The Neurobiology of Addiction
The Neurobiology of Addiction
Addiction is a primary, chronic, neurobiological disease—with genetic, psychosocial, and environmental factors influencing its development and manifestations.126NPC and JCAHO. Pain: Current Understanding of Assessment, Management, and Treatments. 2001 p17
Its behavioral characteristics can include impaired control over drug use, compulsive use, continued use despite harm and craving.127Katz NP et al. Challenges in the Development of Prescription Opioid Abuse-deterrent FormulationClin J Pain, Volume 23, Number 8, October 2007, p650
Dependence is defined as a state of adaptation that is manifested by a drug-class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.128Galinkin J, Koh JL. Recognition and management of iatrogenically induced opioid dependence and withdrawal in children. Pediatrics. 2014. p1.
Tolerance is a state of adaptation in which exposure to a given dose of a drug induces biologic changes that result in diminution of one or more of the drug’s effects over time. Alternatively, escalating doses of a drug are required over time to maintain a given level of effect.129Katz NP et al. Challenges in the Development of Prescription Opioid Abuse-deterrent FormulationClin J Pain, Volume 23, Number 8, October 2007, p650.
Addiction is not an inevitable consequence of substance use. Addiction develops as a complex function of biology, environment, and psychosocial characteristics. These factors include: a person’s genetic makeup and other individual psychological factors related to a person’s unique history and personality.130Surgeon General. Facing addiction in America. U.S. Department of Health & Human Services2016. p64-65
Environmental factors, such as the availability of drugs, family and peer dynamics, financial resources, cultural norms, exposure to stress, and access to social support can play a role in addiction.131Surgeon General. Facing addiction in America. U.S. Department of Health & Human Services2016. p64-65
Risk factors of addiction
Some of these factors increase risk for substance use, misuse, and use disorders, whereas other factors provide buffers against those risks. Nonetheless, specific combinations of factors can drive the emergence and continuation of substance misuse and the progression to a disorder or an addiction.132Surgeon General. Facing addiction in America. U.S. Department of Health & Human Services2016. p64-65
How drugs produce pleasure
Addiction is linked to many of the brain systems involved in motivation and reward. These “rewarding effects” positively reinforce their use and increase the likelihood of repeated use. The rewarding effects of substances involve activity in the nucleus accumbens, including activation of the brain’s dopamine and opioid signaling system.133Surgeon General. Facing addiction in America. U.S. Department of Health & Human Services2016. p71
Such drugs are thought to hijack neural systems that mediate behaviors normally directed towards natural rewards such as food, water, and sex.134 Hunt SP, Urch CE. Pain, opiates and addiction. Wall and Melzack, Textbook of Pain, 5th Edition, p.351.
Which parts of the brain are affected by drug use?
While dopamine is critical for acute reward and the initiation of addiction, end-stage addiction results primarily from cellular adaptations in anterior cingulate and orbitofrontal glutamatergic projections to the nucleus accumbens. These changes are believed to reduce the capacity of the prefrontal cortex to provide executive control over compulsive drug seeking. Simultaneously, the prefrontal cortex is hyperresponsive to stimuli predicting drug availability, resulting in supraphysiological glutamatergic drive in the nucleus accumbens, where excitatory synapses have a reduced capacity to regulate neurotransmission.135Kalivas PW, Volkow ND. “The neural basis of addiction: a pathology of motivation and choice”. Am J Psychiatry 162 (8) 2005. 1403.
How dopamine reinforces drug use
Acute drug use causes the release and prolonged action of dopamine and serotonin within the reward circuit. Different types of drugs produce these effects by different methods. Dopamine (DA) appears to harbor the largest effect and its action is characterized. DA binds to the D1 receptor, triggering a signaling cascade within the cell.136Fulton BS. Physiological Basis of Addiction. Drug Discovery for the Treatment of Addiction: Medicinal Chemistry Strategies. 2014. p1.
In addition to the reward circuit, it is hypothesized that stress mechanisms also play a role in addiction. Koob and Kreek have hypothesized that during drug use corticotropin-releasing factor (CRF) activates the hypothalamic-pituitary-adrenal axis (HPA) and other stress systems in the extended amygdala. This activation influences the dysregulated emotional state associated with drug addiction. They have found that as drug use escalates, so does the presence of CRF in human cerebrospinal fluid (CSF).137Fulton BS. Physiological Basis of Addiction. Drug Discovery for the Treatment of Addiction: Medicinal Chemistry Strategies. 2014. p2.
Drug-seeking behavior is induced by glutamatergic projections from the prefrontal cortex to the nucleus accumbens (NAc). Drug-seeking behavior is most likely a result of the synaptic changes which have occurred due to repeated drug exposure. This idea is supported with data from experiments showing the drug-seeking behavior can be prevented following the inhibition of glutamate receptors and glutamate release in the NAc.138Fulton BS. Physiological Basis of Addiction. Drug Discovery for the Treatment of Addiction: Medicinal Chemistry Strategies. 2014. p2.
Addiction to drugs can cause damage to the brain due to allostatic load. The dysregulation of allostasis gradually occurs as the reward from the drug decreases and the ability to overcome the depressed state following drug use begins to decrease as well.139Fulton BS. Physiological Basis of Addiction. Drug Discovery for the Treatment of Addiction: Medicinal Chemistry Strategies. 2014. p2
Depending on the history of drug use, excitatory synapses in the nucleus accumbens (NAc) experience two types of neuroplasticity: long-term potentiation (LTP) and long-term depression (LTD). Another aspect of drug addiction is a decreased response to normal biological stimuli, such as food, sex, and social interaction. Hyperactivity in areas of the brain of addicted subjects is involved in the more intense motivation to find the drug rather than seeking natural rewards, as well as a decrease in the addicted individual’s ability to overcome this urge. Brain imaging has also shown cocaine-addicted subjects to have decreased activity, as compared to non-addicts, in their prefrontal cortex when presented with stimuli associated with natural rewards.140 Fulton BS. Physiological Basis of Addiction. Drug Discovery for the Treatment of Addiction: Medicinal Chemistry Strategies. 2014. p3.
A transcription factor, known as DeltaFosB, is thought to activate genes that, counter to the effects of cAMP response element binding protein (CREB), actually increase the user’s sensitivity to the effects of the substance. DeltaFosB slowly builds up with each exposure to the drug and remains activated for weeks after the last exposure—long after the effects of CREB have faded. The hypersensitivity that it causes is thought to be responsible for the intense cravings associated with drug addiction and is often extended to even the peripheral cues of drug use, such as related behaviors or the sight of drug paraphernalia. There is some evidence that DeltaFosB even causes structural changes within the nucleus accumbens, which presumably helps to perpetuate the cravings, and may be responsible for the high incidence of relapse that occur in treated drug addicts.141Fulton BS. Physiological Basis of Addiction. Drug Discovery for the Treatment of Addiction: Medicinal Chemistry Strategies. 2014. p4.
Updates for Professionals.
US healthcare professionals can register to be notified when new resources and information become available.