Role of serotonin and norepinephrine systems in functional recovery after stroke

Windle, Victoria (2006) Role of serotonin and norepinephrine systems in functional recovery after stroke. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Stroke is a leading cause of permanent disability worldwide. Physiotherapy facilitates motor recovery after stroke but recovery is often incomplete, highlighting the need to develop other methods (e.g. utilizing more intensive rehabilitation or combining rehabilitation with drug therapy) to augment existing therapies. Depression is a common occurrence after stroke and consequently a large population of stroke patients are treated with antidepressants. Most antidepressants act to facilitate actions of serotonin, norepinephrine, or both. Despite the prevalence of antidepressant use, little is known about how these drugs might affect the recovery of motor function in these patients. The involvement of serotonin and norepinephrine in motor recovery after focal ischemia in the rat was the focus of this thesis. Serotonin selective reuptake inhibitors are often the antidepressants of choice in the stroke population. In the first experiment a chronic dose of fluoxetine (a serotonin specific reuptake inhibitor) was combined with rehabilitation to determine if it facilitated motor recovery. No effect of the drug was found suggesting that facilitating the serotonin system has little or no effect on motor recovery. In the second experiment norepinephrine was depleted using N-(2-chloroethyl)-Nethyl- 2-bromobenzylamine, a neurotoxin specific for terminals of norepinephrine cells of the locus coeruleus. Depleting norepinephrine terminals improved recovery in animals exposed to enriched rehabilitation as well as standard housed animals. This suggests that norepinephrine plays a role in recovery of function but that role may be more complicated than previously thought. The final experiment compared four different endothelin-1 models of focal ischemia, including the models used in the previous experiments (experiment 1: focal ischemia of the cortex and striatum by localized injection or experiment 2: by injection adjacent to the middle cerebral artery). While all four models produced similar behavioural deficits the model that targeted the middle cerebral artery (the most commonly used model) yielded the lowest success rate (as determined by survival and ability to produce a forelimb reaching deficit). The more successful model combining cortical and striatal injections of endothelin-1 was further characterized using magnetic resonance imaging and found to have blood flow dynamics similar to clinical stroke. The results of this thesis help to clarify previous findings regarding the antidepressant, fluoxetine and recovery of function. In addition, the current findings further explore the role of norepinephrine in stroke recovery with indications for future research. Finally, I introduce a new endothelin-1 model of focal ischemia that is a more consistent and clinically relevant alternative to existing models.

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