetite (70) and mood (71) – are known to modulate the HPA axis in response to stressful stimuli (72). For example, Orexin-A stimulates the HPA axis resulting in an increased release of corticosterone and ACTH (73), thus implicating its importance in stress and addiction (74). Furthermore, dense orexinergic innervations are observed in many of the same brain regions as those expressing CRF, and many of these project to the ventral tegmental area and NAc (72), both brain regions comprising the mesolimbic reward pathway widely considered important in addiction (37). Thus, orexins are currently being studied in relation to the motivational drive for rewarding drugs such as psychostimulants (75), morphine (76,77), alcohol (78) and nicotine (79). Therefore, individual differences in the expression of orexins may further contribute to an individual’s vulnerability to addiction, through some of the same pathways that corticosterone/cortisol stimulate in response to stress.
Thus, a growing body of research suggests that, while overuse of some rewarding drugs can result in physical dependency, it is not the drug itself which principally leads to addiction, but the substrate by which it acts – i.e. the innate biochemistry of the user, their environment, and the ways in which the individual responds to and copes with stress. Humans have an innate desire to form connections, and when their environment cannot offer that, they will bond with something which gives them a sense of relief – be it rewarding drugs, gambling, smartphones or pornography (2). Addiction treatment should therefore focus on correcting the individuals’ maladaptive responses to stress, providing social support and fostering a stress-free environment which favours healthy social bonds and healthy, productive connections – rather than social stigma, unemployability and incarceration.
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