Neurodegeneration, Neuroprotection, and Disease-Oriented NeuroscienceResearch PaperIn vivo effect of 5-HT7 receptor agonist on pyramidal neurons in medial frontal cortex of normal and 6-hydroxydopamine-lesioned rats: an electrophysiological study

The 5-hydroxytryptamine (5-HT)-7 receptor began to be cloned and pharmacologically characterized close to 20 years ago. It couples positively via G-proteins to adenylyl cyclase and activation of this receptor increases neuronal excitability, and several studies have shown that degeneration of the nigrostriatal pathway leads to an impairment of 5-HT system. Here we reported that systemic and local administration of 5-HT7 receptor agonist AS 19 produced excitation, inhibition and no change in the firing rate of pyramidal neurons in medial prefrontal cortex (mPFC) of normal and 6-hydroxydopamine-lesioned rats. In normal rats, the mean response of the pyramidal neurons to AS 19 by systemic and local administration in mPFC was excitatory. The inhibitory effect by systemic administration of AS 19 was reversed by GABAA receptor antagonist picrotoxinin. Systemic administration of picrotoxinin excited all the neurons examined in normal rats, and after treatment with picrotoxinin, the local administration of AS 19 further increased the firing rate of the neurons. In the lesioned rats, systemic administration of AS 19, at the same doses, also increased the mean firing rate of the pyramidal neurons. However, cumulative dose producing excitation in the lesioned rats was higher than that of normal rats. Systemic administration of AS 19 produced inhibitory effect in the lesioned rats, which was partially reversed by picrotoxinin. The local administration of AS 19, at the same dose, did not change the firing rate of the neurons in the lesioned rats. Systemic administration of picrotoxinin and the local administration of AS 19 did not affect the firing rate of the neurons in the lesioned rats. These results indicate that activity of mPFC pyramidal neurons is regulated through activation of 5-HT7 receptor by direct or indirect action, and degeneration of the nigrostriatal pathway leads to decreased response of these neurons to AS 19, suggesting dysfunction and/or down-regulation of 5-HT7 receptor on the pyramidal neurons and GABA interneurons in the lesioned rats.

▶5-HT7 agonist AS 19 (i.v.) increased the mean rate of mPFC pyramidal neurons in rats. ▶AS 19 (i.v.) inhibited some neurons in rats, which were reversed by picrotoxinin. ▶Local application of AS 19 in mPFC increased the mean rate of the neurons in rats. ▶AS 19 (i.v.) only at high dose excited the neurons of the 6-OHDA-lesioned rats. ▶Local application of AS 19 did not affect the activity of neurons in lesioned rats.