Electrophysiological effects of repeated administration of agomelatine on the dopamine, norepinephrine, and serotonin systems in the rat brain

Abstract

Agomelatine is a melatonergic MT1/MT2 agonist and a serotonin (5-HT) 5-HT(2C) antagonist. The effects of 2-day and 14-day administration of agomelatine were investigated on the activity of ventral tegmental area (VTA) dopamine (DA), locus coeruleus (LC) norepinephrine (NE), and dorsal raphe nucleus (DRN) 5-HT neurons using in vivo electrophysiology in rats. The 5-HT(1A) transmission was assessed at hippocampus CA3 pyramidal neurons. After a 2-day regimen of agomelatine (40 mg/kg/day, i.p.), an increase in the number of spontaneously active VTA-DA neurons (p<0.001) and in the firing rate of LC-NE neurons (p<0.001) was observed. After 14 days, the administration of agomelatine induced an increase in: (1) the number of spontaneously active DA neurons (p<0.05), (2) the bursting activity of DA neurons (bursts/min, p<0.01 and percentage of spikes occurring in bursts, p<0.05), (3) the firing rate of DRN-5-HT neurons (p<0.05), and (4) the tonic activation of postsynaptic 5-HT(1A) receptors located in the hippocampus. The increase in 5-HT firing rate was D2 dependent, as it was antagonized by the D2 receptor antagonist paliperidone. The enhancement of NE firing was restored by the 5-HT(2A) receptor antagonist MDL-100,907 after the 14-day regimen. All the effects of agomelatine were antagonized by a single administration of the melatonergic antagonist S22153 (except for the increase in the percentage of spikes occurring in burst for DA neurons). The present results suggest that (1) agomelatine exerts direct (2 days) and indirect (14 days) modulations of monoaminergic neuronal activity and (2) the melatonergic agonistic activity of agomelatine contributes to the enhancement of DA and 5-HT neurotransmission.

Figure 1

(a–c) Effect of agomelatine administration (2 days) on the firing activity of VTA-DA, LC-NE, and DRN-5-HT neurons. (d, e) Effect of melatonergic blockade with S22153 on the excitatory effect of agomelatine on the number of spontaneously DA active cells found per track in the VTA and on the firing rate of NE neurons in the LC. Data are expressed as means±SEM of the firing rate and the number of spontaneously active cells found per track (DA neurons only). The number of neurons (firing rate) or rats (cells per track) recorded in each group is provided within the histograms. (a–c) Data were analyzed using t-test. (d, e) Data were analyzed by one-way ANOVA for repeated measures followed by Fisher's PLSD test. ^*Significant effect of the treatment (agomelatine or S22153) in comparison with the corresponding control group, ^**p<0.01, ^***p<0.001.

Figure 2

Effect of agomelatine (▪) administration (14 days) on the firing activity of (a) VTA-DA neurons, (b) DRN-5-HT neurons, and (c) LC-NE neurons in comparison with control (▪). Data are expressed as means±SEM of the firing rate, the number of spontaneously active cells found per track, the number of bursts/min, and the percentage of spikes occurring in burst. The number of neurons or rats recorded in each group is provided within the histograms. Data were analyzed using t-test or one-way ANOVA for repeated measures followed by Fisher's PLSD test (paliperidone and MDL-100,907). ^*Significant effect of the treatment (agomelatine, paliperidone, or MDL-100,907) in comparison with the corresponding control group, ^*p<0.05, ^**p<0.01.

Figure 3

Effect of melatonergic blockade with S22153 on the activity of agomelatine (14 days) on (a) the firing pattern of VTA-DA neurons and on (b) the firing rate of 5-HT neurons in the DRN. The number of animals recorded in each group is provided within the histograms. Data were analyzed by one-way ANOVA for repeated measures followed by Fisher's PLSD test. ^*Significant effect of S22153 (hatched) in comparison with the corresponding 14-day agomelatine-treated group (▪), ^*p<0.05, ^**p<0.01, ^***p<0.001.

Figure 4

(a, b) Data are mean (± SEM) of RT₅₀ values and IT₅₀ index calculated from microiontophoretic applications of 5-HT in control (▪) and rats treated with agomelatine for 14 days (▪). (c, d) Integrated firing rate histograms of dorsal hippocampus CA3 pyramidal neurons illustrating intravenous administration of incremental doses of 25 μg/kg of WAY-100,635 in vehicle (a) and 14-day agomelatine (b) rats. (e) Effect of intravenous administration of incremental doses of the 5-HT_1A antagonist WAY-100,635 on basal firing rate in control (▪) and rats treated with agomelatine for 14 days (▪). ^*Significantly greater effect in agomelatine-treated rats in comparison with the control animals receiving the same dose of WAY-100,635, ^*p<0.05, ^**p<0.01, ^***p<0.001. ^@Significant increase in the firing rate induced by WAY-100,635 in treated rats ^@p<0.05, ^@@p<0.01, ^@@@p<0.001.

Figure 5

Long-term effect of agomelatine on monoaminergic systems. Agomelatine (14 days) induced an excitatory effect on DA cells in the VTA (increase in the number of neuron spontaneously active and bursting activity) that resulted in an increase in DA neurotransmission, leading to the activation of excitatory D2 receptors located on DRN-5-HT cells. The corresponding increase in 5-HT firing activity then induced an activation of the excitatory 5-HT_2A receptors located on GABA interneurons. The increase in GABA activity induced an inhibition of LC-NE neurons. However, agomelatine by itself also exerts an excitatory effect on LC-NE neurons (as seen after a 2-day treatment). Therefore, with the LC-NE neurons being under an excitatory and an inhibitory influence, the firing rate was in the range of that of the control animals. The increase in 5-HT firing activity ( ) also induced a tonic activation of the inhibitory postsynaptic 5-HT_1A receptors that may contribute to decrease the hyperactivity of the hippocampus commonly observed in patients suffering from MDD.