Persistent cognitive dysfunction after traumatic brain injury: A dopamine hypothesis

Abstract

Traumatic brain injury (TBI) represents a significant cause of death and disability in industrialized countries. Of particular importance to patients the chronic effect that TBI has on cognitive function. Therapeutic strategies have been difficult to evaluate because of the complexity of injuries and variety of patient presentations within a TBI population. However, pharmacotherapies targeting dopamine (DA) have consistently shown benefits in attention, behavioral outcome, executive function, and memory. Still it remains unclear what aspect of TBI pathology is targeted by DA therapies and what time-course of treatment is most beneficial for patient outcomes. Fortunately, ongoing research in animal models has begun to elucidate the pathophysiology of DA alterations after TBI. The purpose of this review is to discuss clinical and experimental research examining DAergic therapies after TBI, which will in turn elucidate the importance of DA for cognitive function/dysfunction after TBI as well as highlight the areas that require further study.

Fig. 1

Depiction of TBI induced damage to DA systems in rat brain demonstrating widespread disruption in DA structures. Areas involved in both ascending and descending DAergic signaling pathways are damaged following a TBI. Not pictured is the extensive damage caused to other neurotransmitter systems and brain structures not directly involved in DAergic signaling pathways.

Fig. 2

Schematic of DARPP-32 signaling adapted from Nairn et al. (2004). DARPP-32 represents an important regulator of cell signaling within the medium spiny neurons of the striatum. Changes in phosphorylation state due to DA alterations effectively alter CREB activity and PKA activity, both of which are integral to cell homeostasis function. A number of other kinases and phosphatases regulate DARPP-32 phosphorylation and represent potential therapeutic targets to indirectly modify DA signaling within the striatum. Abbreviations not present in text: CBP, CREB binding protein; CDK5, cyclin-dependent kinase 5; CRE, cAMP response element; MEK 1/2, mitogen-activated protein kinase kinase; RSK 2, ribosomal S6 kinase 2; STEP, striatal enriched phosphatase.

Fig. 3

Schematic of alterations in DA cellular signaling following TBI in the PFC and striatum. Changes in DA at the cellular level both pre and post-synaptically have been observed in the PFC and striatum of rats. These alterations include changes in tissue DA levels, DA receptors, TH, and the DAT. Current research suggests that acutely there is a transient increase in DA tissue levels followed by chronic DAergic hypofunction, as indicated by reduced DAT levels, and decreased evoked DA release. However, it remains unclear what the consequences of acute versus chronic changes are and how to best manage these changes in a clinical setting. Not shown: There are also changes in COMT expression that have been identified in the microglia of the hippocampus but not yet in the striatum or PFC.