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 (po0.001) and in the firing rate of LC-NE neurons (po0.001) was observed. After 14 days, the administration of agomelatine induced an increase in: (1) the number of spontaneously active DA neurons (po0.05), (2) the bursting activity of DA neurons (bursts/min, po0.01 and percentage of spikes occurring in bursts, po0.05), (3) the firing rate of DRN-5-HT neurons (po0.05), 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.

Mouse psychosocial stress reduces motivation and cognitive function in operant reward tests: A model for reward pathology with effects of agomelatine

“…A similar reduction in motivation in the PRS test to that observed in CSD mice is induced by 6-hydroxydopamine depletion of DA in the nucleus accumbens (Bergamini et al, in press Submitted manuscript). Extrapolating to the current findings, this suggests that AGO effects on the VTA-DA pathway mediated via it 5-HT 2C antagonist properties (Chenu et al, 2013) in CSD mice, due to repeated administration of AGO. With regards to underlying mechanisms, the prefrontal cortex and nucleus accumbens are major regions in the regulation of perseveration (Clarke et al, 2004;Cools et al, 2007).…”

“…In VTA, 5-HT 2C receptors are expressed by GABA interneurons that project onto DA neurons (Eberle-Wang et al, 1997). AGO, acute and chronic, increases the number of spontaneously active VTA DA neurons and the bursting activity of VTA dopaminergic neurons (Chenu et al, 2013). Nonetheless, 5-HT 2C antagonism does not disinhibit DA release in nucleus accumbens or dorsal striatum (Millan et al, 2003).…”

“…In Parkinson's disease patients, ι-DOPA increases perseveration in a probabilistic reversal learning test, associated with disrupted activity related to excessive DA signalling in the nucleus accumbens (Cools et al, 2001;Cools et al, 2007). 5-HT 2C receptor antagonists and AGO increase DA release into frontal cortex (Di Giovanni et al, 2006;Millan et al, 2003) and AGO increases bursting activity of VTA dopaminergic neurons (Chenu et al, 2013). Therefore, the AGOrelated increase in perseveration specific to CSD mice could reflect increased sensitivity to upregulated DA signalling following a prolonged period of low DA tone in the mesocorticolimbic pathway.…”

Pooled Analysis of Four Non-Interventional Studies: Effectiveness and Tolerability of the Antidepressant Agomelatine in Daily Practice

“…Its mode of action may be explained by the synergy of MT 1 /MT 2 and 5-HT 2C receptors, which increases noradrenergic and dopaminergic neurotransmission, and a specific release of noradrenaline and dopamine has been described in the prefrontal cortex without effect on the extracellular levels of serotonin [3][4][5]. In addition, an increase of neurotrophic factors (e.g., brain-derived neurotrophic factor, BDNF) and a decrease in stress-related glutamate elevation have also been described [2,6,7] as well as resynchronization of circadian rhythms [8][9][10].…”

The differences in the estimation of depression severity by psychiatrists and patients during the combined treatment with agomelatine (a multicenter study “EMOTSIA”)

“…В качестве антидепрессанта был выбран агомелатин (вальдоксан) -агонист мелатонинергических (MT 1 и MT 2 ) рецепторов и антагонист серотонинергических (5HT 2C ) рецепторов, синергическое действие на которые в областях мозга, связанных с развитием депрессии, приво-дит к опосредованному повышению нор-адренергической и дофаминергической трансмиссии, усилению нейроге-неза, повышению уровня BDNF и уменьшению спрово-цированного стрессом высвобождения глутамата [4][5][6][7][8][9][10][11]. В клинических испытаниях агомелатин зареко-мендовал себя как эффективный препарат при моно-и комбинированной терапии при аффективных расстрой-ствах различной этиологии и степени тяжести.…”