Neurobiological Mechanisms of Opiate Addiction

Opiate use and addiction is a global issue, with approximately 16.5 million people – 0.4% of the world’s population – using worldwide (United Nations Office on Drugs and Crime, 2015). In the United States especially opiate use has become an increasing problem, with approximately 3.8% of the U.S. population engaging in illicit opiate use (United Nations Office on Drugs and Crime, 2015). With the rise in opiate use, there has also been a rise in opiate addiction; a 2016 survey on drug use and abuse found that 2,144 of the 267,286 respondents – approximately 0.8% – met the criteria for an opioid use disorder (Center for Behavioral Health Statistics and Quality, 2017).

Opiate addiction is a serious health concern that often impacts an individual for the rest of their life, as many people with opiate addiction frequently experience relapse; a 33-year follow-up study found that 40.5% of the 242 the people who had received opiate addiction treatment 33 years ago reported using heroin within the past year (Hser, Hoffman, Grella, & Anglin, 2001; Leshner, 1997).  Besides relapse, other hallmarks of opiate addiction include anhedonia, anxiety, and impaired decision making that often results in the person making decisions they would normally have never made, such as lying to and stealing from loved ones in order to continue using (Haertzen, Meketon, & Hook, 1970; Petry, Bickel, & Arnett, 1998; Snodgrass, 2017; Zijlstra, Booij, van den Brink, & Franken, 2008). These symptoms of opiate addiction stem from the neurobiological changes that occur with chronic opiate abuse.

One prominent aspect of opiate addiction is anhedonia, or a lack of pleasure (Franken, Rassin, & Muris, 2007). Anhedonia is largely due to changes in the mesolimbic dopamine system. One major change prompted by chronic opiate abuse is to type-two dopamine receptors; Martinez et al. (2012) found a significant decrease in the number of striatal D2 receptors, meaning that there is less binding potential for dopamine in the mesolimbic dopamine system. Furthermore, although acute opiate use indirectly stimulates the release of dopamine from the VTA, doing so triggers a signaling cascade that results in decreased dopamine use with chronic opiate abuse (Di Chiara & Imperato, 1988). This signaling cascade begins when dopamine released from the VTA binds to the NAc, where it activates cyclic-AMP, or cAMP (Beaulieu & Gainetdinov, 2011). Cyclic-AMP then activates cyclic-AMP response binding element binding protein (CREB), via PKA, and CREB, in turn, increases dynorphin release (Carlezon et al., 1998; Chao & Nestler, 2004; Montminy & Bilezikjian, 1987).

Dynorphin, an endogenous opioid peptide, then binds to the KOP receptors on the VTA and causing a decrease in dopamine release (Chavkin, James, & Goldstein, 1982; Spanagel, Herz, & Shippenberg, 1992). In this way, the acute release of dopamine caused by acute opiate use prompts a negative feedback loop via the cAMP-CREB-dynorphin signaling cascade that ultimately leads to a decrease of dopamine in the mesolimbic dopamine system. The cAMP-CREB-dynorphin signaling cascade contributing to drug-induced anhedonia was confirmed by Newton et al. (2002), who found that inhibiting either CREB or dynorphin decreased anhedonia. Combined, the decrease in striatal D2 receptors and the decreased release of dopamine means there is decreased activation of the mesolimbic dopamine system, resulting in anhedonia. This anhedonia is a key aspect of the negative reinforcement theory of addiction, in which a person continues using to avoid undesirable feelings. In the case of opiate addiction, after chronic use produces the neurobiological changes above, the person continues using opiates to avoid anhedonia (Koob & Volkow, 2010).

Another prominent aspect of opiate addiction, particularly opiate withdrawal, is anxiety (Haertzen, Meketon, & Hook, 1970). One of the main ways opiates can produce anxiety is by dysregulating the hypothalamic-adrenal-pituitary, or HPA, axis. Cortisol-releasing factor, or CRF, is released from the hypothalamus and binds to the anterior pituitary, where it releases both β-endorphins and adrenocorticotropic hormone (ACTH); ACTH then binds to the adrenal cortex, which releases glucocorticoids that bind to the hypothalamus and inhibit the release of CRF, creating a negative feedback loop (Kreek, Nielsen, Butelman, & LaForge, 2005). The main human glucocorticoid, cortisol, rises during times of stress, reflecting activation of the HPA axis (Buchanan, Al’Absi, & Lovallo, 1999). Acute opiate use also activates the HPA axis, raising CRF and ACTH levels and producing an anxiogenic-like response (Buckingham, 1982; Zhou et al., 1999).

Opiate withdrawal can also cause anxiety by dysregulating the HPA axis. Heinrichs, Menzaghi, Schulteis, Koob, and Stinus (1995) found anxiety during withdrawal could be decreased by suppressing CRF activity in the amygdala, suggesting that opiate withdrawal caused HPA activation. Similarly, Bearn, Buntwal, Papadopoulos, and Checkley (2001) found that cortisol levels were increased during opiate withdrawal, showing an increase in HPA activity. Like anhedonia, increased anxiety is another key aspect of the negative reinforcement theory of addiction, with people continuing to use opiates in order to avoid the increased feelings of anxiety (Koob & Volkow, 2010).

Opiate addiction also causes impaired decision making, meaning that the individual often makes choices they typically would not have made before developing an addiction. These choices include the lengths they will go to in order to secure more of the drug, such as stealing from their loved ones or selling sex, as well as continuing to use despite the negative consequences (Ravitz & Somra, 2017; Snodgrass, 2017). The indirect release of dopamine caused by the acute use of opiates plays a role in this impaired decision making. Dopamine release assigns salience, meaning it cues the mind to pay particular attention to the stimulus and assign it importance; this dopamine-driven salience is what creates the intense craving or “needing” of a drug people with addiction experience (Berridge & Valenstein, 1991; Volkow et al., 2002).

Changes in dendritic branching also play a large role in the impaired decision making seen in people with opiate addictions. While acute dopamine release in the NAc assigns increased salience to the drug, chronic morphine use causes decreased dendritic branching in the NAc (Robinson, Gorny, Savage, & Kolb, 2002). This decreased dendritic branching reflects the specialized learning taking place in the NAc, in which the drug is gaining salience and become more important than most everything else in the person’s life – it is this shift in importance that causes people to continue using despite the severe repercussions (Chao & Nestler, 2004; Volkow & Li, 2004). Furthermore, Saal, Dong, Bonci, and Malenka (2003) found an increase in the AMPA to NMDA ratio in midbrain dopamine neurons, reflecting increased long-term potentiation; this finding also supports the idea that a form of specialized learning occurs in the NAc during chronic opiate use (Chao & Nestler, 2004; Volkow & Li, 2004).

While specialized learning occurs in the NAc, changes in dendritic branching are happening elsewhere in the brain as well. Decreased branching occurs in the medial prefrontal cortex (Robinson et al., 2002). Given the mPFC’s role in cognitive control and decision making, this decreased branching reflects the individual’s impaired ability to rationally calculating the pros and cons of continued drug use (Ridderinkhof, Ullsperger, Crone, & Nieuwenhuis, 2004). In contrast, there is increased branching in the orbitofrontal cortex, an area of the brain highly implicated in goal-and-reward-driven decision-making (FitzGerald, Seymour, & Dolan, 2009; Robinson et al., 2002; Valentin, Dickinson, & O’Doherty, 2007). This increased branching reflects the increased salience assigned to the drug; in other words, the individual has learned the drug is the most important thing and the increased branching reflects the biased decision making in evaluating the importance of the reward of using the drug once again compared to everything else (Volkow & Li, 2004). Combined, these neurobiological changes reflect how the drug becomes seemingly the most important thing in the individual’s life, leading them to make decisions they ordinarily would never consider.

These neurobiological changes help explain why people with opiate addiction experience such frequency relapse (Hser et al., 2001; Leshner, 1997). Together, anhedonia and anxiety contribute to the negatively reinforcing effects of opiate withdrawal, which motivates people to continue using or return to using in order to escape these negative feelings (Koob & Volkow, 2010). At the same time people are feeling a lack of pleasure and increased stress, the area of the brain responsible for decision-making has weakened, while the area focused on reward-driven decisions and the area responsible for assigning importance to stimuli have strengthened, reflecting the increased learning about drug using that primes an individual to return to use (Chao & Nestler, 2004; Volkow & Li, 2004).

Given these neurobiological changes, it is unsurprising that opiate addiction is difficult to overcome. This is problematic for individuals struggling to stop using, especially considering how lethal opiates can be; in 2007, 11,499 people died from an unintentional drug overdose while abusing prescription opioids and in 2013, 8,257 people died heroin-related deaths (Okie, 2010; United Nations Office on Drugs and Crime, 2015). The actions people with opiate addiction make in order to secure and use more of the drug – such as lying to or stealing from loved ones – can also put a serious strain on or destroy their personal relationships (Ravitz & Somra, 2017; Snodgrass, 2017). Opiate addiction is also problematic for society as a whole. Although 3.8% (the estimated percentage of opiate users in the United States) may not seem particularly high, Mark, Woody, Juday, and Kleber (2001) estimated that the United States lost approximately $21.9 billion on heroin addiction, reflecting the huge drain of societal resources opiate addiction causes (United Nations Office on Drugs and Crime, 2015). In this way, opiate addiction impacts more than just the individual but their friends, family, and community as well.