Kent Yamamoto

Background: Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder that develops in the months and years following exposure to severe trauma.¹ Current treatment for PTSD includes pharmacotherapies with serotonin reuptake inhibitors and psychotherapies in the form of exposure-based treatment.¹ Serotonergic, dopaminergic, and noradrenergic antidepressants and/or anxiolytic medications have shown some efficacy in relief of PTSD symptoms.¹ Approximately two-thirds of individuals with PTSD experience anhedonia symptoms, which are linked to increased chronicity of distress, suicidality, and functional impairment and worse treatment outcomes in psychotherapy.² In clinical practice, the challenge remains in finding effective and quickly acting therapies for anhedonia, mainly due to an incomplete understanding of the neural mechanisms at play.^3-4

Objective: In this narrative review, the pathway and mechanism of propofol within the Nucleus Accumbens to induce anhedonia relief was explored.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2024 using the following keywords: “dopamine”, “Nucleus Accumbens”, “cAMP”, and “D1-MSN.

Results: Propofol increases dopamine concentration by inhibiting the Dopamine Transporter (DAT) without affecting serotonin concentration.⁴ Three critical binding sites, A81, F155, and D475, in DAT were identified that blocked propofol binding without affecting dopamine transport.⁴ Propofol induced anhedonia relief, measured with the sucrose preference test, involved activation of the Dopamine-receptor-1-expressing Medium Spiny Neuron (D1-MSN) and reduced the activity of the Dopamine-receptor-2-expressing Medium Spiny Neuron.⁴ Inhibition of the Dopamine-1 Receptor abolished the anhedonia relief effect of propofol while inhibition of the GABA_A receptor had no effect on propofol’s anhedonia relief.⁴ A single propofol exposure (100mg/kg) displayed anhedonia reversal with CRS mice through the sucrose preference test, and effects continued with repeat tests after 24 hours and 3 days. Anhedonia reversal was also observed after repeated exposure for 5 consecutive days with the same dose.⁴ Chronic stress mice demonstrated decreased cAMP within D1-MSN, secondary to decreased Adenyl Cyclase activity with dampened Gsa expression, and downregulation of the tight junction protein CLDN-5 in the NAc, but not the Prefrontal Cortex or hippocampus.⁵ The diminished Blood Brain Barrier (BBB) integrity could be improved with increasing cAMP levels within D1-MSN.⁶ Downregulation of CLDN-5 was similarly seen in post-mortem human tissues of the NAc with a known diagnosis of Major Depressive Disorder.⁷

Conclusions: Propofol increases dopamine concentration within the NAc by inhibiting DAT. Anhedonia relief with propofol requires D1-MSN activation and may provide its effect downstream through a cAMP mediated pathway to promote the integrity of the blood brain barrier. Possible off label use of propofol in the future to improve outcome of patients with PTSD that demonstrate worsening treatment outcomes with associated anhedonia.

Works Cited: 

1. Ressler KerryJ, Berretta S, Bolshakov VY, et al. Post-traumatic stress disorder: clinical and translational neuroscience from cells to circuits. Nat Rev Neurol. 2022;18(5):273-288. doi:10.1038/s41582-022-00635-8
2. Bennett MM, Davis KE, Fitzgerald JM. Neural correlates of reward processing in the onset, maintenance, and treatment of posttraumatic stress disorder. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2023;8(9):884-890. doi:10.1016/j.bpsc.2023.05.007
3. Bryant RA. Post‐traumatic stress disorder: a state‐of‐the‐art review of evidence and challenges. World Psychiatry. 2019;18(3):259-269. doi:10.1002/wps.20656
4. Zhu XN, Li J, Qiu GL, et al. Propofol exerts anti-anhedonia effects via inhibiting the dopamine transporter. Neuron. 2023;111(10):1626-1636.e6. doi:10.1016/j.neuron.2023.02.017
5. Zhang Y, Gao J, Li N, et al. Targeting cAMP in D1-MSNs in the nucleus accumbens, a new rapid antidepressant strategy. Acta Pharmaceutica Sinica B. 2024;14(2):667-681. doi:10.1016/j.apsb.2023.12.005
6. Zhang Y, Lu W, Wang Z, et al. Reduced neuronal camp in the nucleus accumbens damages blood-brain barrier integrity and promotes stress vulnerability. Biological Psychiatry. 2020;87(6):526-537. doi:10.1016/j.biopsych.2019.09.027
7. Dudek KA, Dion-Albert L, Lebel M, et al. Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression. Proc Natl Acad Sci USA. 2020;117(6):3326-3336. doi:10.1073/pnas.1914655117