Activation of prelimbic 5-HT1A receptors produces antidepressant-like effects in a unilateral rat model of Parkinson's disease.

Depression is a common symptom in Parkinson's disease (PD), but its pathophysiology remains unclear. Several lines of studies have revealed that the prelimbic (PrL) sub-region of the ventral medial prefrontal cortex and 5-HT1A receptors are involved in the regulation of depression. In this study, we examined whether complete unilateral lesions of the medial forebrain bundle (MFB) using 6-hydroxydopamine in rats are able to induce depressive-like behaviors, the role of PrL 5-HT1A receptors in the regulation of these behaviors, and co-localization of 5-HT1A receptor and neuronal glutamate transporter EAAC1-immunoreactive (EAAC1-ir) neurons in the PrL. The MFB lesions induced depressive-like responses as measured by the sucrose preference and forced swim tests when compared to sham-operated rats. The intra-PrL injection of 5HT1A receptor agonist 8-OH-DPAT (50, 100, and 500ng/rat) increased sucrose consumption, and decreased immobility time in both sham-operated and the lesioned rats, indicating the induction of antidepressant effects. Furthermore, the intra-PrL injection of 5HT1A receptor antagonist WAY-100635 (60, 120, and 240ng/rat) showed a decrease in sucrose consumption, and an increase in immobility time, indicating the induction of depressive-like responses. However, the effective doses in the lesioned rats were higher than those in sham-operated rats, which attribute to down-regulation of 5-HT1A receptor expression on EAAC1-ir neurons in the PrL of the lesioned rats. These findings suggest that unilateral lesions of the MFB in rats may induce depressive-like behaviors, and 5-HT1A receptors of the PrL play an important role in the regulation of these behaviors.

Unilateral lesion of the nigrostriatal pathway decreases the response of fast-spiking interneurons in the medial prefrontal cortex to 5-HT1A receptor agonist and expression of the receptor in parvalbumin-positive neurons in the rat.

5-Hydroxytryptamine(1A) (5-HT(1A)) receptors are expressed in the prefrontal cortical interneurons. Among these interneurons, calcium-binding protein parvalbumin (PV)-positive fast spiking (FS) interneurons play an important role in regulatory function of the prefrontal cortex. In the present study, the response of medial prefrontal cortex (mPFC) FS interneurons to the selective 5-HT(1A) receptor agonist 8-OH-DPAT and change in expression of 5-HT(1A) receptor on PV-positive neurons were examined in rats with 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) by using extracellular recording and double-labeling immunofluorescence histochemistry. Systemic administration of 8-OH-DPAT (1-243 µg/kg, i.v.) dose-dependently inhibited the mean firing rate of the FS interneurons in sham-operated and the lesioned rats, respectively. The cumulative doses producing inhibition in the lesioned rats (243 µg/kg) was significantly higher than that of sham-operated rats (27 µg/kg). Furthermore, the local application of 8-OH-DPAT (0.01 µg) in the mPFC inhibited the FS interneurons in sham-operated rats, while having no effect on firing rate of the FS interneurons in the lesioned rats. In contrast to sham-operated rats, the lesion of the SNc in rats did not cause the change of PV-positive neurons in the prelimbic prefrontal cortex, a subregion of the mPFC, whereas the lesion of the SNc markedly reduced in percentage of PV-positive neurons expressing 5-HT(1A) receptors. Our results indicate that degeneration of the nigrostriatal pathway results in the decreased response of FS interneurons in the mPFC to 5-HT(1A) receptor stimulation, which attributes to down-regulation of 5-HT(1A) receptor expression in these interneurons.

In 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 GABA(A) 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.