Effects of dopamine and serotonin synthesis inhibitors on the ketamine-, d-amphetamine-, and cocaine-induced locomotor activity of preweanling and adolescent rats: sex differences.

The pattern of ketamine-induced locomotor activity varies substantially across ontogeny and according to sex. Although ketamine is classified as an NMDA channel blocker, it appears to stimulate the locomotor activity of both male and female rats via a monoaminergic mechanism. To more precisely determine the neural mechanisms underlying ketamine's actions, male and female preweanling and adolescent rats were pretreated with vehicle, the dopamine (DA) synthesis inhibitor ∝-methyl-DL-p-tyrosine (AMPT), or the serotonin (5-HT) synthesis inhibitor 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA). After completion of the pretreatment regimen, the locomotor activating effects of saline, ketamine, d-amphetamine, and cocaine were assessed during a 2 h test session. In addition, the ability of AMPT and PCPA to reduce dorsal striatal DA and 5-HT content was measured in male and female preweanling, adolescent, and adult rats. Results showed that AMPT and PCPA reduced, but did not fully attenuate, the ketamine-induced locomotor activity of preweanling rats and female adolescent rats. Ketamine (20 and 40 mg/kg) caused a minimal amount of locomotor activity in male adolescent rats, and this effect was not significantly modified by AMPT or PCPA pretreatment. When compared to ketamine, d-amphetamine and cocaine produced different patterns of locomotor activity across ontogeny; moreover, AMPT and PCPA pretreatment affected psychostimulant- and ketamine-induced locomotion differently. When these results are considered together, it appears that both dopaminergic and serotonergic mechanisms mediate the ketamine-induced locomotor activity of preweanling and female adolescent rats. The dichotomous actions of ketamine relative to the psychostimulants in vehicle-, AMPT-, and PCPA-treated rats, suggests that ketamine modulates DA and 5-HT neurotransmission through an indirect mechanism.

5-Hydroxytryptamine-Independent Antidepressant Actions of (R)-Ketamine in a Chronic Social Defeat Stress Model.

Background: Previous reports suggest that 5-hydroxytryptamine might play a role in the antidepressant actions of (R,S)-ketamine. However, its role in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, is unknown. This study was conducted to examine whether 5-hydroxytryptamine depletion affects the antidepressant actions of (R)-ketamine in a chronic social defeat stress model. Methods: An inhibitor of 5-hydroxytryptamine synthesis, para-chlorophenylalanine methyl ester hydrochloride (300 mg/kg, twice daily for 3 consecutive days), or vehicle was administered to control and chronic social defeat stress-susceptible mice. Levels of 5-hydroxytryptamine and its metabolite, 5-hydroxyindoleacetic acid, in mouse brain regions were measured using high-performance liquid chromatography. Furthermore, antidepressant effects of (R)-ketamine (10 mg/kg) in the vehicle- and para-chlorophenylalanine methyl ester hydrochloride-treated susceptible mice were assessed using tail suspension test and 1% sucrose preference test. Results: para-Chlorophenylalanine methyl ester hydrochloride treatment caused marked reductions of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the brain regions of control and chronic social defeat stress susceptible mice. In the tail suspension test, (R)-ketamine significantly attenuated the increased immobility time in the chronic social defeat stress-susceptible mice with or without 5-hydroxytryptamine depletion. In the sucrose preference test (2 and 5 days after a single dose), (R)-ketamine significantly enhanced reduced sucrose consumption in the chronic social defeat stress-susceptible mice with or without 5-hydroxytryptamine depletion. Conclusions: These findings show that 5-hydroxytryptamine depletion did not affect the antidepressant effects of (R)-ketamine in a chronic social defeat stress model. Therefore, it is unlikely that 5-hydroxytryptamine plays a major role in the antidepressant actions of (R)-ketamine.

The protective effects of PCPA against monocrotaline-induced pulmonary arterial hypertension are mediated through the downregulation of NFAT-1 and NF-κB.

Inflammation and remodeling play a role in the pathogenesis of pulmonary arterial hypertension (PAH). Nuclear factor-κB (NF-κB) and nuclear factor of activated T cells-1 (NFAT-1) participate in inflammation and remodeling in a number of diseases. As a tryptophan hydroxylase inhibitor, 4-chloro-DL-phenylalanine (PCPA) had been reported to exert anti-inflammatory and remodeling effects. Therefore, we hypothesized that PCPA may attenuate monocrotaline (MCT)-induced PAH through the NFAT-1 and NF-κB signaling pathways. In order to confirm our hypothesis, we divided 68 Sprague-Dawley male rats into 4 groups as follows: the control, MCT, MCT + P1 and MCT + P2 groups. MCT was administered at a dose of 60 mg/kg once via intraperitoneal injection. PCPA was administered via intraperitoneal injection at a dose of 50 or 100 mg/kg once daily for 21 consecutive days. We then measured the hemodynamic index and morphological analysis was carried out on the lung tissues. Western blot analysis and immunohistochemistry were used to examine the levels of NFAT-1 and NF-κB p-65. The expression levels of phosphorylated inhibitor of NF-κB kinase (p-IKK), IKK, phosphorylated extracellular signal­regulated kinase (p-ERK), ERK, intercellular adhesion molecule-1 (ICAM-1) and inter-leukin-6 (IL-6) were examined by western blot analysis. MCT was found to significantly induce PAH, with inflammation and remodeling of the lung tissues. This was associatd with an increased expression of NFAT-1, p-IKK, p-ERK and nuclear p65. PCPA significantly attenuated MCT-induced inflammation and arterial remodeling, and decreased the expression of NFAT-1, as well as that of relevant proteins of the NF-κB signaling pathway. The above-mentioned findings suggest that the inhibitory effects of PCPA on MCT-induced inflammation and arterial remodeling are related to the downregulation of the NFAT-1 and NF-κB signaling pathways in rats with PAH.

Effect of subacute agomelatine treatment on painful diabetic neuropathy: involvement of catecholaminergic mechanisms.

In this study, we investigated the effects of subacute agomelatine (40 and 80 mg/kg) administration on chronic hyperglycemia, metabolic parameters, and pain perception in streptozotocin-induced diabetic rats. Fasting blood glucose measurements and oral glucose tolerance tests were performed to evaluate the effect of agomelatine on glycemia, while metabolic parameters were monitored using metabolic cages. Potential effect of agomelatine on diabetes-induced mechanical and thermal allodynia was evaluated using dynamic plantar aesthesiometer and warm plate (38 °C) tests, respectively. Additionally, influence of agomelatine on hyperalgesia occurring in connection with diabetic neuropathy was examined using the Randall-Selitto (mechanical nociceptive stimulus), Hargreaves (thermal nociceptive stimulus), and cold plate (4 °C, thermal nociceptive stimulus) tests. Obtained data indicated that, in diabetic rats, agomelatine significantly improved hyperalgesia and allodynia responses, without no effect on hyperglycemia or the associated polydipsia, polyuria, and hyperphagia. Therapeutic potential of agomelatine on neuropathic pain was suppressed with α-methyl-para-tyrosine methyl ester (an inhibitor of catecholamine synthesis), phentolamine (a nonselective α-adrenoceptor antagonist), and propranolol (a nonselective ß-adrenoceptor antagonist) administrations. However, p-chlorophenylalanine methyl ester (an inhibitor of serotonin synthesis) pretreatment could not be achieved to reverse these antihyperalgesic and antiallodynic effects. These results suggest that the curative effect of agomelatine on neuropathic pain is mediated through rising synaptic catecholamine levels as well as through interactions with both α- and ß-adrenoceptors. To our knowledge, this is the first study to show findings that indicate catecholaminergic system mediated antihyperalgesic and antiallodynic effects of agomelatine.

Role of brainstem serotonin in analgesia produced by low-intensity exercise on neuropathic pain after sciatic nerve injury in mice.

Physical exercise is a low-cost, safe, and efficient intervention for the reduction of neuropathic chronic pain in humans. However, the underlying mechanisms for how exercise reduces neuropathic pain are not yet well understood. Central monoaminergic systems play a critical role in endogenous analgesia leading us to hypothesize that the analgesic effect of low-intensity exercise occurs through activation of monoaminergic neurotransmission in descending inhibitory systems. To test this hypothesis, we induced peripheral nerve injury (PNI) by crushing the sciatic nerve. The exercise intervention consisted of low-intensity treadmill running for 2 weeks immediately after injury. Animals with PNI showed an increase in pain-like behaviors that were reduced by treadmill running. Reduction of serotonin (5-hydroxytryptamine) synthesis using the tryptophan hydroxylase inhibitor para-chlorophenylalanine methyl ester prevented the analgesic effect of exercise. However, blockade catecholamine synthesis with the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine had no effect. In parallel, 2 weeks of exercise increased brainstem levels of the 5-HT and its metabolites (5-hydroxyindoleacetic acid), decreased expression of the serotonin transporter, and increased expression of 5-HT receptors (5HT-1B, 2A, 2C). Finally, PNI-induced increase in inflammatory cytokines, tumor necrosis factor-alpha, and interleukin-1 beta, in the brainstem, was reversed by 2 weeks of exercise. These findings provide new evidence indicating that low-intensity aerobic treadmill exercise suppresses pain-like behaviors in animals with neuropathic pain by enhancing brainstem 5-HT neurotransmission. These data provide a rationale for the analgesia produced by exercise to provide an alternative approach to the treatment of chronic neuropathic pain.

Inhalation of Cedrus atlantica essential oil alleviates pain behavior through activation of descending pain modulation pathways in a mouse model of postoperative pain.

ETHNOPHARMACOLOGICAL RELEVANCE: Cedrus atlantica essential oil (CaEO) presents analgesic and anti-inflammatory sedative properties. However, it remains unknown whether CaEO alleviates acute postoperative pain. MATERIALS AND METHODS: Here, we investigated the effect of CaEO on postoperative pain and its mechanisms related to the descending pain control in Swiss males mice induced by a plantar incision surgery (PIS) in the hindpaw. RESULTS: Inhalation of CaEO (5', 30' or 60') markedly reduced mechanical hypersensitivity. This effect was prevented by pre-treatment with naloxone or p-chlorophenylalanine methyl ester (PCPA, 100mg/kg, i.p.)-induced depletion of serotonin. In addition, p-alpha-methyl-para-tyrosin (AMPT, 100mg/kg, i.p.)-induced depletion of norepinephrine, intraperitoneal injection of the α2-adrenergic receptor antagonist yohimbine (0.15 mg/kg, i.p.) or haloperidol (1mg/kg, i.p.) an antagonist of dopaminergic (D1 and D2) receptors prevented the effect of CaEO on hypersensitivity. CONCLUSIONS: These findings suggest that CaEO alleviates postoperative pain by activating the descending pain modulation pathways on the opioidergic, serotonergic, noradrenergic (α2-adrenergic) and dopaminergic (dopamine D1 and D2 receptors) systems.

Involvement of opioidergic and serotonergic systems in the analgesic activity of Cissus quadrangularis L. stem extract in mice.

BACKGROUND: Cissus quadrangularis L. (Vitaceae) is used as a bonesetter and as an analgesic. However, the bioactive fractions and the pharmacological mechanism of analgesic activity are not clearly known. Hence, this study aimed to characterize the analgesic activity profile of successively extracted fractions of C. quadrangularis and the pharmacological mechanism of analgesic activity in mice. METHODS: Dried C. quadrangularis stem was extracted successively with chloroform and methanol. The dried extracts were separately administered to mice intraperitoneally at the doses of 75, 150 and 300 mg/kg. The mice were tested separately in hot plate and tail flick tests. The mechanism of analgesic activity of chloroform extract was explored in the hot plate test at the dose of 300 mg/kg after pretreatment with naloxone, p-chlorophenylalanine methyl ester (pCPA) and phentolamine. The data were analyzed by one-way analysis of variance followed by Dunnett's test. RESULTS: Chloroform extract showed significant (p<0.05) analgesic effect at the doses of 75, 150 and 300 mg/kg in hot plate and tail flick tests. Methanol extract showed significant (p<0.05) analgesic effect at the dose of 300 mg/kg in hot plate and tail flick tests. Analgesic activity was not blocked (p<0.05) in the group pretreated with phentolamine but blocked in the groups pretreated with naloxone and pCPA. CONCLUSIONS: The chloroform extract was found to be more potent than methanol extract in inducing analgesic effect in mice, and the analgesic activity may be mediated through opioidergic and serotonergic pathways.

Plurality of anxiety and depression alteration mechanism by oleanolic acid.

Our study sought to evaluate the anxiolytic and antidepressant activities of oleanolic acid as well as the neural mechanisms involved. Animal models such as barbiturate sleep-induction, light-dark box, elevated plus maze, forced swimming test, tail suspension test and open field test were conducted. Male Albino Swiss mice were treated orally with vehicle 10 mL/kg, fluoxetine 20 mg/kg, imipramine 15 mg/kg, diazepam 1 mg/kg or oleanolic acid 5-40 mg/kg. Pretreatment (intraperitoneal) of animals with pentylenetetrazole (PTZ) 20 mg/kg, 1-(2-methoxyphenyl)-4-[4- (2-phthalimido) butyl]piperazine hydrobromide (NAN-190) 0.5 mg/kg, p-chlorophenylalanine methyl ester (PCPA) 100 mg/kg or α-methyl-p-tyrosine (AMPT) 100 mg/kg, WAY100635 (WAY) 0.3 mg/kg, prazosin (PRAZ) 1 mg/kg, yohimbine 2 mg/kg as well as monoamine oxidase assay and hippocampal brain-derived neurotrophic factor (BDNF) quantification were carried out. Oleanolic acid potentiated the hypnotic effect of barbiturate and demonstrated an anxiolytic effect in both the light-dark box and elevated plus maze. This effect was not reversed by PTZ. Acute and/or chronic oral treatment of mice with oleanolic acid (5-20 mg/kg) elicited an antidepressant effect in the forced swimming test and the tail suspension test without interfering with the locomotor activity. The antidepressant effect of oleanolic acid was attenuated by NAN-190, AMPT, PCPA, WAY and PRAZ. Although monoamine oxidase activity remained unaltered by oleanolic acid, chronic administration of oleanolic acid augmented hippocampal BDNF level. These findings demonstrate multiple mechanisms of the anxiolytic and antidepressant effect of oleanolic acid.

Modulation of the subthalamic nucleus activity by serotonergic agents and fluoxetine administration.

RATIONALE: Within the basal ganglia, the subthalamic nucleus (STN) is the only glutamatergic structure and occupies a central position in the indirect pathway. In rat, the STN receives serotonergic input from the dorsal raphe nucleus and expresses serotonergic receptors. OBJECTIVE: This study examined the consequences of serotonergic neurotransmission modulation on STN neuron activity. METHODS: In vivo single-unit extracellular recordings, HPLC determination, and rotarod and bar test were performed in control, 4-chloro-DL-phenylalanine methyl ester hydrochloride- (pCPA, a serotonin synthesis inhibitor) and chronically fluoxetine-treated rats. RESULTS: The pCPA treatment and the administration of serotonin (5-HT) receptor antagonists increased number of bursting neurons in the STN. The systemic administration of the 5-HT(1A) agonist, 8-OH-DPAT, decreased the firing rate and increased the coefficient of variation of STN neurons in pCPA-treated rats but not in control animals. Additionally, microinjection of 8-OH-DPAT into the STN reduced the firing rate of STN neurons, while microinjection of the 5-HT(2C) agonist, Ro 60-0175, increased the firing rate in both control and fluoxetine-treated animals. Finally, the fluoxetine challenge increased the firing rate of STN neurons in fluoxetine-treated rats and induced catalepsy. CONCLUSIONS: Our results indicate that the depletion and the blockage of 5-HT modify STN neuron firing pattern. STN neuron activity is under the control of 5-HT(1A) and 5-HT(2C) receptors located both inside and outside the STN. Finally, fluoxetine increases STN neuron activity in chronically fluoxetine-treated rats, which may explain the role of this nucleus in fluoxetine-induced extrapyramidal side effects.

Involvement of monoaminergic system in the antidepressant-like effect of aqueous extract of Channa striatus in mice.

BACKGROUND: In our previous study, the aqueous extract of Channa striatus (family: Channidae) fillet (AECSF) showed an antidepressant-like effect in mice. However, the mechanism of the antidepressant-like effect is unknown. AIM: The objective of this study was to explore the involvement of monoamines in the antidepressant-like effect of AECSF in mice. MATERIALS AND METHODS: AECSF was prepared by steaming the fillets of C. striatus. The male ICR mice were pretreated with various monoaminergic antagonists viz., p-chlorophenylalanine (100 mg/kg, i.p.), prazosin (1 mg/kg, i.p.) and yohimbine (1 mg/kg, i.p.), SCH23390 (0.05 mg/kg, s.c.) and sulpiride (50 mg/kg, i.p.) followed by treatment with AECSF and tested in tail suspension test (TST). Two-way ANOVA with Tukey test were used at p < 0.05 for significance. RESULTS: The pretreatments with p-chlorophenylalanine, prazosin and yohimbine, but not with SCH23390 and sulpiride, were able to reverse the antidepressant-like effect of AECSF in TST. CONCLUSIONS: The antidepressant-like effect of AECSF may be mediated through the serotonergic and noradrenergic systems and not through the dopaminergic system.

Ankle joint mobilization affects postoperative pain through peripheral and central adenosine A1 receptors.

BACKGROUND: Physical therapists frequently use joint mobilization therapy techniques to treat people with musculoskeletal dysfunction and pain. Several studies suggest that endogenous adenosine may act in an analgesic fashion in various pain states. OBJECTIVE: The purpose of this study was to investigate the contribution of the adenosinergic system on the antihyperalgesic effect of ankle joint mobilization (AJM). DESIGN: This was a experimental study. METHODS: To test the hypothesis that the adrenosinergic system is involved in the antihyperalgesic effect of AJM, mice (25-35 g) submitted to plantar incision surgery were used as a model of acute postoperative pain. The mice were subjected to AJM for 9 minutes. Withdrawal frequency to mechanical stimuli was assessed 24 hours after plantar incision surgery and 30 minutes after AJM, adenosine, clonidine, or morphine treatments. The adenosinergic system was assessed by systemic (intraperitoneal), central (intrathecal), and peripheral (intraplantar) administration of caffeine. The participation of the A1 receptor was investigated using a selective adenosine A1 receptor subtype antagonist. In addition, previous data on the involvement of the serotonergic and noradrenergic systems in the antihyperalgesic effect of AJM were confirmed. RESULTS: Ankle joint mobilization decreased mechanical hyperalgesia, and this effect was reversed by pretreatment of the animals with caffeine given by intraperitoneal, intraplantar, and intrathecal routes. In addition, intraplanar and intrathecal administrations of 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, a selective adenosine A1 subtype receptor antagonist) or systemic administration of yohimbine or ρ-chlorophenylalanine methyl ester hydrochloride (PCPA) blocked the antihyperalgesia induced by AJM. LIMITATIONS: The results are limited to animal models and cannot be generalized to acute pain in humans. CONCLUSIONS: This study demonstrated the involvement of the adenosinergic system in the antihyperalgesic effect of AJM in a rodent model of pain and provides a possible mechanism basis for AJM-induced relief of acute pain.

AMPA glutamate receptors mediate the antidepressant-like effects of N-acetylcysteine in the mouse tail suspension test.

The aim of this study was to investigate the involvement of noradrenaline, serotonin, and subtypes of glutamate receptors in the antidepressant-like effects of N-acetylcysteine (NAC). The tail suspension test was used with male CF1 albino mice. D,L-α-methyl-ρ-tyrosine and ρ-chlorophenylalanine methyl ester hydrochloride were used as synthesis inhibitors of noradrenaline and serotonin, respectively. N-methyl-D-aspartate (NMDA) and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione were used as an NMDA receptor agonist and an α-amino acid-3-hydroxy-5-methyl-4-isoxazol propionic acid (AMPA) receptor antagonist, respectively. NAC (10, 25, and 50 mg/kg intraperitoneally) significantly (P<0.05) decreased tail suspension test immobility time, whereas pretreatment with D,L-α-methyl-ρ-tyrosine, ρ-chlorophenylalanine methyl ester hydrochloride, and NMDA partially prevented (P<0.05) the effects of NAC (25 mg/kg), and pretreatment with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione completely abolished (P<0.01) this effect. The study corroborates the antidepressant-like effects of NAC in the TST, a model with a well-established predictive value. The results point to the key role of AMPA receptors in the mechanism of the antidepressant-like action of NAC. Like other AMPA potentiators, NAC indirectly modulates noradrenaline and serotonin pathways. It is suggested that the value of NAC as an antidepressant arises from combined and intertwined effects on a variety of pathways.

A test to determine the nature and presence of the memory effect columns packed with the amylose tris(3,5-dimethylphenylcarbamate) stationary phase.

Acid/base mobile phase modifiers affect enantioseparations in ways that are not fully understood yet, for the lack of systematic studies. This makes chiral analysis of some pharmaceuticals difficult to reproduce. Once a column has been exposed to a modifier, the selectivity of certain pairs of enantiomers may change, for the better or the worse. We study the behavior of five enantiomeric pairs, three which are highly sensitive to the addition of certain modifiers and two that have little sensitivity to these modifiers. Their use permits the determination of the extent of the memory effect response on individual columns. The selectivity of 4-chlorophenylalanine methyl and ethyl ester, and of ketoprofen improve as a solution of ethanesulfonic acid is percolated through the column. As a result, these pairs are most useful for the determination of the extent of acid memory effect on a column. The selectivity of propranolol HCl and, to a lesser degree, Tröger's base increases as a solution of diisopropylethylamine is percolated through the column. The separation of each one of these five pairs is inversely affected by the percolation of the opposite acid/base solution. We used trans-stilbene oxide (TSO) as a 'standard' to determine the column stability because no memory effect is observed for it (its retention, enantioselectivity, and resolution remain constant). Understanding whether a column is under the influence of the memory effect is critical to both the analysis of pharmaceutical ingredients and to the development of preparative purification techniques for racemic mixtures. Thus, columns that were unreliable for method development and method transfer, due to the memory effect and a lack of proper solvent exposure records, can now be used.

Involvement of GABAergic non-benzodiazepine sites in the anxiolytic-like and sedative effects of the flavonoid baicalein in mice.

Baicalein (BA), one of the main flavonoids obtained from the Chinese medicinal herb Scutellaria baicalensis, usually exerts several pharmacological effects. In the central nervous system (CNS), BA exerts a protective effect on neurons against several neuronal insults among other effects, but it is not clear if this effect is due to its metabolite, baicalin. The purpose of the present study was to assess the anxiolytic-like and related properties of BA following its central administration (i.c.v.) in mice. BA (0.02, 0.2pmol) exerted an anxiolytic-like effect at low doses, increasing the time spent in open arms and the head-dipping whereas reducing the stretched-attend postures in the elevated plus-maze. BA also increased the duration of ether-induced sleep without affecting the pentylenetetrazol (PTZ)-induced convulsions. In addition, pretreatment with flumazenil (FMZ), PTZ, dehydroepiandrosterone sulfate (DHEAS), and dl-p-chlorophenilalanine ethyl ester (PCPA) were conducted in order to investigate its mechanism of action. PTZ and DHEAS, but not FMZ or PCPA, antagonized the BA's anxiolytic-like effect. Taken together our results showed that BA, when directly injected into the CNS, promotes anxiolytic-like and sedative effects, pharmacological activities dependent on GABAergic non-benzodiazepine sites but not on the 5-HT system.

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.

High-intensity extended swimming exercise reduces pain-related behavior in mice: involvement of endogenous opioids and the serotonergic system.

UNLABELLED: The present study examined the hyponociceptive effect of swimming exercise in a chemical behavioral model of nociception and the mechanisms involved in this effect. Male mice were submitted to swimming sessions (30 min/d for 5 days). Twenty-four hours after the last session, we noticed that swimming exercise decreased the number of abdominal constriction responses caused by acetic acid compared with the nonexercised group. The hyponociception caused by exercise in the acetic acid test was significantly attenuated by intraperitoneal (i.p.) pretreatment of mice with naloxone (a nonselective opioid receptor antagonist, 1 mg/kg), ρ-chlorophenylalanine methyl ester (PCPA, an inhibitor of serotonin synthesis, 100 mg/kg once a day for 4 consecutive days), and by bilateral adrenalectomy. Collectively, the present results provide experimental evidences indicating for the first time that high-intensity extended swimming exercise reduces pain-related behavior in mice. The mechanisms involve an interaction with opioid and serotonin systems. Furthermore, endogenous opioids released by adrenal glands probably are involved in this effect. PERSPECTIVE: Our results indicate that high-intensity extended exercise endogenously controls acute pain by activation of opioidergic and serotonergic pathways. Furthermore, these results support the use of exercise as a nonpharmacological approach for the management of acute pain.

Desipramine potentiation of the acute depressant effects of ethanol: modulation by alpha2-adrenoreceptors and stress.

Ethanol exerts effects on the brain noradrenergic system, and these are thought to contribute to the sedative/hypnotic (depressant) effects of ethanol. Recent studies suggest that the norepinephrine transporter (NET) plays an important role in modulating ethanol's depressant effects. The aim of the present study was to further characterize this role. Transporter blockers with varying affinity for NET versus the serotonin transporter (desipramine>fluoxetine>citalopram) were tested for their ability to alter ethanol's depressant effects, and for comparison, hypothermic effects. Effects of desipramine on another depressant, pentobarbital, were examined. Desipramine potentiation of ethanol's depressant effects was assessed following depletion of brain norepinephrine via N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) treatment, or depletion of brain 5-HT via para-chlorophenylalanine methyl ester hydrochloride (PCPA) treatment. The effects of co-administration of either the selective alpha2-adrenoreceptor agonist (dexmedetomidine) or the selective alpha2-adrenoreceptor antagonist (atipamezole) on desipramine's effect on ethanol's depressant effects were examined. Given the close link between stress, ethanol and norepinephrine, desipramine potentiation of ethanol's depressant effects was tested following repeated forced swim stress. Results showed that desipramine, but not SERT-selective doses of citalopram or fluoxetine, strongly potentiated the depressant (not hypothermic) effects of ethanol. These effects were mimicked by dexmedetomidine and blocked by atipamezole, but not by depletion of either norepinephrine or 5-HT. Desipramine potentiation of ethanol's depressant effects was abolished following repeated stress. Present findings further support a major role for NET and the alpha2-adrenoreceptor in modulating the depressant effects of ethanol, with possible implications for understanding the role of noradrenergic dysfunction in stress-related alcoholism.

Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior.

Hypersecretion of central corticotropin-releasing hormone (CRH) has been implicated in the pathophysiology of affective disorders. Both, basic and clinical studies suggested that disrupting CRH signaling through CRH type 1 receptors (CRH-R1) can ameliorate stress-related clinical conditions. To study the effects of CRH-R1 blockade upon CRH-elicited behavioral and neurochemical changes we created different mouse lines overexpressing CRH in distinct spatially restricted patterns. CRH overexpression in the entire central nervous system, but not when overexpressed in specific forebrain regions, resulted in stress-induced hypersecretion of stress hormones and increased active stress-coping behavior reflected by reduced immobility in the forced swim test and tail suspension test. These changes were related to acute effects of overexpressed CRH as they were normalized by CRH-R1 antagonist treatment and recapitulated the effect of stress-induced activation of the endogenous CRH system. Moreover, we identified enhanced noradrenergic activity as potential molecular mechanism underlying increased active stress-coping behavior observed in these animals. Thus, these transgenic mouse lines may serve as animal models for stress-elicited pathologies and treatments that target the central CRH system.

Antidepressant-like effect of agmatine is not mediated by serotonin.

The aim of this study was to characterize the behavioral effects of systemically administered agmatine in animal models predictive of antidepressant- and anxiolytic-like activity and clarify whether the effects of agmatine depend on the intact serotonergic system. Only the highest dose of agmatine tested (50 mg/kg) decreased immobility of mice in the forced swimming test. The magnitude of the effect was slightly smaller than that of the tricyclic antidepressant imipramine (15 mg/kg). Agmatine did not change the locomotion of mice in the open field. Pretreatment with the tryptophane hydroxylase inhibitor PCPA for 3 days resulted in more than 70% drop in the tissue levels of 5-HT and 5-HIIA but did not counteract the antidepressant-like effect of agmatine. The administration of agmatine did not modify behavior of animals in the light-dark compartment test of anxiety. We conclude that the antidepressant-like effect of agmatine seems not to be mediated by the serotonergic system. We failed to confirm the reported anxiolytic-like activity of agmatine.

cAMP response element-binding protein deficiency allows for increased neurogenesis and a rapid onset of antidepressant response.

cAMP response element-binding protein (CREB) has been implicated in the molecular and cellular mechanisms of chronic antidepressant (AD) treatment, although its role in the behavioral response is unclear. CREB-deficient (CREB(alpha delta) mutant) mice demonstrate an antidepressant phenotype in the tail suspension test (TST) and forced-swim test. Here, we show that, at baseline, CREB(alpha delta) mutant mice exhibited increased hippocampal cell proliferation and neurogenesis compared with wild-type (WT) controls, effects similar to those observed in WT mice after chronic desipramine (DMI) administration. Neurogenesis was not further augmented by chronic DMI treatment in CREB(alpha delta) mutant mice. Serotonin depletion decreased neurogenesis in CREB(alpha delta) mutant mice to WT levels, which correlated with a reversal of the antidepressant phenotype in the TST. This effect was specific for the reversal of the antidepressant phenotype in these mice, because serotonin depletion did not alter a baseline anxiety-like behavior in CREB(alpha delta) mutant mice. The response to chronic AD treatment in the novelty-induced hypophagia (NIH) test may rely on neurogenesis. Therefore, we used this paradigm to evaluate chronic AD treatment in CREB(alpha delta) mutant mice to determine whether the increased neurogenesis in these mice alters their response in the NIH paradigm. Whereas both WT and CREB(alpha delta) mutant mice responded to chronic AD treatment in the NIH paradigm, only CREB(alpha delta) mutant mice responded to acute AD treatment. However, in the elevated zero maze, DMI did not reverse anxiety behavior in mutant mice. Together, these data show that increased hippocampal neurogenesis allows for an antidepressant phenotype as well as a rapid onset of behavioral responses to AD treatment.