The Neurobiology of Cocaine Addiction

Addiction was historically viewed as a disease of “weak personality” and wasnot systematically addressed by the scientific and medical communities until the latter half ofthe 20th century. Pioneering studies in the 1960s and 1970s led to the development of methadone,the first (and still effective and widely used) treatment for the long-term management ofaddictions to heroin and other opiates (1–3). These factors include epigenetic changes, addict mindset, and social influences,including peer pressure, family environment, and especially, response to stress and stressors(see below).

COCAINE’S INITIAL EFFECT: DOPAMINE BUILDUP

• These findings are consistent with theories implicating cocaine-induced damage to the mesencephalic dopamine (DA) system (Franken et al., 2005; Spanagel and Weiss, 1999).
• Thus, a logical extension of these results is that an increase in the relative weight of GluN2B subunits in synaptic NMDARs facilitates the induction of LTP at excitatory synapses.
• (Graph inset) The time courses of cocaine-induced buildup of ΔFosB and cocaine-related structural changes (dendrite sprouting) suggest that these neurobiological effects may underlie some of the drug’s short-term, medium-term, and long-term behavioral effects.
• Taken together, these pre-clinical findings suggest that L-type calcium channels blockers and NMDA antagonists have potential as treatment to alleviate neuronal damage caused by increased calcium influx and chronic ischemia.
• Thus, a selective KOP-r partial agonist could prevent stress-induced activation ofKOP-r, contributing to relapse while also providing required homeostatic countermodulation ofdopaminergic systems (25, 37, 42).

Recruitment of the LIFG may be indicative of short-term abstinence whereas with prolonged abstinence a pattern topographically typical of normal, healthy controls may emerge, though with the LA group displaying elevated activity levels. Should the transition from relying on left to right IFG be a result of abstinence, it is likely this may only develop with protracted abstinence as short periods of abstinence followed by relapse may not allow this to occur (Volkow et al., 2001; Wang et al., 2004). The regions observed for STOPS (Table 2) were consistent with meta-analyses of this and similar tasks (Buchsbaum et al., 2005; Garavan et al., 2006).

Newer approaches to treating addiction: drug vaccines

Introducing lesions into the OFC fostered habitual behavior48 as did inhibiting OFC projection neurons and OFC synapses with the chemogenetic tools using the DREADD procedure.49 Conversely, increasing OFC firing and OFC to DMS input using activation via channelrhodopsin (ChR2) increased habitual behaviors in his model. Finding addiction vulnerability genes will enable us to identify individuals who are at particular risk for an addictive disorder and target them for educational and other preventive measures. It will also help us understand how factors other than genetics contribute to the development of addiction. For example, it has long been known that stress can increase an individual’s risk for addiction, but how stress produces this effect, and why it does so in some individuals but not others, remains a mystery. Extensive epidemiological studies show that roughly half of a person’s risk for addiction to cocaine or other drugs is genetic (Goldstein, 2001; Nestler and Malenka, 2004).

The role of dopamine in addiction

The main active metabolites of heroin and abused prescription opioids act primarily asagonists at MOP-r. Once in the brain, heroin is rapidly converted to the biologically activemetabolites morphine and monoacetylmorphine (45). Thesecompounds bind MOP-r (e.g., on interneurons in the substantia nigra and ventral tegmental area)and relieve GABAergic inhibition of dopaminergic neurons (46).

• Rachel Tyndale (Centre for Addiction and Mental Health, University of Toronto) described how common pharmacogenomic variation in drug‐metabolizing genes affects individuals’ abilities to quit smoking and/or respond to drug treatments for nicotine dependence.
• Those later in treatment were allowed leave the facility on their own recognizance but were evaluated by clinical staff (including urine toxicology) upon their return.
• SiRNA directed toward the mouse Oprm1 or GFP (as a control) wereinfused bilaterally into mouse midbrain dopaminergic areas.

Box 1. Brain reward pathways, the nucleus accumbens (NAc), and addiction.

Two important aspects of executive control implicated in addiction are inhibitory control and performance monitoring (Garavan and Hester, 2007). Performance monitoring processes (e.g., error detection and conflict monitoring) have been ascribed to the anterior cingulate cortex (ACC) (Botvinick et al., 1999; Botvinick et al., 2001; Kiehl et al., 2000; MacDonald et al., 2000; Menon et al., 2001; Ruchsow et al., 2002; Ullsperger and von Cramon, 2001; van Veen and Carter, 2002). Indeed, cocaine misusers are at higher risk of ischemic and hemorrhagic strokes in the brain than non-users (Levine et al., 1987; Tuchman et al., 1987; Levine et al., 1991) and imaging studies in cocaine misusers have documented marked decreases in CBF, which are most prominent in PFC (Volkow et al., 1988). Cocaine can also disrupt the integrity of the blood-brain barrier, making the central nervous system more susceptible to toxins and potentially leading to inflammatory responses (Fiala et al., 1998). The blood-brain barrier acts as a protective shield, preventing harmful substances from entering the brain.

Transcriptional and epigenetic markers of addiction and implications for treatment

This is consistent with the findings reported above in preclinical models of attenuated blood flow in PFC of chronically treated animals. We have used siRNAs to demonstrate the critical role of the MOP-r in the substantia nigra andventral tegmental area (where cell bodies for the nigrostriatal and mesolimbic dopaminergicsystems are located) on heroin-induced rewarding effects (53). SiRNA directed toward the mouse Oprm1 or GFP (as a control) wereinfused bilaterally into mouse midbrain dopaminergic areas. This siRNA infusion significantlyreduced Oprm1 mRNA levels and MOP-r–binding density in these regionsand also reduced the locomotor response to heroin and heroin-induced CPP (53).

A recent meta-analysis looking at functional studies from 2000–2017 using CBF to identify brain structures involved in relapse and remission identified only 3 papers that specifically focused on cocaine use disorders (CUD) (Forster et al., 2018). These papers identified different regions whose activation or inhibition predispose patients to increased risk of relapse or remission. Activation of the left posterior hippocampus as determined by relative CBF increases was the only difference observed in voxel-wise whole brain analysis in CUD patients that predicted relapse within 30 days of discharge (Adinoff et al., 2015). Rachel Tyndale (Centre for Addiction and Mental Health, University of Toronto) described how common pharmacogenomic variation in drug‐metabolizing genes affects individuals’ abilities to quit smoking and/or respond to drug treatments for nicotine dependence.

Other signaling pathways downstream of BDNF, such as AKT-mTOR as just one example, are also likely involved in the regulation of synaptic structure and function and warrant further study. In 1931, Edwin Holt suggested in his well-known essay, entitled “Animal drive and the learning process,” that some embryonic or developmental mechanisms might be used during learning4. It is generally true that younger brains are better in forming memories and, by analogy, are more vulnerable to the plastic changes that underlie addiction5,6. These considerations raise the possibility that the neurobiology of cocaine addiction pmc addiction, and other forms of extremely durable emotional memory, are mediated in part by mechanisms normally involved in development. In other words, drugs of abuse awaken and then utilize in key brain regions highly efficient plasticity mechanisms, which normally occur during development, to produce abnormally robust and stable forms of memories related to addiction. Taken together, the current literature on CUD supports tripartite pathophysiology with neuronal, vascular and astrocytic contributions.

Excessive activation of the reward system, as in the case of excessive drug use, can also engage the brain’s stress system. As individuals who have become dependent on drugs lose normal function of aspects of their reward systems, they can gain activation of their stress system as well. In the last two decades, scientists have determined how cocaine produces intoxication through its initial effects in the brain’s limbic system, and we are beginning to understand the neurobiological mechanisms underlying the drug’s later developing and longer lasting effects of craving and relapse vulnerability. Among the most intriguing of these mechanisms is elevation of the genetic transcription factor ΔFosB, a molecule that lasts for approximately 2 months and theoretically can promote neuron structural changes that have potentially lifelong persistence.

They proposed that this cocaine-induced long-term depression (LTD)-like effect may be accompanied by generation of AMPAR-silent synapses128. Subsequent studies from the Wolf laboratory showed that the cell surface levels of AMPARs in NAc neurons are not altered after short-term cocaine withdrawal, suggesting that the potentially altered AMPAR/NMDAR ratio during early withdrawal periods is likely due to changes in NMDARs129. These studies, together with related work in hippocampus77,80,93, paved the road toward the demonstration of cocaine-induced synaptic insertion of GluN2B NMDARs and generation of silent synapses in the NAc51,52. In contrast to early withdrawal periods, the cell surface and synaptic levels of AMPARs, particularly calcium-permeable AMPARs (CP-AMPARs), are increased in the NAc after prolonged withdrawal from cocaine self-administration130,131.

The dark side of addiction: stress neurocircuitry/mechanisms underlying addiction

Therefore, cocaine effects on cerebrovascular reactivity may complicate the interpretation of BOLD contrast fMRI as well as results from other imaging studies that rely on CBF measurements. To date, most efforts to develop new medications for treatment of cocaine addiction have focused on preventing or suppressing the drug’s acute effects. Cocaine “vaccines,” for example, are designed to bind cocaine molecules in the blood with antibodies and so keep them from getting into the brain. A related approach seeks to develop a medication that keeps cocaine from tying up the dopamine transporter without itself interfering with the transporter’s normal function of dopamine retrieval.

As discussed in prior sections, rodent studies have shown that chronic cocaine triggers vasoconstriction, reduces CBF, and results in cerebral ischemia (Zhang et al., 2016). By applying integrated optical imaging to investigate these phenomena, we documented that despite significant proliferation of blood vessels in areas of vasoconstriction (Zhang et al., 2016; Allen et al., 2019; Du et al., 2020), CBF remained reduced even after 1 month of cocaine detoxification (Du et al., 2020). This could explain why deficits in executive control can persist in cocaine users even months after drug discontinuation (Rezapour et al., 2016). Mark Kleiman (New York University) discussed the societal effects of addiction and public policies aimed to curb addiction. It is clear that addiction and drugs of abuse can have negative consequences on public safety and public health, whether in the form of overdose, sexually transmitted diseases, violence, or drunk driving. What may be less clear, however, is that the public policies put in place to mitigate these harms may have unintended consequences of their own.