Involvement Of Monoaminergic Systems Research Articles

Antidepressant-like effect of hydroalcoholic extract from barks of Rapanea ferruginea: Role of monoaminergic system and effect of its isolated compounds myrsinoic acid A and B

Major Depressive Disorder (MDD) is a highly disabling condition and has been linked to increased inflammatory mediators. Hydroalcoholic extract from barks of Rapanea ferruginea (HEBRF) and the majoritary compounds—myrsinoic acid A (MAA) and B (MAB)—have been studied due to their anti-inflammatory potential, but there is no evidence about its antidepressant-like effects. This research investigated the HEBRF, MAA, and MAB antidepressant-like effect, besides the involvement of the monoaminergic system and MAO-A activity in the HEBRF antidepressant-like effect. HEBRF (50−300 mg/kg, p.o.), MAA (5−30 mg/kg, p.o.) or MAB (3−60 mg/kg, p.o.) were administrated to mice, and behavioral parameters were assessed using the tail suspension test (TST), splash test (ST) and open field test (OFT). The involvement of monoaminergic system in the HEBRF antidepressant-like effect was established through the pretreatment of mice with antagonists. The influence triggered by HEBRF in the monoamine oxidase A (MAO-A) activity was evaluated in the hippocampus (HIP) and prefrontal cortex (PFC) of mice. HEBRF (100−300 mg/kg) promoted antidepressant-like effect in the TST and augmented the total time of grooming in the ST, without compromising the locomotor activity. Pretreatment of mice with serotoninergic, dopaminergic, and noradrenergic antagonists, reversed the HEBRF antidepressant-like effect. Besides, HEBRF inhibited the MAO-A activity in the HIP and PFC. Moreover, MAA (5 mg/kg) and MAB (3 mg/kg) also promoted antidepressant-like and anti-anhedonic effects in mice. Data showed that monoaminergic system is involved in the HEBRF antidepressant-like effect, besides MAA and MAB possibly could be responsible for these pharmacological effects.

Antidepressant-like activity of methyl jasmonate involves modulation of monoaminergic pathways in mice

PurposeThe efficacy of current antidepressant drugs has been compromised by adverse effects, low remission and delay onset of action necessitating the search for alternative agents. Methyl jasmonate (MJ), a bioactive compound isolated from Jasminum grandiflorum has been shown to demonstrate antidepressant activity but its mechanism of action remains unknown. Thus, the role of monoaminergic systems in the antidepression-like activity of MJ was investigated in this study. Materials and methodsMice were given i.p. injection of MJ (5, 10 and 20mg/kg), imipramine (10mg/kg) and vehicle (10mL/kg) 30min before the forced swim test (FST) and tail suspension test (TST) were carried out. The involvement of monoaminergic systems in the anti-depressant-like effect of MJ (20mg/kg) was evaluated using p-chlorophenylalanine (pCPA), metergoline, yohimbine, prazosin, sulpiride and haloperidol in the TST. ResultsMJ significantly decrease the duration of immobility in the FST and TST relative to control suggesting antidepressant-like property. However, pretreatment with yohimbine (1mg/kg, i.p., an α2-adrenergic receptor antagonist) or prazosin (62.5μg/kg, i.p., an α1-adrenoceptor antagonist) attenuated the antidepressant-like activity of MJ. Also, pCPA; an inhibitor of serotonin biosynthesis (100mg/kg, i.p) or metergoline (4mg/kg, i.p., 5-HT2 receptor antagonist) reversed the anti-immobility effect of MJ. Sulpiride (50mg/kg, i.p., a D2 receptor antagonist) or haloperidol (0.2mg/kg, i.p., a dopamine receptor antagonist) reversed the anti-immobility effect of MJ. ConclusionThe results of this study suggest that serotonergic, noradrenergic and dopaminergic systems may play a role in the antidepressant-like activity of MJ.

Modulation of PKA, PKC, CAMKII, ERK 1/2 pathways is involved in the acute antidepressant-like effect of (octylseleno)-xylofuranoside (OSX) in mice

(Octylseleno)-xylofuranoside (OSX) is an organoselenium compound from the class of alkylseleno carbohydrates possessing a C8 alkyl chain. Members of this class of organoselenium compounds have promising pharmacological activities, among them are antioxidant and acute antidepressant-like activities with the involvement of monoaminergic system, as previously presented by our research group. The objective of the study was to investigate the possible involvement of cellular signalling pathways in the antidepressant-like effect caused by OSX (0.01mg/kg, oral route (p.o.) by gavage) in the tail suspension test (TST) in mice. Mice were treated by intracerebroventricular (i.c.v.) injection either with vehicle or with H-89 (1μg/site i.c.v., an inhibitor of protein kinase A-PKA), KN-62 (1μg/site i.c.v., an inhibitor of Ca2+/calmodulin-dependent protein kinase II-CAMKII), chelerythrine (1μg/site i.c.v., an inhibitor of protein kinase C-PKC) or PD098059 (5μg/site i.c.v., an inhibitor of extracellular-regulated protein kinase 1/2-ERK1/2). Fifteen minutes after, vehicle or OSX was injected, and 30min later, the TST and open field tests (OFT) were carried out. The antidepressant-like effect of orally administered OSX was blocked by treatment of the mice with H-89, KN-62, chelerythrine and PD098059; all inhibitors of signalling proteins involved with neurotrophic signalling pathways. The number of crossings in the OFT was not altered by treatment with OSX and/or signalling antagonists. The results demonstrated that OSX showed an antidepressant-like effect in the TST in mice through the activation of protein kinases PKA, PKC, CAMKII and ERK1/2 that are involved in intracellular signalling pathways.

Involvement of monoaminergic systems in anxiolytic and antidepressive activities of the standardized extract of Cocos nucifera L.

Extracts from the husk fiber of Cocos nucifera are used in folk medicine, but their actions on the central nervous system have not been studied. Here, the anxiolytic and antidepressant effects of the standardized hydroalcoholic extract of C. nucifera husk fiber (HECN) were evaluated. Male Swiss mice were treated with HECN (50, 100, or 200mg/kg) 60min before experiments involving the plus maze test, hole-board test, tail suspension test, and forced swimming test (FST). HECN was administered orally (p.o.) in acute and repeated-dose treatments. The forced swimming test was performed with dopaminergic and noradrenergic antagonists, as well as a serotonin release inhibitor. Administration of HECN in the FST after intraperitoneal (i.p.) pretreatment of mice with sulpiride (50mg/kg), prazosin (1mg/kg), or p-chlorophenylalanine (PCPA, 100mg/kg) caused the actions of these three agents to be reversed. However, this effect was not observed after pretreating the animals with SCH23390 (15µg/kg, i.p.) or yohimbine (1mg/kg, i.p.) The dose chosen for HECN was 100mg/kg, p.o., which increased the number of entries as well as the permanence in the open arms of the maze after acute and repeated doses. In both the forced swimming and the tail suspension tests, the same dose decreased the time spent immobile but did not disturb locomotor activity in an open-field test. The anxiolytic effect of HECN appears to be related to the GABAergic system, while its antidepressant effect depends upon its interaction with the serotoninergic, noradrenergic (α1 receptors), and dopaminergic (D2 dopamine receptors) systems.

Piperine potentiates the effects of trans-resveratrol on stress-induced depressive-like behavior: involvement of monoaminergic system and cAMP-dependent pathway.

Stress can act as a precipitation factor in the onset of emotional disorders, particularly depression. Trans-resveratrol is a polyphenolic compound enriched in polygonum cuspidatum and has been found to exert antidepressant-like effects in our previous studies. In present study, we assessed the effects of trans-resveratrol used in combination with piperine, commonly known as a bioavailability enhancer, on chronic unpredictable mild stress-induced depressive-like behaviors and relevant molecular targets. Trans-resveratrol used alone reduced the immobility time of rats in the forced swimming test, with the maximal effects of trans-resveratrol around 60% inhibition at the highest dose tested, 40mg/kg. However, when a subthreshold dose of piperine, 2.5mg/kg was used in combination with trans-resveratrol, the minimum effective dose of trans-resveratrol in reducing the immobility time was reduced to 20mg/kg. Further evidence from neurochemical (monoamines in the frontal cortex and the hippocampus), biochemical (monoamine oxidase, MAO activities) and molecular biological (cAMP, PKA, CREB and BDNF) assays supported the findings in the behavioral studies. These results suggest that the co-treatment strategy with trans-resveratrol and piperine might be an alternative therapy that provides efficacious protection against chronic stress.

Involvement of monoaminergic system in the antidepressant-like effect of (octylseleno)-xylofuranoside in the mouse tail suspension test

Depression is one of the most commonly diagnosed neuropsychiatric disorders and several studies have demonstrated a role for selenium in mood disorders. For this reason, the present study investigated the role of the monoaminergic system in the antidepressant-like action of (octylseleno)-xylofuranoside (OSX), an organoselenium compound, in the tail suspension test (TST) in mice. For this purpose, OSX (0.001–10mg/kg) was administered orally (p.o.) 30min prior to testing, and all of the tested doses reduced the immobility time in the TST without changing the locomotor activity measured in the open field test (OFT). Furthermore, the antidepressant-like effect of OSX (0.01mg/kg, p.o.) in the TST was prevented by pre-treatment in mice with ketanserin (1mg/kg, intraperitoneal route (i.p.); a 5-HT2A/2C receptor antagonist), WAY100635 (0.1mg/kg, subcutaneous (s.c.); a selective 5-HT1A receptor antagonist), p-chlorophenylalanine methyl ester-PCPA (100mg/kg, i.p.; a selective inhibitor of tryptophan hydroxylase), prazosin (1mg/kg, i.p.; an α1-adrenoceptor antagonist), yohimbine (1mg/kg, i.p.; an α2-adrenoceptor antagonist), SCH233390 (0.05mg/kg, s.c., a dopaminergic D1 receptor antagonist) and sulpiride (50mg/kg, i.p., a dopaminergic D2 receptor antagonist), but not with ondansetron (1mg/kg, i.p.; a selective 5-HT3 receptor antagonist). Taken together, these data demonstrate that OSX has a potent antidepressant-like effect in TST at lower doses (0.001–10mg/kg), which is dependent on its interaction with the serotonergic, noradrenergic and dopaminergic systems.

Synergistic antidepressant-like effect of ferulic acid in combination with piperine: involvement of monoaminergic system.

The lifetime prevalence rate for major depressive disorder (MDD) is approximately 17 % for most developed countries around the world. Dietary polyphenols are currently used as an adjuvant therapy to accelerate the therapeutic efficacy on depression. Ferulic acid (FA) or 4-hydroxy-3-methoxy-cinnamic acid (Fig. 1a) is a main polyphenolic component of Chinese herb Radix Angelicae Sinensis, which is found to have antidepressant-like effects through regulating serotonergic and noradrenergic function. The present study examined the synergistic effect of low doses of FA combined with subthreshold dose of piperine, a bioavailability enhancer, on depression-like behaviors in mice, and investigated the possible mechanism. The administration of FA, even in the highest dose tested, reduced immobility time by 60 % in the tail suspension and forced swimming tests (TST and FST) in mice when compared to control. The maximal antidepressant-like effect of FA was obtained with 200 mg/kg. In addition, piperine only produced a weak antidepressant-like effect in the TST and FST. However, the evidence from the interaction analysis suggested a synergistic effect when low doses of FA were combined with a subthreshold dose of piperine. Further neurochemical evidence such as monoamine levels in the frontal cortex, hippocampus, and hypothalamus and measurements of monoamine oxidase activity also supported a synergistic effect of FA and piperine in the enhancement of monoaminergic function. This finding supports the concept that the combination strategy might be an alternative therapy in the treatment of psychiatric disorders with high efficacy and low side effects.

Involvement of monoaminergic systems in the antidepressant-like properties of Lafoensia pacari A. St. Hil

Ethnopharmacological relevanceLafoensia pacari A. St.-Hil. (Lythraceae), known popularly as “pacari” or “mangaba-brava” is popularly used in the state of Goiás, Brazil. The stem bark or leaves are used to treat cancer, gastric disorders, inflammation and as a tonic to treat loss of enthusiasm. Aim of the studyPrevious results suggest that the ethanol:water 7:3 extract of the stem bark of L. pacari (PEx) has antidepressant-like activity in male mice. Our aim was to perform the PEx׳s bioguided fractionation and evaluate the monoaminergic system involvement in the antidepressant effect as well as progress in the study of L. pacari mechanism of action. Material and methodsMice (30–35g) orally treated (24, 5 and 1h) with PEx (100, 300 or 1000mg/kg), chloroform (ChloF—70mg/kg), ethyl acetate (180mg/kg), n-butanol (370mg/kg) and aqueous (1g/kg) fractions were submitted to the forced swimming test. To assess the mechanism of action, different groups of mice were pretreated with p-chlorophenylalanine (PCPA—100mg/kg, 4 days, i.p.) and alpha-methyl-p-tyrosine (AMPT—100mg/kg, 4h, i.p.) to assess the involvement of serotoninergic and catecholaminergic systems in the ChloF effects, respectively. A putative in vitro inhibition of monoamine oxidase (MAO) activity as well as the ex vivo hippocampal brain-derived neurotrophic factor (BDNF) quantification were carried out. Phytochemical screening, spectroscopy and chromatography analysis were used for identification of compounds present in ChloF. Results and discussionAfter the fractionation, the ChloF 70mg/kg was the most active fraction, reducing the immobility time by 22%. Pre-treatments with both PCPA and AMPT abolished the ChloF effects, suggesting that ChloF antidepressant-like effect is dependent on serotonergic and catecholaminergic systems. ChloF did not inhibited MAO-A or MAO-B activity, excluding this as possible mechanism of action. ChloF augmented hippocampal BDNF level, which could be accounted for its antidepressant-like effect. Phytochemical screening showed the presence of saponins, tannins, steroids and triterpene in the PEx, and the presence of triterpene and steroids in ChloF. The spectroscopy and chromatography analysis identified lupeol, β-sitosterol and stigmasterol in ChloF. ConclusionChloF is the fraction that better retained the crude extract active constituents. ChloF presents antidepressant-like effect that involves both serotonergic and catecholaminergic systems without inhibiting MAO enzymatic activity; this fraction also increases the hippocampal BDNF levels.

Potential of novel phytoecdysteroids isolated from Vitex doniana in the treatment depression: Involvement of monoaminergic systems

Vitex doniana Sweet (Verbanaceae) is used in traditional African medicine for the treatment of neurological disorders including depression. In our previous studies, three new phytoecdysteroids were isolated from methanol stem bark extract of V. doniana (VD) (11β-hydroxy-20-deoxyshidasterone, 21-hydroxyshidasterone, and 2,3-acetonide-24-hydroxyecdysone) along with known ecdysteroids. This study was designed to investigate antidepressant-like effect of VD and the isolated phytoecdysteroids in behavioral models of despair, forced-swim test (FST) and tail-suspension test (TST) in mice. VD (100 and 200mg/kg, p.o.) treatment reduced (P<0.05) the duration of immobility in both tests without affecting the locomotor activity and exploratory behavior as observed in the open field test. Similarly, 21-hydroxyshidasterone, 11β-hydroxy-20-deoxyshidasterone, ajugasterone and 24-hydroxyecdysone acute oral treatments significantly reduced immobility time with peak effect at 10mg/kg, which was similar to the effect of conventional antidepressants (imipramine and fluoxetine) in the FST. Conversely, pretreatment of mice with yohimbine (1mg/kg, i.p., α2-adrenoceptor antagonist), ketanserin (5mg/kg, i.p., 5-HT2A/2C receptor antagonist) or sulpiride (dopamine D2 receptor antagonist) prevented the antidepressant-like effect of 21-hydroxyshidasterone while the effects of 11β-hydroxy-20-deoxyshidasterone and 24-hydroxyecdysone were blocked by yohimbine or ketanserin in the FST. Moreover, the anti-immobility effect elicited by ajugasterone was prevented by prazosin (62.5μg/kg, i.p., α1-adrenoceptor antagonist) pretreatment. Our findings demonstrated that V. doniana and its phytoecdysteroids constituents elicited antidepressant-like effect in behavioral paradigm of despair. Furthermore, 21-hydroxyshidasterone produces its antidepressant-like effect through interaction with α2-adrenoceptor, 5-HT2A/2C receptor and dopamine D2-receptors but 11β-hydroxy-20-deoxyshidasterone and 24-hydroxyecdysone effects depend on interaction with α2-adrenoceptor and 5-HT2A/2C receptors while ajugasterone produces its action through interaction with post-synaptic α1-adrenoceptors. Thus, phytoecdysteroids could play a pivotal role in the treatment of major depression.

Genetically Modified Mice as Tools to Understand the Neurobiological Substrates of Depression

The pathophysiological mechanisms underlying depression are still poorly understood. An initial hypothesis postulated to explain the substrates of depression was based on the involvement of monoaminergic systems. This early theory was proposed from different findings obtained using pharmacological tools and can explain the mechanism of action of the drugs currently used to treat depression. However, more recent studies have revealed that other neurobiological processes different from monoamines also participate in the substrates of depression. These mechanisms include the participation of several neuromodulatory systems, stress-related circuits and neuroplastic changes that could represent a direct substrate for these pathophysiological processes. The lack of selective pharmacological tools for several of these potential targets of depression represents an important limitation to study their potential involvement. In the last two decades, different lines of genetically modified mice have been generated with selective deletions in specific genes related to the control of emotional responses. This review summarizes the main findings that have been obtained with these novel genetic tools to clarify the neurobiological substrates of depression. A particular focus has been devoted to the advances obtained with mice deficient in specific components of the monoaminergic, opioid and cannabinoid system and those with mutations in elements of the hypothalamic-pituitary-adrenal axis.

Piperine potentiates the antidepressant-like effect of trans-resveratrol: involvement of monoaminergic system

Major depression is characterized by dysfunction of neuroendocrine and immune networks. Trans-resveratrol, a phenolic compound presented in polygonum cuspidatum, was demonstrated previously to exert antidepressant-like effects through regulating monoaminergic system, oxidative/antioxidant defense and inflammatory response. The present study investigated the synergistic antidepressant-like effect of trans-resveratrol and piperine, a bioavailability enhancer, in mice and explored the possible mechanism. Trans-resveratrol was shown to reduce the immobility time both in the tail suspension and forced swimming tests (TST and FST). But the maximal inhibition was nearly 60% even if the doses were increased by 160 mg/kg; while piperine produced weak antidepressant-like effects in these two models. The interaction between trans-resveratrol and piperine was shown a clear-cut synergistic effect as evidenced by an isobolographic analysis. The further study suggested that the anti-immobility response from the subthreshold dose of piperine (2.5 mg/kg) and low doses of trans-resveratrol (10 and 20 mg/kg) was abolished by pretreatment with para-chlorophenylalanine (PCPA, 300 mg/kg, i.p.) in TST and FST, indicating the involvement of serotonergic system. Moreover, treatment with the subthreshold dose of piperine and low doses of trans-resveratrol attenuated reserpine-induced hypothermia and ptosis arguing for the relevance of noradrenaline. Additional evidence from neurochemical (monoamines in the frontal cortex, hippocampus, and hypothalamus) and biochemical (monoamine oxidase, MAO activity) assays corroborated the synergistically elevated monoaminergic system after co-treatment with trans-resveratrol and piperine. The present results indicate the effect of trans-resveratrol combined with piperine on depressive-like behaviors may be partly due to the potentiated activation of monoaminergic system in the brain. Further studies are necessary to elucidate the involvement of the oxidative/nitrosative stress, inflammatory and neuroprotective pathway in the antidepressant-like effect of this combination. The synergistic effect obtained from the combination may provide innovative clues for designing novel antidepressants with high efficacy and low side effects.

Involvement of monoaminergic systems in the antidepressant-like effect of nobiletin

Nobiletin isolated from citrus peels up-regulates synaptic transmission and improves memory impairment in rodents. This study investigated the antidepressant-like effect of nobiletin in the forced swimming test (FST) and tail suspension test (TST) in mice. Additionally, the monoaminergic mechanisms involved in the antidepressant-like effect of nobiletin in mice were also assessed. Nobiletin (25, 50 and 100mg/kg, p.o.) decreased the immobility time in both the FST and TST without locomotor alterations in the open-field test (OFT). The anti-immobility effect of nobiletin (50mg/kg, p.o.) was completely prevented by the pretreatment of mice with WAY 100635 (0.1mg/kg, s.c., a serotonin 5-HT(1A) receptor antagonist), cyproheptadine (3mg/kg, i.p., a serotonin 5-HT(2) receptor antagonist), prazosin (62.5μg/kg, i.p., an α(1)-adrenoceptor antagonist), SCH23390 (0.05mg/kg, s.c., a dopamine D(1) receptor antagonist) or sulpiride (50mg/kg, i.p., a dopamine D(2) receptor antagonist). On the other hand, the pretreatment of mice with yohimbine (1mg/kg, i.p., an α(2)-adrenoceptor antagonist) or propranolol (5mg/kg, i.p., a β-adrenoceptor antagonist) did not block the antidepressant-like effect of nobiletin in the TST. Taken together, the data demonstrated that nobiletin produced an antidepressant-like effect that seems to be dependent on its interaction with the serotonergic, noradrenergic and dopaminergic systems. Thus, the present study suggests the therapeutic potential of this dietary flavonoid for the treatment of depression.

Involvement of monoaminergic system in the antidepressant-like effect of the flavonoid naringenin in mice

Dietary flavonoids possess a multiplicity of neuroprotective actions in various central nervous pathophysiological conditions including depression. In this study, the neuropharmacological mechanism of the dietary flavonoid naringenin was investigated in the mouse behavioral models of depression. For this purpose, we investigated the influence of pretreatment with the inhibitors of serotonin or noradrenaline synthesis, p-chlorophenylalanine methyl ester or α-methyl- p-tyrosine, respectively in the anti-immobility effect of naringenin. Compared to the control group, naringenin significantly decreased the immobility time after acute treatment in the mouse tail suspension test (10, 20 and 50 mg/kg), but not in the forced swimming test, without producing locomotor alteration in the open-field test. In addition, pretreatment of mice with p-chlorophenylalanine methyl ester (100 mg/kg) or α-methyl- p-tyrosine (100 mg/kg) prevented the anti-immobility effect of naringenin (20 mg/kg) in the tail suspension test. Taken together, this data demonstrated that naringenin possessed potent antidepressant-like property via the central serotonergic and noradrenergic systems. Thus, our findings suggest the therapeutic potential of this dietary flavonoid in central nervous system disorders especially depression where monoaminergic systems are involved.

Antidepressant-like effect of low molecular proanthocyanidin in mice: Involvement of monoaminergic system

Proanthocyanidin is a phenolic product present in plants which has antioxidant, antinociceptive and neuroprotective properties, without inducing significant toxicological effects. The present study tested the hypothesis that low molecular proanthocyanidin from grapes that has optimized bioavailability, would exert antidepressant-like activities in behavioral despair tests. The results suggested that oral administration proanthocyanidin at doses of 25 and 50 mg/kg for 7 days significantly reduced the duration of immobility in both the tail suspension and forced swimming tests. The doses that affected the immobile response did not affect locomotor activity. In addition, the neurochemical and neuropharmacological assays showed that proanthocyanidin produced a marked increase of 5-HT levels at 25 and 50 mg/kg in three brain regions, the frontal cortex, hippocampus and hypothalamus. Noradrenaline and dopamine levels were also increased when higher dose of proanthocyanidin (50 mg/kg) administration both in the frontal cortex and hippocampus. These effects were similar to those observed for the classical antidepressant imipramine (10 mg/kg, i.p.). Moreover, Our study suggested that proanthocyanidin (12.5, 25 and 50 mg/kg) dose dependently inhibited monoamine oxidase-A (MAO-A) activity, while MAO-B inhibitory activity was also found at higher doses (25 and 50 mg/kg) after 7 days administration. MAO-A selective inhibitor, moclobemide (20 mg/kg, i.g.) produced MAO-A inhibition of 70.5% in the mouse brain. These findings suggest that the antidepressant-like effects of proanthocyanidin may involve the central monoaminergic neurotransmitter systems.

Muscarinic acetylcholine neurotransmission enhances the late-phase of long-term potentiation in the hippocampal–prefrontal cortex pathway of rats in vivo: A possible involvement of monoaminergic systems

The prefrontal cortex is continuously required for working memory processing during wakefulness, but is particularly hypoactivated during sleep and in psychiatric disorders such as schizophrenia. Ammon's horn CA1 hippocampus subfield (CA1) afferents provide a functional modulatory path that is subjected to synaptic plasticity and a prominent monoaminergic influence. However, little is known about the muscarinic cholinergic effects on prefrontal synapses. Here, we investigated the effects of the muscarinic agonist, pilocarpine (PILO), on the induction and maintenance of CA1-medial prefrontal cortex (mPFC) long-term potentiation (LTP) as well as on brain monoamine levels. Field evoked responses were recorded in urethane-anesthetized rats during baseline (50 min) and after LTP (130 min), and compared with controls. LTP was induced 20 min after PILO administration (15 mg/kg, i.p.) or vehicle (NaCl 0.15 M, i.p.). In a separate group of animals, the hippocampus and mPFC were microdissected 20 min after PILO injection and used to quantify monoamine levels. Our results show that PILO potentiates the late-phase of mPFC LTP without affecting either post-tetanic potentiation or early LTP (20 min). This effect was correlated with a significant decrease in relative delta (1–4 Hz) power and an increase in sigma (10–15 Hz) and gamma (25–40 Hz) powers in CA1. Monoamine levels were specifically altered in the mPFC. We observed a decrease in dopamine, 5-HT, 5-hydroxyindolacetic acid and noradrenaline levels, with no changes in 3,4-hydroxyphenylacetic acid levels. Our data, therefore, suggest that muscarinic activation exerts a boosting effect on mPFC synaptic plasticity and possibly on mPFC-dependent memories, associated to monoaminergic changes.

Monoaminergic agents modulate antidepressant-like effect caused by diphenyl diselenide in rats

In this study, the antidepressant-like effect caused by diphenyl diselenide on rat forced swimming test (FST) was investigated. The involvement of the monoaminergic system in the antidepressant-like effect was also evaluated. Diphenyl diselenide (0.1–30 mg/kg), given by oral route (p.o.), 30 min earlier, reduced the immobility time in the FST, without accompanying changes in ambulation when assessed in an open field. The anti-immobility effect of diphenyl diselenide (1 mg/kg, p.o.) on the FST was prevented by pretreatment of rats with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis, given once a day, for 3 consecutive days), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT 1A receptor antagonist), ketanserin (1 mg/kg, i.p., a 5-HT 2A/ 2C receptor antagonist), ondasentron (1 mg/kg, i.p., a 5-HT 3 receptor antagonist), haloperidol (1 mg/kg, i.p., a D 1, D 2 and D 3 receptor antagonist), SCH233390 (0.05 mg/kg, s.c., a D 1 receptor antagonist), sulpiride (50 mg/kg, i.p., a D 2 receptor antagonist), prazosin (1 mg/kg, i.p., an α 1-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α 2-adrenoceptor antagonist). However, the anti-immobility effect caused by diphenyl diselenide (1 mg/kg, p.o.) on the FST was not affected by pretreatment with propanolol (2 mg/kg, i.p., a β-adrenoceptor antagonist). Furthermore, monoamine oxidase (MAO) activity was inhibited (39%) in the animals treated with diphenyl diselenide (30 mg/kg, p.o.) when compared to the control group. Taken together these data demonstrated that the antidepressant-like effect caused by diphenyl diselenide seems to be mediated by involvement of the central monoaminergic system.

Involvement of monoaminergic system in the antidepressant-like effect of the hydroalcoholic extract of Siphocampylus verticillatus

The antidepressant-like effect of the hydroalcoholic extract obtained from aerial parts of Siphocampylus verticillatus, a Brazilian medicinal plant, was investigated in two models of depression in mice and against synaptosomal uptake of serotonin, noradrenaline and dopamine. The immobility times in the forced swimming test (FST) and in the tail suspension test (TST) were significantly reduced by the extract (dose range 100–1000 mg/kg, i.p.), without accompanying changes in ambulation when assessed in an open-field. In addition when given orally the extract was also effective in reducing the immobility time in the TST. The efficacy of extract in the TST was comparable to that of the tricyclic antidepressant imipramine (15 mg/kg, i.p.) and with fluoxetine (32 mg/kg, i.p.). The anti-immobility effect of the extract (600 mg/kg, i.p.) assessed in the TST was not affected by pre-treatment with naloxone (1 mg/kg, i.p., a non-selective opioid receptor antagonist) or L-arginine (750 mg/kg, i.p., a nitric oxide precursor). In contrast, the extract (600 mg/kg, i.p.) antidepressant-like effect was significantly reduced by pre-treatment of animals with p-chlorophenylalanine (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis), sulpiride (50 mg/kg, i.p., a selective D 2 receptor antagonist), prazosin (62.5 μg/kg, i.p., an α 1 adrenoreceptor antagonist) or by guanosine 5′-monophosphate (GMP, 250 mg/kg, i.p., a nucleotide known to block some actions elicited by NMDA). The biochemical data show that the extract of S. verticillatus inhibited in a graded manner the uptake of monoamines. However, at the IC 50 level, the extract was approximately 3.2 to 3.4-fold more potent and also more efficacious in inhibiting the synaptosomal uptake of noradrenaline and serotonin than dopamine. Taken together these data demonstrate that the extract of S. verticillatus elicited a significant antidepressant-like effect, when assessed in the TST and FST in mice. Its action seems to involve an interaction with adrenergic, dopaminergic, glutamatergic and serotonergic systems.

Role of opioidergic and monoaminergic neurotransmission in the GnRH release mechanism of EBP-primed OVX rats

We examined the effect of intracerebroventricular (i.c.v.) administration of μ-opioid agonist, morphine, and its antagonist naloxone followed by morphine on the activities of monoamine-metabolizing enzymes, namely tyrosine hydroxylase (TH) and monoamine oxidase (MAO) along with adenosinetriphosphatase (Na +, K + -ATPase), the enzyme responsible for the maintenance of ionic gradients across the membrane, in seven discrete regions of brain from estrogen- and progesterone-primed ovariectomized rats. TH activity decreased after morphine treatment in some areas such as the median eminence-arcuate region (ME-ARC), the amygdala, and the thalamus, showing statistically significant change. MAO activity increased in all the areas studied, but more appreciable change was observed in medial preoptic area (mPOA), the ME-ARC region, and the cortex. Pronounced increase in Na +, K + -ATPase enzyme activity was observed after the drug treatment. Naloxone given prior to morphine injection resulted in recovery of the enzyme activities in most of the areas studied. Our study may provide insights into the precise opioidergic modulation of gonadotropin releasing hormone (GnRH) release mechanisms through the involvement of monoaminergic system, elucidating the basis of various neuronal dysfunctions and their management in opioid addicts.