In Vivo Effect of a 5-HT7 Receptor Agonist on 5-HT Neurons and GABA Interneurons in the Dorsal Raphe Nuclei of Sham and PD Rats

Abstract

The 5-hydroxytryptamine (5-HT; serotonin) neurotransmission is severely affected by the degeneration of nigrostriatal dopaminergic neurons. Here, we report the effects of the systemic administration of the 5-HT₇ receptor agonist AS-19. In sham rats, the mean response of the 5-HT neurons in the dorsal raphe nucleus (DRN) to systemic AS-19 was excitatory and the mean response of the γ-aminobutyric acid (GABA) interneurons was inhibitory. In Parkinson disease (PD) rats, the same dose did not affect the 5-HT neurons and only high doses (640 μg/kg intravenous) were able to the increase GABA interneuron activity. These results indicate that DRN 5-HT neurons and GABA interneurons are regulated by the activation of 5-HT₇ receptors and that the degeneration of the nigrostriatal pathway leads to decreased responses of these neurons to AS-19, which in turn suggests that the 5-HT₇ receptors on 5-HT neurons and GABA interneurons in PD rats are dysfunctional and downregulated.

Keywords: 5-HT neurons; 5-HT7 receptor; GABA interneurons; Parkinson disease; dorsal raphe nucleus; extracellular recordings.

Figure 1.

Histological photomicrograph showing the recording site (arrow) in a dorsal raphe nucleus (DRN) marked with iontophoretically injected pontamine sky blue in a sham-operated rat (A). Representative spikes of 5-hydroxytryptamine (5-HT; B) and γ-aminobutyric acid (GABA; C) neurons in the DRN. Scale bar = 0.5 mm.

Figure 2.

Photomicrographs of the tyrosine hydroxylase (TH) immunocytochemical staining of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) after sham (A; n = 15) or 6-OHDA lesion surgeries (B; n = 21). The SNc dopaminergic neurons on the injected side (right) are compared to those on the uninjected side (left). Note the complete and partial degeneration of the TH-immunoreactive (IR) neurons in the SNc and VTA, respectively, on the lesioned side. Scale bar = 0.5 mm (A).

Figure 3.

Histograms showing the effects of the systemic administration of the selective 5-hydroxytryptamine (5-HT)₇ receptor agonist AS-19 on the 5-HT neurons in the dorsal raphe nucleus (DRN) of sham-operated and SNc-lesioned rats. The systemic administration of AS-19 at 40 to 640 μg/kg (intravenous [IV]) to sham-operated rats affected the firing rates of the 5-HT neurons in the DRN in an excitatory manner (A and C; n = 8). The excitatory effect of AS-19 was reversed by the administration of the selective 5-HT₇ receptor antagonist SB 269970 at 200 μg/kg (IV) in the sham rats. At the same dose, AS-19 exhibited no effect on the 5-HT neurons in the DRNs of the substantia nigra pars compacta (SNc)-lesioned rats (B and C; n = 11). The arrows indicate the time of the IV administration of AS-19 or SB 269970. *P < .01 versus the baseline firing rate. Compare to the sham rats, the firing rate increased significantly at baseline, 40, and 160 dose in PD rats (C; n = 11). ^# P < .05 versus the firing rate of sham operation.

Figure 4.

Histograms showing the effects of the systemic administration of the selective 5-hydroxytryptamine (5-HT)₇ receptor agonist AS-19 on the γ-aminobutyric acid (GABA) neurons in the dorsal raphe nuclei (DRNs) of sham-operated and substantia nigra pars compacta (SNc)-lesioned rats. The systemic administration of AS-19 at 640 μg/kg (intravenous [IV]) in the sham-operated rats affected the firing rates of the GABA neurons in DRN in an inhibitory manner (A and C; n = 7). The inhibitory effect of AS-19 was reversed by the administration of the selective 5-HT₇ receptor antagonist SB 269970 at 200 μg/kg (IV) in the sham-operated rats. AS-19 increased the firing rates of the GABA neurons in the DRNs of the SNc-lesioned rats, and this excitation was significant only at the high dose of 640 μg/kg (B and C; n = 10). The excitatory effect of AS-19 was reversed by the administration of the selective 5-HT₇ receptor antagonist SB 269970 at 200 μg/kg (IV) in the SNc-lesioned rats. The arrows indicate the time of the IV administration of AS-19 or SB 269970. *P < .01 versus the baseline firing rate. Compare to the sham rats, the firing rate decreased significantly at baseline and 40 dose and increased at 640 dose in PD rats (C; n = 10). ^# P < .05 versus the firing rate of sham operation.