Activation or blockade of prelimbic 5-HT₄ receptors improves working memory in hemiparkinsonian rats

Working memory deficits commonly occur in Parkinson's disease. 5-hydroxytryptamine₄ (5-HT₄) receptors are widely distributed in the prelimbic cortex (PrL) and involved in cognition. Here we tested the effects of activation and blockade of PrL 5-HT₄ receptors on working memories by T-maze rewarded alternation and Morris water maze tests in rats with unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle. The lesion induced working memory deficits, decreased dopamine levels in the limbic-related brain regions, changed normalized δ, high θ, α, β, low and high γ power of the PrL, and upregulated expression of PrL 5-HT₄ receptor. Intra-PrL injection of 5-HT₄ receptor agonist BIMU8 or antagonist GR113808 did not impact working memories in sham rats, but improved working memory deficits in the lesioned rats. Intra-PrL injection of BIMU8 or GR113808 had no effect on monoamine levels in the limbic-related brain regions or normalized low and high γ power of the PrL in sham rats. However, in the lesioned rats, intra-PrL injection of BIMU8 significantly increased dopamine and 5-HT levels in the medial prefrontal cortex, amygdala and dorsal hippocampus, while intra-PrL injection of GR113808 significantly increased dopamine levels in these brain regions and increased normalized low and high γ power of the PrL. These results suggest that 6-OHDA lesion in rats induces working memory deficits, while activation or blockade of PrL 5-HT₄ receptors improves the deficits in the lesioned rats, which possibly due to the changes of monoamine levels in the limbic-related brain regions and network activity of neurons in the PrL.