AbstractUnlike conventional antidepressive treatments ketamine exerts antidepressant (AD) efficacy within hours of administration. This rapid AD action is caused by a distinct pharmacological mechanism to conventional ADs and has renewed hope in a field with a once stagnant research effort. However, this effect is accompanied by psychotomimetic side effects, thus prompting the search for similar more tolerable ADs. To this end, animal research using rodents has been applied to understand the basic science behind ketamine’s antidepressant mechanism.
Ketamine’s AD effect manifests at low subanaesthetic doses, normally applied as a 0.5 mg/kg infusion in humans. In rodent research, doses of 10 – 25 mg/kg are predominantly applied on non-translational behavioural assays. With emerging evidence of an AD effect in rats at 1 mg/kg, we argue that the 10 – 25 mg/kg dose range is not optimally suited to investigate ketamine’s AD mechanism in rodents, as increased non-AD side effects will result.
This work aimed to explore the influence of 1 mg/kg ketamine in rats and differentiate this from the 10 – 25 mg/kg dose range commonly applied in the literature, as well as compare this to the effects of ketamine’s non-AD structural analogue PCP. Here, neural activation was assessed with immunohistochemistry whilst the object in place task was used to examine differences in memory impairment, a known side effect of ketamine. From this, we found evidence of differentiation between 1 mg/kg and 10 – 25 mg/kg ketamine. A novel rat behaviour assay using flavour preference was also explored, which could be applied to future AD research efforts.
Overall, whilst further work with larger n numbers is required, we propose that ketamine’s AD efficacy lies with an excitatory “sweet spot”, whereby ketamine’s AD action is facilitated by a subtle stimulatory influence on the prefrontal cortex.
|Date of Award||23 Jan 2020|
|Supervisor||Emma S J Robinson (Supervisor)|