UBC Theses and Dissertations
Chronic lithium treatment influences impulse control and cognition and regulates gene expression Levesque, Dominique Louise
Lithium is an effective treatment for bipolar disorder (BD) as it reduces the occurrence of mania, which is associated with deficits in impulse control, pathological gambling, drug-seeking, and suicidality. Whether lithium regulates impulsivity directly is unclear. We determined the effects of chronic lithium administration on performance of the five-choice serial reaction time task (5-CSRTT)—a rodent analogue of the continuous performance test used clinically—and the delay discounting task (DDT), as well as its influence on drug-induced behaviours. In the 5-CSRTT, animals respond to a brief visual stimulus to earn a reward. Accuracy of target detection measures attentional ability whilst responses made prior to stimulus presentation provide an index of motor impulsivity. The DDT measures impulsive choice by assessing animals' tendency to choose smaller, immediate food rewards over larger, delayed rewards. Lithium treatment improved target detection and attenuated stress-induced impulsive responding. There were no differences between the groups on the initial delay discounting task—animals abruptly shifted their preference towards the smaller reward as the larger reward became increasingly delayed. We re-trained these animals using shorter delays to obtain a more meaningful discounting pattern. Lithium treatment facilitated behavioural flexibility as rats adapted this change more rapidly, and animals displayed a consistent pattern of choice between both delay sets. We trained another cohort of animals using the shorter delays only. Again, lithium treatment accelerated task acquisition, but did not affect choice behaviour. Lithium treatment blocked stimulant-induced changes in choice behaviour. Real-time PCR analyses revealed that lithium treatment decreased gene expression in the prefrontal cortex and nucleus accumbens. Notable changes were detected in intracellular components and neuronal processes associated with a behavioural and cognitive profile relevant to BD and other impulse control disorders, including monoaminergic receptors, neurotrophins, synaptic proteins, signalling kinases, and transcription and apoptotic factors, to name a few. Results generated herein suggest that chronic lithium treatment may enhance attention, attenuate stress-induced motor impulsivity, accelerate task acquisition, enhance behavioural flexibility, and block stimulant-induced changes in choice behaviour. These findings contribute to our understanding of lithium’s clinical efficacy and may lead to better treatments for BD and other impulse-control disorders.
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