Serotonergic modulation of extrapyramidal motor disorders in mice and rats: Role of striatal 5-HT3 and 5-HT6 receptors

Previous studies showed that 5-HT_1A and 5-HT₂ receptors play an important role in controlling the extrapyramidal motor disorders. However, the functions of other 5-HT receptor subtypes remain elusive. To elucidate the role of 5-HT receptors, specifically of 5-HT₃～5-HT₇ subtypes, in modifying antipsychotic- induced extrapyramidal side effects (EPS), we studied the effects of the 5-HT stimulant 5-hydroxytryptophan (5-HTP) and various 5-HT receptor antagonists on haloperidol (HAL)-induced bradykinesia and catalepsy in mice and rats. Pretreatment of mice with 5-HTP (25–100 mg/kg, i.p.) dose-dependently enhanced HAL (0.3 mg/kg, i.p.)-induced bradykinesia and catalepsy. The potentiation of HAL-induced EPS by 5-HTP (50 mg/kg, i.p.) was significantly inhibited by ritanserin (5-HT₂ antagonist, 0.3-3 mg/kg, i.p.), ondansetron (5-HT₃ antagonist, 0.1–1 mg/kg, i.p.), or SB-258585 (5-HT₆ antagonist, 1–10 mg/kg, i.p.) in a dose-dependent manner. However, neither WAY-100135 (5-HT_1A antagonist, 1–10 mg/kg, i.p.), GR-125487 (5-HT₄ antagonist, 1–10 mg/kg, i.p.), SB-699551 (5-HT_5A antagonist, 1–10 mg/kg, i.p.) nor SB-269970 (5-HT₇ antagonist, 1–10 mg/kg, i.p.) reduced the 5-HTP and HAL-induced bradykinesia or catalepsy. In addition, both ondansetron (0.1–1 mg/kg, i.p.) and SB-258585 (3 and 10 mg/kg, i.p.) also alleviated bradykinesia and catalepsy induced by HAL (0.5 mg/kg, i.p.) alone in mice. Furthermore, bilateral microinjection of ondansetron (5 μg (13.7 nmol) per side) or SB-258585 (5 μg (8.92 nmol) per side) into the dorsolateral striatum (dlST) attenuated haloperidol-induced catalepsy in rats. These results suggest that serotonergic stimulation augments extrapyramidal motor disorders by activating the striatal 5-HT₃ and 5-HT₆ receptors and the antagonism of these receptors effectively alleviates antipsychotic-induced EPS.     

Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: A potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism

We previously reported that the investigational multimodal antidepressant, vortioxetine, reversed 5-HT depletion-induced memory deficits while escitalopram and duloxetine did not. The present report studied the effects of vortioxetine and the potential impact of its 5-HT_1A receptor agonist and 5-HT₃ receptor antagonist properties on 5-HT depletion-induced memory deficits. Recognition and spatial working memory were assessed in the object recognition (OR) and Y-maze spontaneous alternation (SA) tests, respectively. 5-HT depletion was induced in female Long-Evans rats using 4-cholro-DL-phenylalanine methyl ester HCl (PCPA) and receptor occupancies were determined by ex vivo autoradiography. Rats were acutely dosed with vortioxetine, ondansetron (5-HT₃ receptor antagonist) or flesinoxan (5-HT_1A receptor agonist). The effects of chronic vortioxetine administration on 5-HT depletion-induced memory deficits were also assessed. 5-HT depletion reliably impaired memory performance in both the tests. Vortioxetine reversed PCPA-induced memory deficits dose-dependently with a minimal effective dose (MED) ≤0.1 mg/kg (∼80% 5-HT₃ receptor occupancy; OR) and ≤3.0 mg/kg (5-HT_1A, 5-HT_1B, 5-HT₃ receptor occupancy: ∼15%, 60%, 95%) in SA. Ondansetron exhibited a MED ≤3.0 μg/kg (∼25% 5-HT₃ receptor occupancy; OR), but was inactive in the SA test. Flesinoxan had a MED ≤1.0 mg/kg (∼25% 5-HT_1A receptor occupancy; SA); only 1.0 mg/kg ameliorated deficits in the NOR. Chronic p.o. vortioxetine administration significantly improved memory performance in OR and occupied 95%, 66%, and 9.5% of 5-HT₃, 5-HT_1B, and 5-HT_1A receptors, respectively. Vortioxetine′s effects on SA performance may involve 5-HT_1A receptor agonism, but not 5-HT₃ receptor antagonism, whereas the effects on OR performance may involve 5-HT₃ receptor antagonism and 5-HT_1A receptor agonism.     

Differential influence of selective 5-HT5A vs 5-HT1A, 5-HT1B,or 5-HT2C receptor blockade upon light-induced phase shifts in circadian activity rhythms: Interaction studies with citalopram

Though serotonergic mechanisms modulate circadian rhythms, roles of individual serotonin (5-HT) receptors remain uncertain since data are lacking for antagonists. Herein, both the 5-HT_5A receptor antagonist, A843277 (10 mg/kg), and the 5-HT_1B antagonist, SB224289 (1 mg/kg), inhibited light-induced phase advances in hamster circadian wheel-running rhythms. Conversely, though 5-HT_1A and 5-HT₇ receptors are likewise implicated in circadian scheduling, their blockade by WAY100635 (0.5 mg/kg) and SB269970 (1 mg/kg), respectively, was ineffective. Since actions of 5-HT reuptake inhibitors are modified by antagonists, we evaluated their influence on suppression of phase advances by citalopram (10 mg/kg). Its action was potentiated by WAY100635 and the 5-HT_2C antagonist, SB242084 (1 mg/kg), but not by A842377, SB224289, SB269970, and antagonists at 5-HT_2A (MDL100907) and 5-HT₆ (SB399885) receptors. In conclusion, this is the first in vivo evidence for an influence of 5-HT_5A receptors upon circadian rhythms, but no single class of 5-HT receptor mediates their control by citalopram.     

5-HT1D receptor inhibits renal sympathetic neurotransmission by nitric oxide pathway in anesthetized rats

Although serotonin has been shown to inhibit peripheral sympathetic outflow, serotonin regulation on renal sympathetic outflow has not yet been elucidated. This study investigated which 5-HT receptor subtypes are involved. Wistar rats were anesthetized (sodium pentobarbital; 60 mg/kg, i.p.), and prepared for in situ autoperfused rat kidney, which allows continuous measurement of systemic blood pressure (SBP), heart rate (HR) and renal perfusion pressure (PP). Electrical stimulation of renal sympathetic nerves resulted in frequency-dependent increases in PP (18.3 ± 1.0, 43.7 ± 2.7 and 66.7 ± 4.0 for 2, 4 and 6 Hz, respectively), without altering SBP or HR. 5-HT, 5-carboxamidotryptamine (5-HT_1/7 agonist) (0.00000125–0.1 μg/kg each) or l-694,247 (5-HT_1D agonist; 0.0125 μg/kg) i.a. bolus inhibited vasopressor responses by renal nerve electrical stimulation, unlike i.a. bolus of agonists α-methyl-5-HT (5-HT₂), 1-PBG (5-HT₃), cisapride (5-HT₄), AS-19 (5-HT₇), CGS-12066B (5-HT_1B) or 8-OH-DPAT (5-HT_1A) (0.0125 μg/kg each). The effect of l-694,247 did not affect the exogenous norepinephrine-induced vasoconstrictions, whereas was abolished by antagonist LY310762 (5-HT_1D; 1 mg/kg) or l-NAME (nitric oxide; 10 mg/kg), but not by indomethacin (COX_1/2; 2 mg/kg) or glibenclamide (ATP-dependent K⁺ channel; 20 mg/kg). These results suggest that 5-HT mechanism-induced inhibition of rat vasopressor renal sympathetic outflow is mainly mediated by prejunctional 5-HT_1D receptors via nitric oxide release.     

An in vivo pharmacological evaluation of pardoprunox (SLV308) — A novel combined dopamine D2/D3 receptor partial agonist and 5-HT1A receptor agonist with efficacy in experimental models of Parkinson's disease

Partial D_2/3 dopamine (DA) receptor agonists provide a novel approach to the treatment of the motor symptoms of Parkinson's disease (PD) that may avoid common dopaminergic side-effects, including dyskinesia and psychosis. The present study focussed on the in vivo pharmacological and therapeutic characterisation of the novel D_2/3 receptor partial agonist and full 5-HT_1A receptor agonist pardoprunox (SLV308; 7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone monochloride). Pardoprunox induced contralateral turning behaviour in rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra pars compacta (SNpc) (MED = 0.03 mg/kg; po). In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, pardoprunox dose-dependently increased locomotor activity (MED = 0.03 mg/kg; po) and decreased motor disability (MED = 0.03 mg/kg; po). The effects of pardoprunox were reversed by the D₂ antagonist sulpiride. In contrast pardoprunox attenuated novelty-induced locomotor activity (MED = 0.01 mg/kg; po), (+)-amphetamine-induced hyperlocomotion (MED = 0.3 mg/kg; po) and apomorphine-induced climbing (MED = 0.6 mg/kg; po) in rodents. Pardoprunox also induced 5-HT_1A receptor-mediated behaviours, including flat body posture and lower lip retraction (MED = 0.3 mg/kg; po) and these were reversed by the 5-HT_1A receptor antagonist WAY100635. Collectively, these findings demonstrate that pardoprunox possesses dopamine D2/3 partial agonist effects, 5-HT1A agonist effects and reduces parkinsonism in animal models. functional DA D₂ receptor partial agonist activity and is effective in experimental models predictive of efficacy in PD. The presence of functional 5-HT_1A agonist activity might confer anti-dyskinetic activity and have effects that control neuropsychiatric components of PD.     

Effect of co-treatment with fluoxetine or mirtazapine and risperidone on the active behaviors and plasma corticosterone concentration in rats subjected to the forced swim test

BackgroundSeveral clinical reports have postulated a beneficial effect of the addition of a low dose of risperidone to the ongoing treatment with antidepressants in treatment-resistant depression.MethodsThe present study aimed to examine the effect of treatment with fluoxetine or mirtazapine, given separately or jointly with risperidone, on active behavior and plasma corticosterone level in male Wistar rats subjected to the forced swim test (FST).ResultsThe obtained results showed that fluoxetine (5 mg/kg), mirtazapine (5 and 10 mg/kg) or risperidone (0.05 and 0.1 mg/kg) did not change the active behavior of rats in the FST. However, co-treatment with fluoxetine (10 mg/kg) and risperidone (0.1 mg/kg) induced an antidepressant-like effect in that test because it significantly increased the swimming time and decreased the immobility time, while combined treatment with mirtazapine at 5 and 10 mg/kg and risperidone at 0.05 and 0.1 mg/kg evoked a significant increase in the swimming time and also climbing, and decreased the immobility time. WAY 100635 (a 5-HT_1a receptor antagonist) at a dose of 0.1 mg/kg inhibited the antidepressant-like effect induced by co-administration of fluoxetine or mirtazapine and risperidone. Active behavior in that test did not reflect an increase in general activity, since combined treatment with fluoxetine or mirtazapine and risperidone failed to enhance the exploratory activity of rats. Co-treatment with fluoxetine or mirtazapine and risperidone did not reduce the stress-induced increase in plasma corticosterone concentration in animals subjected to the FST.ConclusionThe obtained results indicate that risperidone applied in a low dose enhances the antidepressant-like activity of fluoxetine and mirtazapine in the FST (but does not normalize the stress-induced increase in corticosterone level in these rats), and that 5-HT_1a receptors may play some role in these effects.     

KMUP-1 inhibits pulmonary artery proliferation by targeting serotonin receptors/transporter and NO synthase,inactivating RhoA and suppressing AKT/ERK phosphorylation

KMUP-1 inhibits monocrotaline (MCT)-induced pulmonary artery (PA) proliferation by targeting serotonin (5-HT) receptors, inactivating RhoA and reducing phosphorylation of AKT/ERK. In MCT-treated rats, KMUP-1 f (5 mg/kg p.o.; 1 mg/kg i.p. × 21 days) decreased proliferation (PCNA-positive) cells and 5-HTT-expression in lung and 5-HT levels in plasma. In isolated PA, KMUP-1 and simvastatin (0.1–100 μM) inhibited 5-HT (10 μM)-induced PA constriction. l-NAME-pretreatment reduced KMUP-1-induced relaxation. In pulmonary arterial smooth muscle cells (PASMCs), KMUP-1 (1–100 μM) and simvastatin (10 μM) inhibited 5-HT-induced cell migration and proliferation and KMUP-1 (1–100 μM) inhibited 5-HT-induced Ca²⁺ influx. Similar to Y27632, KMUP-1 (1–100 μM) inhibited 5-HT-induced RhoA/ROCK expression, while KMUP-1, Y27632 and simvastatin at 10 μM inhibited 5-HT-induced 5-HTT expression and KMUP-1 inhibited 5-HT-induced phosphorylation of AKT and ERK1/2 in PASMCs. In human pulmonary arterial endothelial cell (HPAEC), KMUP-1 (1–100 μM) increased the expression of eNOS and 5-HT_2B and also at 10 μM augmented eNOS expression and production of nitric oxide (NO) in 5-HT-treated HPAEC. In radioligand binding, the IC₅₀/K_i values of KMUP-1 for 5-HT_2A, 5-HT_2B and 5-HT_2C receptors were 0.34/0.0971, 0.04/0.0254, and 0.408/0.214 μM respectively. In conclusion, KMUP-1 inhibits MCT-induced PA proliferation by binding to 5-HT_2A, 5-HT_2B and 5-HT_2C receptors, increasing endothelial eNOS/5-HT_2B receptor expression and NO release and inhibiting 5-HTT/RhoA/ROCK expression and AKT/ERK phosphorylation. KMUP-1 is suggested to be useful in the treatment of 5-HT-induced pulmonary artery proliferation.     

Buspirone improves 6-hydroxydopamine-induced catalepsy through stimulation of nigral 5-HT1A receptors in rats

Receptors for 5-HT_1A are widely distributed throughout the basal ganglia, and their activation results in an inhibition of dopamine (DA) release. This study aimed to investigate the effect of buspirone, as a partial agonist of 5-HT_1A receptors, on 6-hydroxydopamine (6-OHDA)-induced catalepsy in male Wistar rats. Catalepsy was induced by unilateral infusion of 6-OH-DA (6 μg/2 μl/rat) into the central region of the substantia nigra pars compacta (SNc) and assayed by the bar-test method 60,120 and 180 min after drug administration. The results demonstrated that intraperitoneal (ip) injection of buspirone at doses of 5,7.5 and 10 mg/kg decreased catalepsy compared with the control group. In addition, intra-SNc injection of 8-hydroxy-2-[di-n-propylamino]tetralin (8-OH-DPAT; 10 μg/rat), a 5-HT_1A receptor agonist, decreased 6-OHDA-induced catalepsy. The effects of buspirone (7.5 mg/kg, ip) and 8-OH-DPAT (10 μg/rat, intra-SNc) were abolished by 1-(2-methoxyphenyl)-4-[4-(2-phthalimido) butyl]piperazine hydro-bromide (NAN-190; 10 μg/rat, intra-SNc), a 5-HT_1A receptor antagonist. Our study indicates that buspirone improves catalepsy in a 6-OHDA-induced animal model of Parkinson's disease through activation of nigral 5-HT_1A preceptors. However, further investigations should be undertaken to clarify the exact mechanism of interaction between 5-HT_1A and DA receptors.     

Effects of repeated risperidone exposure on serotonin receptor subtypes in developing rats

Risperidone is an atypical antipsychotic drug that is widely prescribed to young patients with different psychotic disorders. The long-term effects of this antipsychotic agent on neuronal receptors in developing brain remain unclear and require further investigation. In this study, we examined the effects of long-term treatment of risperidone on two serotonin receptor subtypes in brain regions of juvenile rat. Levels of 5-HT_1A and 5-HT_2A receptors in forebrain regions of juvenile rats were quantified after 3 weeks of treatment with three different doses of risperidone (0.3, 1.0 and 3.0 mg/kg). Findings were compared to previously reported changes in 5-HT receptors after risperidone treatment (3.0 mg/kg) in adult rat brain. The three doses of risperidone selectively and dose-dependently increased levels of 5-HT_1A receptors in medial–prefrontal and dorsolateral–frontal cortices of juvenile animals. The higher doses (1.0 and 3.0 mg/kg) of risperidone also increased 5-HT_1A receptor binding in hippocampal CA₁ region of juvenile but not adult rats. In contrast, the three doses of risperidone significantly reduced 5-HT_2A labeling in medial–prefrontal and dorsolateral–frontal cortices in juvenile as well as in adult animals in an equipotent fashion. 5-HT_1A and 5-HT_2A receptors in other forebrain regions were not altered by repeated risperidone treatment. These findings indicate that there are differential effects of risperidone on 5-HT_1A and 5-HT_2A receptors in juvenile animals, and that the 5-HT system in developing animals is more sensitive than adults to the long-term effects of risperidone.     

Inhibitory actions of mGlu4 receptor ligands on cocaine-, but not nicotine-, induced sensitizing and conditioning locomotor responses in rats

BackgroundMale Wistar rats were used to verify the hypothesis that metabotropic glutamate 4 (mGlu₄) receptor ligands may modulate the locomotor effects evoked by cocaine or nicotine.MethodsThe preferential mGlu₄ receptor orthosteric agonist (2S)-2-amino-4-[hydroxy[hydroxy(4-hydroxy-3-methoxy-5-nitrophenyl)methyl]phosphoryl]butanoic acid (LSP1-2111) and the mGlu₄ receptor positive allosteric modulator (+)-cis-N¹-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide (Lu AF21934) were used in the study. Rats were given repeated pairings of a test environment with cocaine (10 mg/kg), nicotine (0.4 mg/kg) or the respective vehicles for 5 days. On day 10, animals were challenged with cocaine (10 mg/kg, cocaine sensitization), nicotine (0.4 mg/kg, nicotine sensitization) or vehicle (conditioned hyperlocomotion) in experimental cages.ResultsGiven on day 10, LSP1-2111 (3 mg/kg) as well as Lu AF21934 (2.5–5 mg/kg) decreased the expression of cocaine sensitization. In another set of experiments, LSP1-2111 (3 mg/kg) and Lu AF21934 (5 mg/kg) administered on day 10 attenuated the conditioned hyperlocomotion in rats treated repeatedly with cocaine. Neither LSP1-2111 (1–3 mg/kg) nor Lu AF21934 (2.5–5 mg/kg) changed the expression of nicotine sensitization and conditioned hyperlocomotion in rats treated repeatedly with nicotine. None of the mGlu₄ receptor agonist/modulator altered the basal locomotor activity or acute hyperactivity to cocaine or nicotine.ConclusionsThe present data indicate that pharmacological stimulation of mGlu₄ receptors reduces the cocaine-induced expression of sensitization as well as conditioned hyperactivity. In contrast, mGlu₄ receptor activation seems to be devoid of any effect on the locomotor effects of nicotine.     

Effect of acute and chronic treatment with QCF-3 (4-benzylpiperazin-1-yl) (quinoxalin-2-yl) methanone,a novel 5-HT3 receptor antagonist,in animal models of depression

The serotonin type 3 (5-HT₃) receptor is unique among the seven recognized serotonin receptor “families”. The existence serotonin type 3 receptor (5-HT₃) in neuro-anatomical regions stimulated the research interest for novel therapeutic targets such as anxiety, depression, nociception and cognitive function. In the current study, (4-benzylpiperazin-1-yl) (quinoxalin-2-yl) methanone (QCF-3), a novel 5-HT₃ receptor antagonist, with an optimal log P (the logarithm of the ratio of the concentrations of the un-ionized solute in the solvents is called log P) and significant pA2 value (is a negative logarithm of the molar concentration of antagonist required to reduce the effect of multiple dose agonist to that of single dose) was screened for its anti-depressant potential using rodent behavioral models of depression. Psycho-pharmacological investigations involved acute and chronic treatment (14 days) with QCF-3 and assessment of behavior during the forced swim test (FST) and tail suspension test (TST) in mice and olfactory bulbectomised rats. A dose response study in mice revealed an initial anti-depressant-like effect of QCF-3 (0.5–4 mg/kg, ip) in the FST and TST. Interaction studies showed that QCF-3 (1 and 2 mg/kg) significantly enhanced the antidepressant action of fluoxetine and bupropion in the FST and TST, respectively. QCF-3 (1 and 2 mg/kg) potentiated the 5-hydroxytryptophan (5-HTP) induced head twitches response in mice and reversed reserpine-induced hypothermia in rats. Further, OBX rats exhibited behavioral anomalies in the open field and hyper-emotionality tests that were attenuated by chronic QCF-3 treatment. In conclusion, this behavioral study describes an antidepressant-like effect of QCF-3 in rodent behavioral models of depression.     

Potentiation of the antidepressant-like effect of desipramine or reboxetine by metyrapone in the forced swimming test in rats

The obtained results revealed that joint administration of desipramine or reboxetine and metyrapone (a glucocorticoid synthesis inhibitor) had more potent antidepressant-like activity in the forced swimming test (FST) in rats compared to treatment with either drug alone. WAY 100636 (a 5-HT_1A antagonist), and prazosin (an α₁-adrenergic antagonist), used in doses ineffective in the FST, inhibited the antidepressant-like effect induced by co-administration of desipramine (10 mg/kg) or reboxetine (10 mg/kg) and metyrapone (50 mg/kg). The above-mentioned findings suggest that, among other mechanisms, the 5-HT_1A and α₁-adrenergic receptors may play a role in this effect. Furthermore, they may be of particular importance to the pharmacotherapy of drug-resistant depression.     

Effects of co-administration of the GABAB receptor agonist baclofen and a positive allosteric modulator of the GABAB receptor,CGP7930, on the development and expression of amphetamineinduced locomotor sensitization in rats

BackgroundSeveral of the behavioral effects of amphetamine (AMPH) are mediated by an increase in dopamine neurotransmission in the nucleus accumbens. However, evidence shows that γ-aminobutyric acid B (GABA_B) receptors are involved in the behavioral effects of psychostimulants, including AMPH. Here, we examined the effects of co-administration of the GABA_B receptor agonist baclofen and a positive allosteric modulator of theGABA_B receptor, CGP7930, on AMPH-induced locomotor sensitization.MethodsIn a series of experiments, we examined whether baclofen (2.0, 3.0 and 4.0 mg/kg), CGP7930 (5.0, 10.0 and 20.0 mg/kg), or co-administration of CGP7930 (5.0, 10.0 and 20.0 mg/kg) with a lower dose of baclofen (2.0 mg/kg) could prevent the development and expression of locomotor sensitization produced by AMPH (1.0 mg/kg).ResultsThe results showed that baclofen treatment prevented both the development and expression of AMPH-induced locomotor sensitization in a dose-dependent manner. Furthermore, the positive allosteric modulator of the GABA_B receptor, CGP7930, increased the effects of a lower dose of baclofen on AMPH-induced locomotor sensitization under both conditions.ConclusionThese data provide further evidence thatGABA_B receptor ligands may modulate psychostimulant-induced behaviors.     

5-HT2 receptor blockade exhibits 5-HT vasodilator effects via nitric oxide,prostacyclin and ATP-sensitive potassium channels in rat renal vasculature

The aim of this study was to determine whether orally sarpogrelate (selective 5-HT₂ antagonist) treatment (30 mg/kg/day; 14 days) could modify 5-HT renal vasoconstrictor responses, characterizing 5-HT receptors and mediator mechanisms involved in serotonergic responses in the in situ autoperfused rat kidney. Intra-arterial (i.a.) injections of 5-HT (0.00000125 to 0.1 μg/kg) decreased renal perfusion pressure (RPP) but did not affect the mean blood pressure (MBP). i.a. agonists 5-CT (5-HT_1/7), CGS-12066B (5-HT_1B), L-694,247 (5-HT_1D) or AS-19 (5-HT₇) mimicked renal 5-HT vasodilator effect. However, neither 8-OH-DPAT (5-HT_1A) nor 1-phenylbiguanide (5-HT₃) modified RPP. Moreover: (i) GR-55562 (5-HT_1B antagonist) and L-NAME (nitric oxide synthase [NOS] inhibitor) blocked CGS-12066B-induced vasodilator response, (ii) LY310762 (5-HT_1D antagonist) and indomethacin (non-selective cyclooxygenase inhibitor) blocked L-694,247-induced vasodilator response; (iii) SB-258719 (5-HT₇ antagonist) and glibenclamide (ATP-sensitive K⁺ channel blocker) blocked AS-19-induced vasodilator response; and (iv) 5-HT- or 5-CT-elicited renal vasodilation was significantly blocked by the mixture of GR-55562 + LY310762 + SB-258719. Furthermore, eNOS and iNOS proteins and prostacyclin levels are overexpressed in sarpogrelate-treated rats. Our data suggest that 5-HT exerts renal vasodilator effect in the in situ autoperfused sarpogrelate-treated rat kidney, mediated by 5-HT_1D, 5-HT_1B and 5-HT₇ receptors, involving cyclooxygenase-derived prostacyclin, nitric oxide synthesis/release and ATP-sensitive K⁺ channels, respectively.     

Gestational manganese intoxication and anxiolytic-like effects of diazepam and the 5-HT1A receptor agonist 8-OH-DPAT in male Wistar rats

In the present study, the effects of prenatal manganese (Mn) intoxication on the anxiolytic-like effects of diazepam and the 5-HT_1A receptor agonist R-(+)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) were examined. Wistar dams were exposed to MnCl₂?4H₂O at 5, 000 ppm in the drinking water for the duration of pregnancy. On the day of parturition, Mn was discontinued as an additive in the drinking water. Control rats were derived from dams that consumed tap water and had no exposure to Mn. Male offspring were tested at the age of 12 weeks. The anxiolytic-like effect was assessed in an elevated plus maze device and with the Vogel conflict test. The benzodiazepine anxiolytic diazepam (5 mg/kg, ip) increased the percentage of time spent in open arms in control rats (in comparison to saline treatment) (p < 0.05); no such effect was seen in Mn-exposed rats. Conversely, the serotoninergic 5-HT_1A agonist 8-OH-DPAT (0.3 mg/kg, ip) increased the percentage of time spent in open arms in both experimental groups. In the Vogel drinking test, an anxiolytic-like effect was also observed in both test groups (in controls this was of borderline significance). In contrast, 8-OH-DPAT did not evoke an anxiolytic-like action in control or in Mn-exposed rats in the anticonflict test. In conclusion, findings indicate that gestational Mn exposure attenuated benzodiazepine-mediated anxiolytic-like effects but not those of the 5-HT_1A receptor agonist 8-OH-DPAT.     

Effect of co-treatment with mirtazapine and risperidone in animal models of the positive symptoms of schizophrenia in mice

BackgroundSeveral clinical reports have suggested that the mirtazapine-induced augmentation of risperidone activity may effectively improve the positive, negative and some cognitive symptoms of schizophrenia.MethodsThe present study was aimed at examining the effect of mirtazapine and risperidone, given separately or jointly in mice, on the locomotor hyperactivity induced by D-amphetamine or MK-801 as well as a 5-HT_2A receptor agonist DOI-induced head twitches as models for positive symptoms of psychosis.ResultsThe obtained results showed that co-treatment with mirtazapine (2.5 or 5 mg/kg) and risperidone (0.01 mg/kg) inhibited the locomotor hyperactivity induced by D-amphetamine or MK-801. Moreover, co-administration of mirtazapine (1.25 or 2.5 mg/kg) and risperidone (0.01 mg/kg) reduced the number of head twitches induced by DOI, whereas those drugs given separately changed neither the locomotor hyperactivity induced by D-amphetamine or MK-801 nor the syndrome induced by DOI.ConclusionThe obtained results indicated that lower doses of mirtazapine enhanced the antipsychotic-like effect of risperidone in animal tests of positive symptoms of schizophrenia. Further studies are necessary to elucidate its mechanism of action.     

The effect of risperidone on the mirtazapine-induced changes in extracellular monoamines in the rat frontal cortex

BackgroundThe aim of our study was to understand the mechanism of clinical efficacy of the combination of an antidepressant and risperidone in drug-resistant depression.MethodsWe studied the effect of an antidepressant (mirtazapine) and risperidone (atypical antipsychotic), given separately or jointly on extracellular levels of dopamine (DA), serotonin (5-HT) and noradrenaline (NA) in the rat frontal cortex. The animals were given a single intraperitoneal injection of risperidone (1 mg/kg) and mirtazapine (10 and 20 mg/kg). The release of monoamines in the rat frontal cortex was investigated using a microdialysis in freely moving animals, and monoamine levels were assayed by HPLC with coulochemical detection.ResultsRisperidone increased the cortical extracellular levels of DA, 5-HT and NA. Similarly, mirtazapine dose-dependently increased the cortical extracellular levels of the monoamines studied. A combination of mirtazapine either at the higher dose (20 mg/kg) or at both doses (10 and 20 mg/kg) with risperidone produced a significant effect on DA and NA release, respectively compared to the effect of any drug given alone. The increase in the DA (but not NA) release induced by mirtazapine plus risperidone was partly blocked by the selective 5-HT_1A antagonist WAY 100635 (0.2 mg/kg).ConclusionsOur data indicate that the increase of cortical extracellular levels of DA and NA by combined administration of mirtazapine and risperidone may be of crucial importance to the pharmacotherapy of drug resistant depression, and that, among other mechanisms, 5-HT_1A, 5-HT_2A, α₂-adrenergic and histamine H₁ receptors may play some role in this effect.     

Effect of repeated co-treatment with fluoxetine and amantadine on the behavioral reactivity of the central dopamine and serotonin system in rats

In the present study we found that repeated co-treatment with fluoxetine and amantadine for 14 days (but not for 7 days) enhanced the hyperactivity induced by amphetamine or quinpirole (a dopamine D_2/3 agonist), compared to treatment with either drug alone. Whereas repeated co-treatment with fluoxetine and amantadine for 7 days more potently inhibited the behavioral syndrome evoked by the 5-hydroxytryptamine (5-HT)_1A receptor agonist ( ± )-8-hydroxy-2(di-n-propylamino)-tetralin hydrobromide (8-OH-DPAT), it did not change the action of the 5-HT₂ receptor agonist ( ± )-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (/ ± /-DOI). The obtained results support the hypothesis that repeated co-treatment with fluoxetine and amantadine may evoke more effective antidepressant activity than treatment with fluoxetine alone.Moreover, our results suggest that 5-HT_1Areceptors are useful targets for the development of more rapidly acting and more effective medication.     

Spinal serotonin 5-HT7 and adenosine A1 receptors,as well as peripheral adenosine A1 receptors,are involved in antinociception by systemically administered amitriptyline

The present study explored a link between spinal 5-HT₇ and adenosine A₁ receptors in antinociception by systemic amitriptyline in normal and adenosine A₁ receptor knock-out mice using the 2% formalin test. In normal mice, antinociception by systemic amitriptyline 3 mg/kg was blocked by intrathecal administration of the selective adenosine A₁ receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) 10 nmol. Blockade was also seen in adenosine A₁ receptor +/+ mice, but not in ?/? mice lacking these receptors. In both normal and adenosine A₁ receptor +/+ mice, the selective 5-HT₇ receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride (SB269970) 3 μg blocked antinociception by systemic amitriptyline, but it did not prevent antinociception in adenosine A₁ receptor ?/? mice. In normal mice, flinching was unaltered when the selective 5-HT₇ receptor agonist (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin (AS-19) 20 μg was administered alone, but increased when co-administered intrathecally with DPCPX 10 nmol or SB269970 3 μg. Intrathecal AS-19 decreased flinching in adenosine A₁ receptor +/+ mice compared to ?/? mice. Systemic amitriptyline appears to reduce nociception by activating spinal adenosine A₁ receptors secondarily to 5-HT₇ receptors. Spinal actions constitute only one aspect of antinociception by amitriptyline, as intraplantar DPCPX 10 nmol blocked antinociception by systemic amitriptyline in normal and adenosine A₁ receptor +/+, but not ?/? mice. Adenosine A₁ receptor interactions are worthy of attention, as chronic oral caffeine (0.1, 0.3 g/L, doses considered relevant to human intake levels) blocked antinociception by systemic amitriptyline in normal mice. In conclusion, adenosine A₁ receptors contribute to antinociception by systemic amitriptyline in both spinal and peripheral compartments.     

Luminal melatonin stimulates pancreatic enzyme secretion via activation of serotonin-dependent nerves

BackgroundSerotonin (5-HT) is released from enterochromaffin cells in the gastrointestinal tract. Serotonin, via the activation of 5-HT₂ and 5-HT₃ receptors on vagal fibers, mediates pancreatic secretion through the mechanism independent from cholecystokinin. Melatonin (5-HT derivative) or L-tryptophan (melatonin or 5-HT precursor) given systemically or intraduodenally to the rats stimulate amylase secretion, but the mechanism is not clear. The aims of this study was to investigate the involvement of 5-HT in the pancreatostimulatory effect of melatonin or L-tryptophan, administered intraduodenally.MethodsWistar rats were surgically equipped with silicone catheters; inserted into pancreato-biliary duct and into the duodenum. Melatonin, L-tryptophan or serotonin were given to the rats as a bolus. Combination of 5-HT₂ or 5-HT₃ receptor antagonists: ketanserin (100 μg/kg) and MDL72222 (250 μg/kg) was given intraperitoneally to the animals, 15 min. prior to the administration of the examined substances. The role of the vagal nerve, sensory fibers and CCK in the control of pancreatic exocrine function were determined. Blood samples were taken for the determination of 5-HT.ResultsMelatonin, 5-HT or L-tryptophan increased pancreatic amylase secretion. The stimulatory effect of the above substances was decreased by pretreatment of the rats with ketanserin and MDL72222. Bilateral vagotomy completely abolished the increase of amylase output caused by 5-HT, while capsaicin deactivation of sensory nerves or blockade of CCK₁ receptor only partially reversed the stimulatory effect of 5-HT on the pancreas. Intraduodenal L-tryptophan, but not melatonin, increased plasma 5-HT concentrations in a dose- and time-dependent manner.ConclusionStimulation of pancreatic exocrine function caused by intraluminal administration of melatonin, or L-tryptophan is modified, at least in part, by serotoninergic mechanisms and vagal nerves.