Pritam Dutta  M.Optom, FAAO

ERC Eye Hospital Sibsagar, Assam, India

Background:

Due to the anatomic features of the dopaminergic system, dopamine pathways appear to be particularly sensitive to brain injury among the neurotransmitter systems. Both dopaminergic cell death and metabolic abnormalities of the dopaminergic system are seen in Traumatic Brain Injury (TBI) animal models. ⁽¹⁾ There is compelling evidence that dopamine disruption contributes to post-TBI impairments, and that dopaminergic modulation may have important neuroprotective properties. Because dopamine affects numerous brain regions, including the hippocampus, striatum, and frontal cortex (FC), targeting dopamine signaling in TBI could be extremely beneficial. Damage to these regions has been linked to cognitive failure in TBI. ^(2-6) Furthermore, TBI has been linked to variations in dopamine levels.⁽⁷⁾

TBI affects several brain regions, including the FC, hippocampus, and striatum.^(4-6) These three areas are very essential because they play a role in learning, memory, executive function, and attention, and they may be affected by a TBI.^(8,9) Damage to brain tissue following a TBI, on the other hand, is not limited to specific brain regions. The clinical picture of TBI is further complicated by diffuse axonal injury in white matter tracts, as well as grey matter damage.^(10,11) Dopamine, whether depleted or overexpressed, can induce severe cellular dysfunction; hence, changes in dopamine levels and corresponding abnormalities in dopaminergic systems could have a significant impact on functional results [Fig 1].

Figure 1: Changes in the dopamine levels and functional outcome following TBI.

Dopamine release changes following TBI

The nucleus accumbens (NAC), which has an inner core and an outside shell with very diverse roles, is a significant site of dopamine activity. If discrepancies in dopamine release patterns are linked to TBI symptoms like cognitive impairment, which is influenced by different regions of the NAC, differences in dopamine physiology between the core and shell are likely to have significant clinical ramifications.⁽¹²⁾ However; more study into the effect of TBI on stimulus-related dopamine dynamics in distinct regions of the NAC is needed. Chen et al. found that TBI was linked to significant alterations in dopamine release in both the core and shell of the NAC, with the core being slightly more sensitive to TBI-related changes.⁽¹²⁾ Furthermore, their findings showed that the most severe changes in dopamine dynamics happened within the first two weeks following damage, with modest recovery over time. These electrochemical findings in NAC could help to elucidate the mechanisms underlying post-TBI psychological disorders and justify the use of dopaminergic modulation as a clinical treatment for TBI.

Changes in dopamine receptor expression following TBI

Dopamine receptors are classified into five subtypes: D1, D2, D3, D4 and D5. Dopamine receptors are classified as D1-class (D1 and D5), which are mostly found in the kidney, heart, and mesenteric tissue, or D2-class (D2, D3, and D4), which are mostly found in presynaptic adrenergic nerve endings and sympathetic ganglia. ^(13,14) Transient mechanical violence acts on the neural system during TBI, causing neuronal hyperexcitability, calcium channel opening, and activation of dopaminergic neurons, which results in dopamine release.⁽¹⁵⁾ Calcium channel activation increases tyrosine hydroxylase (TH) activity in neurons, and TH activation speeds up dopamine synthesis in dopaminergic neurons, resulting in a substantial quantity of dopamine build up. Calcium channel activation may thus influence dopamine levels. It’s been established that dopamine D1 receptor activation can affect calcium channel currents in a modulatory manner.⁽¹⁶⁾ Thus, transient reductions in dopamine D1 receptor binding have been observed in the early aftermath of injury, although they do not last long.⁽¹⁷⁾

References

1. Chen YH, Huang EY, Kuo TT, Miller J, Chiang YH, Hoffer BJ. Impact of traumatic brain injury on dopaminergic transmission. Cell Transplant. 2017;26:1156–1168.
2. Kempadoo KA, Mosharov EV, Choi SJ, Sulzer D, Kandel ER. Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory. Proc Natl Acad Sci U S A. 2016;113:14835–14840.
3. McNamara CG, Dupret D. Two sources of dopamine for the hippocampus. Trends Neurosci. 2017;40:383–384.
4. Howe MW, Tierney PL, Sandberg SG, Phillips PE, Graybiel AM. Prolonged dopamine signalling in striatum signals proximity and value of distant rewards. Nature. 2013;500:575–9.
5. Ye Y, Mastwal S, Cao VY, Ren M, Liu Q, Zhang W, Elkahloun AG, Wang KH. Dopamine is required for activity-dependent amplification of Arc mRNA in developing postnatal frontal cortex. Cereb Cortex. 2017;27:3600–3608.
6. Trujillo P, van Wouwe NC, Lin YC, Stark AJ, Petersen KJ, Kang H, Zald DH, Donahue MJ, Claassen DO. Dopamine effects on frontal cortical blood flow and motor inhibition in Parkinson’s disease. Cortex. 2019;115:99–111.
7. Bales JW, Kline AE, Wagner AK, Dixon CE. Targeting dopamine in acute traumatic brain injury. Open Drug Discov J. 2010;2:119–128.
8. Daba Feyissa D, Sialana FJ, Keimpema E, Kalaba P, Paunkov A, Engidawork E, Höger H, Lubec G, Korz V. Dopamine type 1- and 2-like signaling in the modulation of spatial reference learning and memory. Behav Brain Res. 2019;362:173–180.
9. Woytowicz EJ, Sours C, Gullapalli RP, Rosenberg J, Westlake KP. Modulation of working memory load distinguishes individuals with and without balance impairments following mild traumatic brain injury. Brain Inj. 2018;32:191–199
10. Palacios EM, Sala-Llonch R, Junque C, Roig T, Tormos JM, Bargallo N, Vendrell P. White matter/gray matter contrast changes in chronic and diffuse traumatic brain injury. J Neurotrauma. 2013;30:1991–4
11. Kirov II, Tal A, Babb JS, Lui YW, Grossman RI, Gonen O. Diffuse axonal injury in mild traumatic brain injury: a 3D multivoxel proton MR spectroscopy study. J Neurol. 2013;260:242–52.
12. Chen YH, Huang EY, Kuo TT, Ma HI, Hoffer BJ, Tsui PF, Tsai JJ, Chou YC, Chiang YH. Dopamine release impairment in striatum after different levels of cerebral cortical fluid percussion injury. Cell Transplant. 2015;24:2113–28.
13. Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011;63:182–217. [PubMed] [Google Scholar]
14. Takahashi H, Takano H, Kodaka F, Arakawa R, Yamada M, Otsuka T, Hirano Y, Kikyo H, Okubo Y, Kato M, Obata T, Ito H, Suhara T. Contribution of dopamine D1 and D2 receptors to amygdala activity in human. J Neurosci. 2010;30:3043–7.
15. 42. Louin G, Besson VC, Royo NC, Bonnefont-Rousselot D, Marchand-Verrecchia C, Plotkine M, Jafarian-Tehrani M. Cortical calcium increase following traumatic brain injury represents a pitfall in the evaluation of Ca²⁺-independent NOS activity. J Neurosci Methods. 2004;138:73–9.
16. Liu X, Grove JC, Hirano AA, Brecha NC, Barnes S. Dopamine D1 receptor modulation of calcium channel currents in horizontal cells of mouse retina. J Neurophysiol. 2016;116:686–97.
17. Karelina K, Gaier KR, Weil ZM. Traumatic brain injuries during development disrupt dopaminergic signaling. Exp Neurol. 2017;297:110–117

Read Part – 2