July 26, 2025

To fully benefit from reading this article, I’d highly recommend reading about the hormones first. Also, I don’t claim to be an expert in neuroscience, so I heavily rely on various academic papers and books to understand the mechanics myself and to later translate them into human language.

Oxytocin

The Rat Park experiment.

References

Lewis, M. (2015). The desire.

Plotik, D. Psychodynamic.

Volkow, N. D., & Morales, M. (2015). The brain on drugs: from reward to addiction. Cell, 162(4), 712–725. doi:10.1016/j.cell.2015.07.046.

McGregor, I. S., & Bowen, M. T. (2012). Breaking the loop: oxytocin as a potential treatment for drug addiction. Hormones and Behavior, 61(3), 331–339. doi:10.1016/j.yhbeh.2011.12.00

Müller, C. P., & Homberg, J. R. (2015). The role of serotonin in drug use and addiction. Behavioural Brain Research, 277, 146–192. doi:10.1016/j.bbr.2014.04.007.

The addiction macro-circuit & the “dark side”

• Koob, G. F., & Volkow, N. D. (2016). Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry.

Definitive, schematic review of the three-stage addiction cycle (binge/intoxication → withdrawal/negative affect → preoccupation/craving) and the anti-reward/dysphoria systems.

• Volkow, N. D., Fowler, J. S., & Wang, G. J. (2003). The addicted human brain: insights from imaging studies. J Clin Invest.

PET imaging overview showing how repeated drug use reshapes dopamine signalling, frontal control, and motivation.

• Everitt, B. J., & Robbins, T. W. (2016). Drug addiction: updating the neurobiology of compulsion. Annu Rev Psychol.

Elegant explanation of how goal-directed drug taking “slides” into dorsal-striatal habits and compulsions.

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2) Striatal D2 receptor loss & impaired control

• Volkow, N. D., Wang, G.-J., Fowler, J. S., et al. (2002). Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine addiction. Synapse.

Classic PET work linking lower D2 in striatum to weaker frontal (PFC) metabolism/control.

• Volkow, N. D., Wang, G.-J., Telang, F., et al. (2007). Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: possible contributing factors. NeuroImage.

Extends the D2–PFC control story to compulsive overeating—useful trans-diagnostic perspective.

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3) Ventral → dorsal striatum shift (reward → habit)

• Everitt, B. J., & Robbins, T. W. (2005). Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci Rev.

Foundational synthesis on the accumbens (ventral) → dorsal striatum recruitment as drug use becomes a habit.

• Belin, D., Jonkman, S., Dickinson, A., Robbins, T. W., & Everitt, B. J. (2009). Parallel and interactive learning processes within the basal ganglia: relevance for the understanding of addiction. Behav Brain Res.

Animal data showing parallel goal-directed and habitual controllers and how drugs bias the system.

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4) Serotonin & anxiety (5-HT1A as the “calming” brake)

• Neumeister, A., Bain, E., Nugent, A. C., et al. (2004). Reduced serotonin type 1A receptor binding in social anxiety disorder. Arch Gen Psychiatry.

PET evidence that less 5-HT1A availability tracks with more anxiety.

• Savitz, J., Lucki, I., & Drevets, W. C. (2009). 5-HT1A receptor function in major depressive disorder. Prog Neurobiol.

Meta-analytic style review; while focused on depression, it clarifies pre- vs postsynaptic 5-HT1A roles relevant to anxiety too.

• Harmer, C. J., & Cowen, P. J. (2013). ‘It’s the way that you look at it’—a cognitive neuropsychological account of SSRI action in anxiety/depression. Br J Psychiatry.

Explains how SSRIs shift emotional processing early, long before mood “catches up.”

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5) 5-HT2C (and other 5-HT receptors) restraining dopamine & impulsivity

• Di Matteo, V., Cacchio, M., Di Giulio, C., & Esposito, E. (2002). Serotonin control of central dopaminergic function: focus on in vivo microdialysis studies. Prog Brain Res.

Mechanistic review: 5-HT2C activation often suppresses accumbens dopamine and impulsivity.

• Higgins, G. A., & Fletcher, P. J. (2003). Serotonin and drug reward: focus on 5-HT2C receptors. Eur J Pharmacol.

Directly reviews the 5-HT2C “brake” on reward seeking and stimulant intake.

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6) Oxytocin: amygdala dampening & social reward

• Kirsch, P., Esslinger, C., Chen, Q., et al. (2005). Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci.

Seminal fMRI paper: intranasal oxytocin reduces amygdala activation to fearful faces.

• Domes, G., Heinrichs, M., Glascher, J., et al. (2007). Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biol Psychiatry.

Replicates and extends the amygdala-dampening story.

• Shahrokh, D. K., Zhang, T.-Y., Diorio, J., Gratton, A., & Meaney, M. J. (2010). Oxytocin-dopamine interactions mediate variations in maternal behavior in the rat. Endocrinology.

Animal evidence for oxytocin–dopamine crosstalk in the VTA–NAcc, relevant for “social reward” as a drug competitor.

• Bethlehem, R. A. I., Baron-Cohen, S., van Honk, J., Auyeung, B., & Bos, P. A. (2014/2017). The oxytocin paradox. Front Behav Neurosci / Biol Psychiatry reviews.

Nuanced: oxytocin doesn’t always “increase trust”—context, personality, and diagnosis matter.

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7) BNST vs amygdala: sustained anxiety vs phasic fear

• Davis, M., Walker, D. L., Miles, L., & Grillon, C. (2010). Phasic vs. sustained fear in rats and humans: role of the extended amygdala (BNST). Biol Psychiatry.

The go-to paper separating amygdala (phasic fear) from BNST (sustained anxiety).

• Shackman, A. J., & Fox, A. S. (2016). Contributions of the BNST to anxiety and threat monitoring. Trends Cogn Sci.

Modern, integrative view on BNST as a sustained-threat hub.

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8) SSRIs: why the delay? (autoreceptors → postsynaptic effects)

• Blier, P., & de Montigny, C. (1999). Serotonin and drug-induced therapeutic responses in major depression, OCD and anxiety disorders. Neuropsychopharmacology.

Classic explanation: raphe 5-HT1A autoreceptor desensitisation → more 5-HT reaches postsynaptic calming sites.

• Artigas, F. (2013/2017). Future directions for SSRI antidepressants: combining pharmacology with cognitive neuroscience. (various reviews).

Updates the “autoreceptor desensitisation + emotional processing shift” story in humans.

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9) Endorphins, anti-reward, and opioids

• Koob, G. F. (2014). The dark side of addiction: the horse appears to be white. Neuropsychopharmacology.

Short, sharp piece on anti-reward (dynorphin/kappa, CRF) and why withdrawal feels so bad.

• Maldonado, R., Berrendero, F., Ozaita, A., & Robledo, P. (2014). Neurochemical basis of addiction. In The Neurobiology of Brain and Behavioral Development.

Broad, opioid system & endorphins in addiction overview.

• Leknes, S., & Tracey, I. (2008). A common neurobiology for pain and pleasure. Nat Rev Neurosci.

Explains how opioid/endorphin circuits sit at the intersection of relief and reward—key for both anxiety relief and addiction maintenance.

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10) PFC control, dopamine, and stress

• Robbins, T. W., & Arnsten, A. F. T. (2009). The neuropsychopharmacology of fronto-executive function: monoamine modulation. Annu Rev Neurosci.

Gold-standard review on how dopamine (and noradrenaline) tune PFC control—too little or too much both hurt.

• Arnsten, A. F. T. (2015). Stress weakens prefrontal networks: molecular insults to higher cognition. Nat Neurosci Rev.

Shows how stress chemistry (CRF, catecholamines) collapses PFC top-down control, relevant for both anxiety and relapse.

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11) (Optional) Psychedelics & MDMA—why they’re being tested

• Mitchell, J. M., Bogenschutz, M., et al. (2021). MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled Phase 3 study. Nat Med.

Demonstrates large, durable effects in PTSD—relevant to anxiety/addiction comorbidity and the oxytocin/serotonin surge model.

• Carhart-Harris, R. L., & Friston, K. J. (2019). REBUS and the anarchic brain: toward a unified model of the brain action of psychedelics. Pharmacol Rev.

Explains how 5-HT2A agonism may “relax” rigid priors, potentially useful for addiction and anxiety stuck patterns.