Dependence, tolerance and addiction issues

Addiction is a primary, chronic, neurobiologic disease — with genetic, psychosocial, and environmental factors influencing its development and manifestations. Its behavioral characteristics can include impaired control over drug use, compulsive use, continued use despite harm and craving.¹ Addiction is not defined by physical dependence, which is the state of adaptation that is manifested by a withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and administration of an antagonist.²

Addiction is also not defined by tolerance, which describes the 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.³

Addiction is linked to many of the brain systems involved in motivation and reward.⁴ Most addictive drugs directly or indirectly cause the release of dopamine in the reward circuit of the mesolimbic pathway.^5, 6

Addictive drugs are thought to highjack neural systems that mediate behaviors normally directed towards natural rewards such as food, water and sex.⁷

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.^{8, 9, 10} These changes are believed to reduce the capacity of the prefrontal cortex to provide executive control over compulsive drug seeking.¹¹

Addiction also produces persistent stress and depression as the central nervous system and hypothalamic-pituitary-adrenal axis are chronically dysregulated by corticotropin-releasing factor.¹² This can cause long-term increases in mesolimbic dopaminergic neuronal excitability.¹³ With time, cues associated with drug taking—rather than the drug itself—can excite dopaminergic neurons.¹⁴ Structural changes within the nucleus accumbens also produce increased sensitivity that may perpetuate the intense cravings and lead to the high incidence of relapse that occurs in addicts.^{15, 16, 17, 18, 19, 20, 21, 22}

¹Katz NP et al. Challenges in the Development of Prescription Opioid Clin J Pain. p 649. 2007.
²Katz NP et al. Challenges in the Development of Prescription Opioid Clin J Pain. p 649. 2007.
³Katz NP et al. Challenges in the Development of Prescription Opioid Clin J Pain. p 649. 2007.
⁴Hunt SP, Urch CE. Pain, opiates and addiction. Wall and Melzack, Textbook of Pain, 5th Edition, p.349.
⁵Jones S, Bonci A (2005). Synaptic plasticity and drug addiction. Curr Opin Pharmacol 5 (1): 20–5.
⁶Kauer JA, Malenka RC. Synaptic plasticity and addiction. Nature Reviews Neuroscience 8, 844-858 (November 2007)
⁷Hunt SP, Urch CE. Pain, opiates and addiction. Wall and Melzack, Textbook of Pain, 5th Edition, p.351.
⁷Koob G, Kreek MJ (2007). Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am J Psychiatry 164 (8): 1149–59.
⁹Kalivas PW, Volkow ND (2005). The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162 (8): 1403–13.
¹⁰Jones S, Bonci A (2005). Synaptic plasticity and drug addiction. Curr Opin Pharmacol 5 (1): 20–5.
¹¹Kalivas PW, Volkow ND (2005). The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162 (8): 1403–13.
¹²Koob G, Kreek MJ (2007). Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am J Psychiatry 164 (8): 1149.
¹³Hunt SP, Urch CE. Pain, opiates and addiction. Wall and Melzack, Textbook of Pain, 5th Edition, p.352.
¹⁴Hunt SP, Urch CE. Pain, opiates and addiction. Wall and Melzack, Textbook of Pain, 5th Edition, p.353.
¹⁵Chao J, Nestler EJ (2004). Molecular neurobiology of drug addiction. Annual Review of Medicine 55: 113–32.
¹⁶Nestler EJ (December 2005). The neurobiology of cocaine addiction. Science & Practice Perspectives / a Publication of the National Institute on Drug Abuse, National Institutes of Health 3 (1): 4–10.
¹⁷Conversi D, Bonito-Oliva A, Orsini C, Colelli V, Cabib S (January 2008). DeltaFosB accumulation in ventro-medial caudate underlies the induction but not the expression of behavioral sensitization by both repeated amphetamine and stress. The European Journal of Neuroscience 27 (1): 191–201.
¹⁸Perrotti LI, Weaver RR, Robison B, Renthal W, Maze I, Yazdani S, Elmore RG, Knapp DJ, Selley DE, Martin BR, Sim-Selley L, Bachtell RK, Self DW, Nestler EJ (May 2008). Distinct patterns of DeltaFosB induction in brain by drugs of abuse. Synapse (New York, N.Y.) 62 (5): 358–69.
¹⁹Nikulina EM, Arrillaga-Romany I, Miczek KA, Hammer RP (May 2008). Long-lasting alteration in mesocorticolimbic structures after repeated social defeat stress in rats: time course of mu-opioid receptor mRNA and FosB/DeltaFosB immunoreactivity. The European Journal of Neuroscience 27 (9): 2272–84.
²⁰Nestler EJ (October 2008). Review. Transcriptional mechanisms of addiction: role of DeltaFosB. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 363 (1507): 3245–55
²¹Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (February 2009). Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens. Proceedings of the National Academy of Sciences of the United States of America 106 (8): 2915–20.
²²Chen JC, Chen PC, Chiang YC (2009). Molecular mechanisms of psychostimulant addiction. Chang Gung Medical Journal 32 (2): 148–54.