Role of the medial prefrontal cortex in 5-HT1A receptor-induced inhibition of 5-HT neuronal activity in the rat

Abstract

1. We examined the involvement of the frontal cortex in the 5-HT2A receptor-induced inhibition of 5-HT neurones in the dorsal raphe nucleus (DRN) of the anaesthetized rat using single-unit recordings complemented by Fos-immunocytochemistry. 2. Both transection of the frontal cortex as well as ablation of the medial region of the prefrontal cortex (mPFC) significantly attenuated the inhibition of 5-HT neurones induced by systemic administration of the 5-HT1A receptor agonist, 8-OH-DPAT (0.5-16 microg kg(-1), i.v.). In comparison, the response to 8-OH-DPAT was not altered by ablation of the parietal cortex. The inhibitory effect of 8-OH-DPAT was reversed by the 5-HT1A receptor antagonist, WAY 100635 (0.1 mg kg(-1), i.v.) in all neurones tested. 3. In contrast, cortical transection did not alter the sensitivity of 5-HT neurones to iontophoretic application of 8-OH-DPAT into the DRN. Similarly, cortical transection did not alter the sensitivity of 5-HT neurones to systemic administration of the selective 5-HT reuptake inhibitor, paroxetine (0.1-0.8 mg kg(-1) , i.v.). 4. 8-OH-DPAT evoked excitation of mPFC neurones at doses (0.5-32 microg kg(-1), i.v.) in the range of those which inhibited 5-HT cell firing. At higher doses (32-512 microg kg(-1), i.v.) 8-OH-DPAT inhibited mPFC neurones. 8-OH-DPAT (0.1 mg kg(-1), s.c.) also induced Fos expression in the mPFC. The neuronal excitation and inhibition, as well as the Fos expression, were antagonized by WAY 100635. 5. These data add further support to the view that the inhibitory effect of 5-HT1A receptor agonists on the firing activity of DRN 5-HT neurones involves, in part, activation of a 5-HT1A receptor-mediated postsynaptic feedback loop centred on the mPFC.

Figure 1

Firing rate histograms of two 5-HT neurones recorded from either an intact control rat (a) or from a rat which underwent a mPFC ablation (b). Arrows indicate i.v. administration of 8-OH-DPAT or WAY 100635.

Figure 2

Inhibition of activity of 5-HT neurones (expressed as percentage of firing rate) induced by cumulative doses of i.v. administered 8-OH-DPAT in control rats and in rats after transection of the frontal cortex (Transection) or ablation of the medial prefrontal cortex (Ablation).

Figure 3

Dose-response curves showing the inhibitory effect of i.v. administration of paroxetine on the firing rate of 5-HT neurones in control and cortically transected rats.

Figure 4

Typical responses of individual 5-HT neurones to iontophoretic 8-OH-DPAT application with increasing currents before (a) and after (b) transection of the frontal cortex. Systemic administration of WAY 100635 (0.1 mg kg⁻¹, i.v.; indicated by arrow) antagonized the inhibitory effect of iontophoretically applied 8-OH-DPAT (c; neurone recorded after transection). Bars represent the duration of drug application at the current (nA) indicated.

Figure 5

Effect of local, bilateral microinjection of 8-OH-DPAT (1 μg μl⁻¹) into the mPFC (a) or CPu (b) on the activity of DRN 5-HT neurones. Horizontal bars indicate the duration of 8-OH-DPAT infusion. Systemic administration of WAY 100635 (0.1 mg kg⁻¹, i.v.; indicated by arrows) reversed the inhibition of 5-HT neurones induced by either mPFC or CPu microinjection of 8-OH-DPAT.

Figure 6

Firing rate histograms of two cortical neurones recorded from the mPFC. (a) Application of 8-OH-DPAT (i.v.) induced an excitation which was reversed by WAY 100635 (arrows indicate drug application). (b) Increasing doses of 8-OH-DPAT led to inhibition and finally cessation of firing activity of the neurone, the 8-OH-DPAT-induced inhibition was reversed by WAY 100635.

Figure 7

(a) Schematic drawing of a frontal section of the rat brain at anterior +2.7 mm (according to Paxinos & Watson, 1986) illustrating regions of the prefrontal cortex (asterisks) in which the number of Fos-positive neurones were determined. Fos positive neurones were counted in a tissue area of 0.09 mm² in the frontal cortex area 1 (Fr1), cingulate cortex (Cg3) and infralimbic cortex (IL). The grey area represents part of the mPFC shown on the photomicrographs (Figure 8). (b) Effects of saline (n=5), 8-OH-DPAT (0.1 mg kg⁻¹, s.c.; n=7) and WAY 100635 (1 mg kg⁻¹, s.c.)/8-OH-DPAT (0.1 mg kg⁻¹, s.c.; n=4) on the number of Fos-positive neurones in different areas of the frontal cortex. ^*P<0.001 compared to vehicle treatment, ⁺P<0.02 compared to 8-OH-DPAT treatment (one-way ANOVA followed by Dunnett t-test).

Figure 7

(a) Schematic drawing of a frontal section of the rat brain at anterior +2.7 mm (according to Paxinos & Watson, 1986) illustrating regions of the prefrontal cortex (asterisks) in which the number of Fos-positive neurones were determined. Fos positive neurones were counted in a tissue area of 0.09 mm² in the frontal cortex area 1 (Fr1), cingulate cortex (Cg3) and infralimbic cortex (IL). The grey area represents part of the mPFC shown on the photomicrographs (Figure 8). (b) Effects of saline (n=5), 8-OH-DPAT (0.1 mg kg⁻¹, s.c.; n=7) and WAY 100635 (1 mg kg⁻¹, s.c.)/8-OH-DPAT (0.1 mg kg⁻¹, s.c.; n=4) on the number of Fos-positive neurones in different areas of the frontal cortex. ^*P<0.001 compared to vehicle treatment, ⁺P<0.02 compared to 8-OH-DPAT treatment (one-way ANOVA followed by Dunnett t-test).

Figure 8

Effects of saline (a) or 8-OH-DPAT (b; 0.1 mg kg⁻¹, s.c.) injection to non-anaesthetized rats on the distribution of Fos in the mPFC. Photomicrographs represent the ventral part of the cingulate cortex (Cg3) and infralimbic cortex (as indicated on Figure 7). Arrows point to the midline; calibration bar represents 200 μm.