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. 2021 Aug 12;11:424. doi: 10.1038/s41398-021-01542-0

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 2 — Progression to addiction is defined as a transition between three consecutive phases [252]: (1) Recreational, sporadic drug taking, in which drug of abuse administration is occasional and one activity among many other distractions of the individual. (2) Intensified and sustained drug use, in which drug administration strengthens and becomes the principal recreational activity of the individual; at this phase drug taking becomes a habit. (3) Loss of control of drug use and addiction, in which drug seeking and taking are now the principal activity of the patient. The first phase can occur to every person as drugs of abuse hijack the same brain circuit as natural rewards. The second phase occurs only in vulnerable users. The phase of addiction seems to be due to a second vulnerable trait with loss of control and compulsivity. Three stages of addiction are described [27]: (1) Binge/intoxication stage: reinforcing effects of drugs may initially use mainly dopamine and opioid peptides in the nucleus accumbens (NAc) and involves the ventral tegmental area (VTA). Subsequently, cue–response habits develop and includes the substantia nigra pars compacta (SNc) and the dorsal striatum. (2) Withdrawal/negative affect stage: the negative emotional state of withdrawal may involve the extended amygdala with corticotropin-releasing factor (CRF), norepinephrine and dynorphin as key neurotransmitters. Main projections of the extended amygdala consist of the hypothalamus and brainstem. (3) Craving stage: this stage includes conditioned reinforcement in the basolateral amygdala (BLA) and contextual processes in the hippocampus. This is controlled by cortical areas (prefrontal cortex (PFC) and orbitofrontal cortex (OFC)). A key neurotransmitter involved in the craving stage is glutamate.