Discriminative stimulus properties of the 5-HT1A receptor biased agonists NLX-101 and F13714, in rats trained to discriminate 8-OH-DPAT from saline.

NLX-101 and F13714 are selective, full efficacy, biased agonists of the serotonin (5-HT1A) receptor. NLX-101 preferentially activates cortical postsynaptic 5-HT1A receptors, whereas F13714 preferentially activates raphe nuclei presynaptic 5-HT1A receptors. We compared NLX-101 and F13714 for their efficacy and potency to substitute for the discriminative cue produced by the prototypical, nonbiased 5-HT1A receptor agonist 8-OH-DPAT (racemate). Male and female Sprague-Dawley rats were trained to discriminate 8-OH-DPAT (0.1 mg/kg i.p., 20 min pretreatment) from saline using a classical two-lever drug-discrimination procedure. 8-OH-DPAT (0.01 and 0.05 mg/kg i.p.) dose-dependently substituted for the training dose, with about 50% responding on the 8-OH-DPAT-associated lever at 0.05 mg/kg. F13714 fully and very potently substituted for the training dose of 8-OH-DPAT from 0.018 mg/kg i.p., whereas NLX-101 only achieved full substitution at 0.5 mg/kg i.p., a dose which is known to also activate presynaptic 5-HT1A receptors. The 5-HT1A receptor partial agonist, buspirone, partially substituted (~80%) at 1 and 2 mg/kg i.p., doses which also decreased response rates. F13714 decreased response rates at 0.05 mg/kg. The selective 5-HT1A receptor antagonist WAY-100 635 (1 mg/kg s.c., 40 min pretreatment) elicited almost no responding on the 8-OH-DPAT-associated lever by itself, but blocked the discriminative stimulus effects produced by administration (20 min pretreatment) of 8-OH-DPAT (0.1 mg/kg), F13714 (0.025 mg/kg), NLX-101 (0.5 mg/kg) or buspirone (1 mg/kg). These data suggest that the discriminative cue produced by 0.1 mg/kg i.p. 8-OH-DPAT results from activation of presynaptic 5-HT1A receptors. They also further demonstrate the distinct profiles in behavioral models of 5-HT1A receptor-biased agonists.

Pharmacokinetics and bioavailability after intramuscular injection of the 5-HT1A serotonin agonist R-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in domestic goats (Capra aegagrus hircus).

To determine the bioavailability and pharmacokinetic properties of the serotonin 5-HT1A receptor agonist R-8-OH-DPAT in goats, and 0.1 mg kg-1 R-8-OH-DPAT hydrobromide was administered intramuscularly (i.m.) and intravenously (i.v.) to six goats in a two-phase cross-over design experiment. Venous blood samples were collected from the jugular vein 2, 5, 10, 15, 20, 30, 40 and 60 min following treatment and analysed by liquid chromatography tandem mass spectrometry. Bioavailability and pharmacokinetic parameters were determined by a one-compartment analysis. Mean bioavailability of R-8-OH-DPAT when injected i.m. was 66%. The mean volume of distribution in the central compartment was 1.47 L kg-1 . The mean plasma body clearance was 0.056 L kg-1  min-1 . All goats injected i.v. and two of six goats injected i.m. showed signs of serotonin toxicity. In conclusion, R-8-OH-DPAT is well absorbed following i.m. injection and the observed pharmacokinetics suggest that administration via dart is feasible. Administration of R-8-OH-DPAT hydrobromide, at a dosage of 0.1 mg kg-1 , resulted in the observation of clinical signs of serotonin toxicity in the goats. It is suggested that dosages for the clinical use of the compound should be lower in order to achieve the desired clinical effect without causing serotonin toxicity.

Dose-effect study of the serotonin agonist R-8-OH-DPAT on opioid-induced respiratory depression in blesbok (Damaliscus pygargus philipsi) and impala (Aepyceros melampus).

OBJECTIVE: To determine whether the R-enantiomer of 8-hydroxy-2-(di-n-propylamino) tetralin (R-8-OH-DPAT) alleviates respiratory depression in antelope species immobilized with etorphine. The experiment also aimed to establish the most clinically effective dose of this serotonin 5- HT1A receptor agonist. ANIMALS: A group of six female blesbok and six female impala. STUDY DESIGN: Each animal was subjected to four immobilization treatments in a prospective four-way crossover design-control treatment consisting of only etorphine at 0.09 mg kg-1 and three treatments consisting of etorphine at 0.09 mg kg-1 combined with 0.005, 0.02 and 0.07 mg kg-1 of R-8-OH-DPAT, respectively. Induction, quality of immobilization and recovery were monitored in each treatment. Physiological variables including heart rate, respiratory rate, arterial blood pressure and blood gases were measured for 35 minutes during immobilization. A linear mixed model was used to assess the effects of treatments over the recumbency period. RESULTS: R-8-OH-DPAT did not influence induction, immobilization or recovery scores. Respiratory rate in blesbok was increased in the medium- and high-dosage R-8-OH-DPAT treatment group. However, this increased respiratory rate did not translate into improvements of arterial partial pressure of oxygen (PaO2) values in the blesbok. The medium and higher dosages of R-8-OH-DPAT in impala led to an improved PaO2 as well as to decreased opioid-induced tachycardia during the first 10 minutes of immobilization. CONCLUSIONS AND CLINICAL RELEVANCE: Previous reports indicated that the racemic mixture of 8-OH-DPAT injected intravenously had a positive effect on blood-gas values in etorphine-treated hypoxemic goats. In this experiment, similar effects could be seen in impala at the higher dosage rates of R-8-OH-DPAT. However, failure to achieve an improvement of blood-gas values in blesbok was an unexpected result. It could be speculated that the dosage, species-specific differences of serotonin receptors or the use of the R-enantiomer of 8-OH-DPAT might play a role.

[Establishment of a rat model of premature ejaculation with 8-OH-DPAT].

OBJECTIVE: To explore the feasibility and practicability of establishing a rat model of premature ejaculation (PE) by injection of 8-OH-DPAT into the subarachnoid space of the lumbosacral spinal cord segments. METHODS: Twenty-four male Wistar rats were equally randomized into a PE model and a blank control group. The PE model was established by injection of 8-OH-DPAT in 10 ml normal saline at 0.8 mg per kg of the body weight per day into the subarachnoid space of the lumbosacral spinal cord segments and the control rats were injected with the same volume of normal saline only, both for 4 weeks. Another 24 female Wistar rats were injected subcutaneously with benzoic acid estradiol at 20 µg to induce estrus at 36 hours before mated with the male animals. At 2 and 4 weeks, the male rats were mated with the female ones for 30 minutes each time and meanwhile observed for their mating behavior indicators, such as mount latency, intromission latency, ejaculation latency, mount frequency, intromission frequency, and ejaculation frequency. RESULTS: Compared with the controls, the PE model rats showed a significantly lower ejaculation latency (ï¼»712.35 ± 36.77ï¼½ vs ï¼»502.35 ± 46.72ï¼½ s, P<0.05), mount latency (ï¼»11.22 ± 3.60ï¼½ vs ï¼»8.69 ± 2.48ï¼½ s, P<0.05), mount frequency (13.28 ± 0.24 vs 7.53 ± 1.84, P<0.05), and intromission latency (ï¼»22.33 ± 2.45ï¼½ vs ï¼»12.08 ± 1.39ï¼½ s, P<0.05), but a remarkably higher ejaculation frequency (2.01 ± 0.48 vs 4.26 ± 0.89, P<0.05). No statistically significant difference was observed between the control and model animals in the intromission frequency (7.49 ± 2.21 vs 6.45 ± 1.89, P>0.05). CONCLUSIONS: A rat model of premature ejaculation was successfully established by injection of 8-OH-DPAT into the subarachnoid space of the lumbosacral spinal cord segments, which is of great significance for further study of the mechanism of premature ejaculation.

Effects of the 5-HT1A receptor agonists buspirone and 8-OH-DPAT on pupil size in common marmosets.

As pupil size is affected by psychotropic drugs in all mammals, it has been used as a well-established clinical indicator for the preclinical and clinical development of novel drugs. It has been reported that activation of the serotonin (5-HT)1A receptor differently affects pupil response in rodents (mydriasis) and humans (miosis). Thus, it is important to establish a quantitative system for measuring pupil size using other species, such as nonhuman primates. Common marmosets have recently attracted a great deal of attention as suitable experimental animals in the psychoneurological field because of handling ease compared with other nonhuman primates and the requirement for small amounts of test drugs. In this study, we constructed a system for measuring changes in pupil size using an infrared eye-tracking camera and evaluated the effects on pupil size of the 5-HT1A receptor agonists buspirone, 8-OH-DPAT and buspirone active metabolite 1-(2-pyrimidinyl) piperazine. Our results show that both buspirone and 8-OH-DPAT significantly decrease pupil size in a dose-dependent manner. The 5-HT1A receptor antagonist WAY 100635 completely blocked both buspirone and 8-OH-DPAT-induced miosis, whereas 1-(2-pyrimidinyl) piperazine had no effect on pupil size. These results suggest that measurement of pupil size may be a useful biomarker for predicting the pharmacodynamics of new 5-HT1A receptor agonists.

Effects of L-dopa priming on cortical high beta and high gamma oscillatory activity in a rodent model of Parkinson's disease.

Prolonged L-dopa treatment in Parkinson's disease (PD) often leads to the expression of abnormal involuntary movements known as L-dopa-induced dyskinesia. Recently, dramatic 80 Hz oscillatory local field potential (LFP) activity within the primary motor cortex has been linked to dyskinetic symptoms in a rodent model of PD and attributed to stimulation of cortical dopamine D1 receptors. To characterize the relationship between high gamma (70-110 Hz) cortical activity and the development of L-dopa-induced dyskinesia, cortical LFP and spike signals were recorded in hemiparkinsonian rats treated with L-dopa for 7 days, and dyskinesia was quantified using the abnormal involuntary movements (AIMs) scale. The relationship between high gamma and dyskinesia was further probed by assessment of the effects of pharmacological agents known to induce or modulate dyskinesia expression. Findings demonstrate that AIMs and high gamma LFP power increase between days 1 and 7 of L-dopa priming. Notably, high beta (25-35 Hz) power associated with parkinsonian bradykinesia decreased as AIMs and high gamma LFP power increased during priming. After priming, rats were treated with the D1 agonist SKF81297 and the D2 agonist quinpirole. Both dopamine agonists independently induced AIMs and high gamma cortical activity that were similar to that induced by L-dopa, showing that this LFP activity is neither D1 nor D2 receptor specific. The serotonin 1A receptor agonist 8-OH-DPAT reduced L-dopa- and DA agonist-induced AIMs and high gamma power to varying degrees, while the serotonin 1A antagonist WAY100635 reversed these effects. Unexpectedly, as cortical high gamma power increased, phase locking of cortical pyramidal spiking to high gamma oscillations decreased, raising questions regarding the neural substrate(s) responsible for high gamma generation and the functional correlation between high gamma and dyskinesia.

A dose-response study of separate and combined effects of the serotonin agonist 8-OH-DPAT and the dopamine agonist quinpirole on locomotor sensitization, cross-sensitization, and conditioned activity.

Chronic treatment with the dopamine D2/D3 agonist, quinpirole, or the serotonin 1A agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), induces behavioral sensitization. It is not known whether both drugs produce sensitization through a shared mechanism. Here, we examine whether quinpirole and 8-OH-DPAT show cross-sensitization and impact sensitization, as would be expected from shared mechanisms. Male rats (N=208) were assigned randomly to 16 groups formed by crossing four doses of quinpirole (0, 0.03125, 0.0625, or 0.125 mg/kg) with four doses of 8-OH-DPAT (0, 0.03125, 0.625, or 0.125 mg/kg). After a course of 10 drug treatments administered twice per week in locomotor activity chambers, all groups were challenged on separate tests with quinpirole (0.1 mg/kg), 8-OH-DPAT (0.1 mg/kg), or saline, and locomotor activity was evaluated. Challenge tests with quinpirole and 8-OHDPAT showed no cross-sensitization between the drugs. Chronic quinpirole (0.125 mg/kg) administration induced a sensitized quinpirole response that was attenuated dose-dependently by chronic 8-OH-DPAT cotreatment. Cotreatment with quinpirole (0.0625 mg/kg) and 8-OH-DPAT (all doses) induced quinpirole sensitization. Chronic 8-OH-DPAT (0.125 mg/kg) induced a sensitized 8-OHDPAT response that was prevented by chronic cotreatment with the lowest but not the highest dose of quinpirole. Cotreatment with 8-OHDPAT (0.0625) and quinpirole (0.125 mg/kg) induced sensitization to 8-OH-DPAT. The saline challenge test showed elevated locomotor activity in chronic quinpirole (0.125 mg/kg) and 8-OHDPAT (0.0625, 0.125 mg/kg) alone groups, and in seven of nine cotreated groups. The absence of cross-sensitization suggests separate mechanisms of sensitization to quinpirole and 8-OH-DPAT. Cotreatment effects suggest that induction of sensitization can be modulated by serotonin 1A and D2/D3 activity.

Effects of Dopamine and Serotonin Systems on Modulating Neural Oscillations in Hippocampus-Prefrontal Cortex Pathway in Rats.

Theta and gamma oscillations are believed to play an important role in cognition and memory, and their phase coupling facilitates the information transmission in hippocampal-cortex network. In a rat model of chronic stress, the phase coupling of both theta and gamma oscillations between ventral hippocampal CA1 (vCA1) and medial prefrontal cortex (mPFC) was found to be disrupted, which was associated with the impaired synaptic plasticity in the pathway. However, little was known about the mechanisms underlying the process. In order to address this issue, both dopamine and serotonin as monoaminergic neurotransmitters were involved in this study, since they were crucial factors in pathological basis of depressive disorder. Local field potentials (LFPs) were recorded simultaneously at both vCA1 and mPFC regions under anesthesia, before and after the injection of dopamine D1 receptor antagonist and 5-HT1A receptor agonist, respectively. The results showed that the blockage of D1 receptor could lead to depression-like decrement on theta phase coupling. In addition, the activation of 5-HT1A receptor enhanced vCA1-mPFC coupling on gamma oscillations, and attenuated CA1 theta-fast gamma cross frequency coupling. These data suggest that the theta phase coupling between vCA1 and mPFC may be modulated by dopamine system that is an underlying mechanism of the cognitive dysfunction in depression. Besides, the serotonergic system is probably involved in the regulation of gamma oscillations coupling in vCA1-mPFC network.

Enhancement of the FGFR1 signaling in the FGFR1-5-HT1A heteroreceptor complex in midbrain raphe 5-HT neuron systems. Relevance for neuroplasticity and depression.

New findings show existence of FGFR1-5-HT1A heteroreceptor complexes in 5-HT nerve cells of the dorsal and median raphe nuclei of the rat midbrain and hippocampus. Synergistic receptor-receptor interactions in these receptor complexes indicated their enhancing role in hippocampal plasticity. The existence of FGFR1-5-HT1A heteroreceptor complexes also in midbrain raphe 5-HT nerve cells open up the possibility that antidepressant drugs by increasing extracellular 5-HT levels can cause an activation of the FGF-2/FGFR1 mechanism in these nerve cells as well. Therefore, the agonist modulation of the FGFR1-5-HT1A heteroreceptor complexes and their specific role is now determined in rat medullary raphe RN33B cells and in the caudal midline raphe area of the midbrain rich in 5-HT nerve cells. The combined i.c.v. treatment with FGF-2 and the 5-HT1A agonist 8-OHDPAT synergistically increased FGFR1 and ERK1/2 phosphorylation in the raphe midline area of the midbrain and in the RN33B cells. Cotreatment with FGF2 and the 5-HT1A agonist induced RN33B cell differentiation as seen from development of an increased number and length of extensions per cell and their increased 5-HT immunoreactivity. These signaling and differentiation events were dependent on the receptor interface since they were blocked by incubation with TMV but not by TMII of the 5-HT1A receptor. Taken together, the 5-HT1A autoreceptors by being part of a FGFR1-5-HT1A heteroreceptor complex in the midbrain raphe 5-HT nerve cells appears to have also a trophic role in the central 5-HT neuron systems besides playing a key role in reducing the firing of these neurons.

Targeting melanocyte and melanoma stem cells by 8-hydroxy-2-dipropylaminotetralin.

Monobenzyl ether of hydroquinone (MBEH) is cytotoxic towards melanocytes. Its treatment efficacy is limited by an inability to eradicate stem cells. By contrast, 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-DPAT) affects melanocyte stem cell survival. MBEH and 8-DPAT were added to melanocytes and melanoma cells to compare cytotoxicity. Stem cell content among viable cells was determined by fluorocytometry using markers CD34, Pax3, and CD271. Immunostaining was used to identify stem cells in skin explants treated with MBEH or 8-DPAT ex vivo. Mice were exposed to MBEH or 8-DPAT and scanned for depigmentation before harvesting skin. MBEH exposure prompted a relative increase in stem cells among cultured melanocytes and melanoma cells, as treatment preferentially eliminated differentiated cells and spared the stem cells. Viability of this remaining, enriched stem cell population was however rapidly reduced by exposure to 8-DPAT within melanocyte and melanoma cell cultures. In human skin explants, the abundance of melanocyte stem cells was also visibly reduced after 8-DPAT treatment, in contrast to tissue exposed to MBEH. Meanwhile, significant depigmentation of the mouse pelage and loss of differentiated melanocytes was observed in vivo in response to topical application of MBEH, but not 8-DPAT. Prolonged application of the latter agent instead appeared to effectively reduce the abundance of melanocyte stem cells in the dermis. This furthers the idea that MBEH and 8-DPAT target complementary cell populations. Results indicate that combination treatment may demonstrate superior therapeutic activity by eliminating both differentiated and tumor initiating populations.

Chronic administration of 5-HT1A receptor agonist relieves depression and depression-induced hypoalgesia.

Previous studies have shown that depressed patients as well as animal models of depression exhibit decreased sensitivity to evoked pain stimuli, and serotonin is indicated to be involved in depression-induced hypoalgesia. The purpose of this study was to investigate the potential role of 5-HT1A receptor in the depression-induced hypoalgesia. Acute or chronic administration of 5-HT1A receptor agonist, 8-OH-DPAT, was performed in olfactory bulbectomy (OB) and sham-operated rats. The depression-like behavior and pain thresholds were measured using open-field test and radiant heat thermal pain test, respectively. We found that acute administration of 8-OH-DPAT increased locomotor activity and pain thresholds in the sham rats but had no effect on the OB rats. In contrast, chronic administration of 8-OH-DPAT reduced locomotor activity and pain thresholds and restored them to normal level. Increased pain thresholds were also observed in the sham rats after the chronic administration. These results demonstrated that chronic administration of 8-OH-DPAT reversed the depression-induced decrease in pain sensitivity in rats, suggesting that 5-HT1A receptor may play a role in the depression-associated hypoalgesia.

[The Effects of Inhibitors of Rho- and tyrosine c-Src-kinases on serotonin-induced constrictions of the aorta and mesenteric artery in rats].

We found that the inhibitor of Rho-kinase fasudil selectively inhibited constriction of isolated rings of the aorta and mesenteric artery in rats in response to application of the agonists of 5HT2A-(DOI and TBC-2) and 5HT1A-receptors (8-OH-DPAT) and did not influence vasoconstriction induced by serotonin. We demonstrate for the first time that application of the agonists of 5HT2C-receptors (MK 212 and SCH 23390) did not influence the tone of "intact" vessels. The marked vasoconstrictory effect of the agonists of 5HT2C-receptors was observed in the vessels preconstricted due to angiotensin II or vasopressin. We found that the inhibitor of Rho-kinase did not influence negatively on MK 212 or SCH 23390-induced constriction of isolated rings of the aorta and mesenteric artery in rats. We suppose.that, in the presence of fasudil, serotonin induces constriction of vessels through the interaction with 5HT2C-receptors and signal transduction from these receptors does not involve Rho-kinase activity. We found that fasudil attenuated vasoconstriction induced by norepinephrine and vasopressin by 40%. We.demonstrated that tyrosine c-Src-kinase plays the most important role in signal transduction from 5HT-receptors because its effects are specific with relation to these receptors.

Targeting 5-HT(1A) receptors in astrocytes to protect dopaminergic neurons in Parkinsonian models.

Astrocytes are abundant neuron-supporting glial cells that harbor a powerful arsenal of neuroprotective antioxidative molecules and neurotrophic factors. Here we examined whether enrichment with healthy striatal astrocytes can provide neuroprotection against progressive dopaminergic neurodegeneration. Serotonin 1A (5-HT1A) agonist 8-OH-DPAT induced astrocyte proliferation and increased metallothionein-1/-2 (MT-1/-2), antioxidative molecules, in cultured astrocytes and the striatum of mice. Primary cultured mesencephalic dopamine neurons were protected against oxidative stress by preincubation with conditioned media from 8-OH-DPAT-treated astrocytes. These protective effects were canceled by 5-HT1A antagonist or MT-1/-2-specific antibody. Furthermore, reduction of nigrostriatal dopaminergic neurons in 6-hydroxydopamine-lesioned parkinsonian model mice was significantly abrogated by repeated injections of 8-OH-DPAT. Treatment with 8-OH-DPAT markedly increased the expression of MT in striatal astrocytes in the hemi-parkinsonian mice. Our study provides a promising therapeutic strategy of neuroprotection against oxidative stress and progressive dopaminergic neurodegeneration by demonstrating the efficacy of targeting 5-HT1A receptors in astrocytes.

Brain region-specific transcriptomic markers of serotonin-1A receptor agonist action mediating sexual rejection and aggression in female marmoset monkeys.

INTRODUCTION: In a marmoset model of hypoactive female sexual function, we have shown that repeated administration of the serotonin (5-HT)-1A agonist R-(+)-8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) inhibits sexual receptivity in female marmoset monkeys and increases aggression toward the male pairmate. AIM: The aims of this study are to investigate gene expression changes induced by 8-OH-DPAT in laser-microdissected brain areas that regulate female sexual function and to identify genes, functional gene classes, and pathways associated with 8-OH-DPAT-mediated inhibition of female sexual receptivity. METHODS: Gene expression was measured in the medial prefrontal cortex (mPFC), medial preoptic area (mPOA), cornu ammonis-1 (CA1) area of the hippocampus (CA1), and dorsal raphé nucleus (DRN) of four 8-OH-DPAT-treated (0.1 mg/kg; daily administration for 16 weeks) and four vehicle-treated female marmosets using a marmoset-specific microarray (European Marmoset Microarray [EUMAMA]) and validated by real-time quantitative polymerase chain reaction (RTqPCR). Enriched functional gene classes were determined. In a parallel candidate gene approach, the expression of serotonergic candidate genes, i.e., the 5-HT1A, 5-HT2A, and 5-HT7 receptors and the 5-HT transporter (5-HTT), was measured by RTqPCR. MAIN OUTCOME MEASURES: The main outcome is the differential expression of genes between 8-OH-DPAT- and vehicle-treated marmosets. RESULTS: 8-OH-DPAT affected the gene classes important to neural development (mPFC, mPOA, and DRN), neurotransmission (mPOA), energy production (mPFC and mPOA), learning and memory (CA1), and intracellular signal transduction (DRN). Oxytocin (OXT) in the mPOA and 5-HTT in the DRN were strongly increased by 8-OH-DPAT. 5-HT1A tended to increase in the mPFC, while 5-HT7 was decreased in the CA1. CONCLUSIONS: Brain region-specific alterations of gene expression regulating neural circuitries, energy demands, and learning processes are associated with 8-OH-DPAT-induced decrease in female sexual receptivity and increase in pairmate aggression. The role of OXT in the serotonergic regulation of female sexual behavior and partner interactions warrants attention in future studies.

[Behavioral effects during the local activation and blockade of serotonin and dopamine receptors in the frontal cortex in cats in the model with a choice of reinforcements of different value].

In the model with a choice of reinforcements of different value animals were able to "impulsive" and "self-controlled" behavior with an equal probability. Five adult cats were tested. A local application of agonists of 5-HT(1A) and 5-HT(2A/C) receptors (8-OH-DPAT, DOI) in the frontal cortex have resulted in a significant decrease of the "impulsive" reactions and an increase of omissions. The administration of antagonists of 5-HT(2A/C) receptors (ketanserin) and D1/D2 receptors (SCH 23390, raclopride) have impaired the "impulsive" behavior. However the combined administration of agonists/antagonists of 5-HT(2A/C) receptors and antagonists of D1/D2 receptors have not shown the significant changes in behavior as compared with control experiments. The data showed the realization of the optimal behavior with the "impulsive" and "self-controled" reactions in ambivalent animals requires the involvement of both dopaminergic and serotoninergic systems for the regulation of the activity of neurons in frontal cortex areas.

Effect of a 5-HT(1A) receptor agonist (8-OH-DPAT) on the external urethral sphincter activity in the rat.

BACKGROUND/PURPOSE: This study examined the effects of a 5-HT(1A) receptor agonist (8-OH-DPAT) on external urethral sphincter (EUS) activity in urethane-anesthetized rats. METHODS: An EUS electromyogram (EMG) and intravesical pressure (IVP) were simultaneously recorded during continuous cystometrographic monitoring, to provide a quantitative evaluation of EUS activity and urethral urodynamics of voiding. RESULTS: When examining the EUS burst activity, durations of the active (AP) and silent periods (SP) as a function of the time axis, respectively, exhibited concave- and convex-shaped curves. The burst discharges of the EUS-EMG were divided into nonvoiding and voiding burst activities based on the oscillation waves of the IVP, which were located in Phases 1 and 2 of the IVP. After 8-OH-DPAT treatment, the entire burst period in Phases 1 to 2 of the IVP was significantly prolonged. The average SP in both Phases 1 and 2 significantly increased but the average APs were not affected. Urodynamic results showed decreases in the volume threshold, contraction amplitude, and residual volume as well as an increase in the contraction duration. In addition, the amplitude of bladder high-frequency oscillatory waves in the IVP and the average urethral flow rate were reduced, but the entire voiding efficiency increased. CONCLUSION: The influences of 8-OH-DPAT on EUS burst activity and urodynamics were exactly detected by the sophisticated EMG analytic design, and the results could be a reference for the pharmacological treatment of patients with lower urinary tract dysfunction.

[Effect of the selective ligands 5-HT(1A) receptors administration on the impulsive and self-control behavior in rats].

The influence of drugs, agonist and antagonist of serotonin receptors 5-HT(1A) on the behavior of rats tested by the method of choice to the value of reinforcement was investigated. Depending on their preferences in food reinforcement rats were divided into self-monitoring (choosing more valuable, delayed reinforcement) and impulsive (low value, immediate reinforcement). An hour before the test animals were administrated i.p. agonist 5-HT(1A) receptors 8-OH-DPAT, [(+)-8-Hydroxy-2-(dipropylamino)tetralin] in a dose of 0.1 mg/kg or antagonist WAY-100635, [N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleat salt] at a dose of 0.2 mg/kg. Evaluated parameters, such as number of clicks on a particular pedal, the latencies and number of omitted responses. The results showed that the administration of drugs to modify individual behavior parameters both groups of animals. The introduction of 5-HT(1A) agonist receptors in impulsive animals caused an increase in the number of clicks on the pedal for more valuable reinforcement, and administration of an antagonist did not have any significant effect to behavior.

[Effect of activation of serotonin 5-HT1A-receptors on the immune response in mice of the ASC strain with depressive-like behavior].

Selective activation of serotonin 5-HT(1A)-receptors produced different effects on immunological reactivity in mice of ASC strain with genetic predisposition to depressive-like behavior, and parental CBA and AKR strains displaying no depressive reactions. Administration of 5-HT(1A)-receptors agonist 8-OH-DPAT at low dose (0.1 mg/kg) affecting upon presynaptic receptors resulted in immunostimulation in CBA mice and did not change the immune response level in mice of ASC strain. Activation of postsynaptic 5-HT(1A)-receptors with higher dose of 8-OH-DPAT (1.0 mg/kg) caused immunosuppression in CBA and AKR strains while under the same conditions the immune response of ASC mice was increased. Decrease the immune reactions in ASC mice was observed only after application of 8-OHDPAT at dose of 5 mg/kg. The changes of functional activity of pre- and postsynaptic 5-HT(1A)-receptors under a high predisposition to depressive-like behavior providing different effects of this receptor activation on immune function are discussed.

Systemic 8-OH-DPAT challenge causes hyperventilation largely via activating pre-botzinger complex 5-HT1A receptors.

Systemic 8-OH-DPAT (a 5-HT1A receptor agonist) challenge evokes hyperventilation independent of peripheral 5-HT1A receptors. Though the pre-Botzinger Complex (PBC) is critical in generating respiratory rhythm and activation of local 5-HT1A receptors induces tachypnea via disinhibition of local GABAA neurons, its role in the respiratory response to systemic 8-OH-DPAT challenge is still unclear. In anesthetized rats, 8-OH-DPAT (100 µg/kg, iv) was injected twice to confirm the reproducibility of the evoked responses. The same challenges were performed after bilateral microinjections of (S)-WAY-100135 (a 5-HT1A receptor antagonist) or gabazine (a GABAA receptor antagonist) into the PBC. Our results showed that: 1) 8-OH-DPAT caused reproducible hyperventilation associated with hypotension and bradycardia; 2) microinjections of (S)-WAY-100135 into the PBC attenuated the hyperventilation by ˜60 % without effect on the evoked hypotension and bradycardia; and 3) the same hyperventilatory attenuation was also observed after microinjections of gabazine into the PBC. Our data suggest that PBC 5-HT1A receptors play a key role in the respiratory response to systemic 8-OH-DPAT challenge likely via disinhibiting local GABAergic neurons.

Evaluation of the anxiolytic-like effects of clomipramine in two rat strains with different anxiety vulnerability (Wistar and Wistar-Kyoto rats): participation of 5-HT1A receptors.

The main aim of this study was to evaluate the anxiolytic-like effects of the serotonergic antidepressant, clomipramine (0.6-5.0 mg/kg), and the 5-HT1A agonist, (±)8-hydroxy-2-(di-n)-propil-aminotetraline hydrobromide (8-OH-DPAT; 0.01-0.5 mg/kg), in two strains of rat with different anxiety vulnerability: Wistar-Kyoto (WKY; with trait anxiety) and Wistar rats (control strain). The anxiety model used was the burying behavior test; decreases in burying, grooming of the snout, and freezing were interpreted as a reduction of anxiety-like levels. A second objective was to explore the participation of 5-HT1A receptors in the effects of clomipramine and 8-OH-DPAT. Behavior in the burying behavior test was strain dependent. In addition to the burying behavior, WKY rats showed high levels of freezing and grooming of the snout. Clomipramine and 8-OH-DPAT decreased the burying behavior in both strains of rats through a direct interaction with the 5-HT1A receptor. 8-OH-DPAT decreased freezing behavior in both strains through a mechanism that was not related to 5-HT1A receptors. Finally, clomipramine was able to block freezing and grooming behaviors only in WKY rats. In conclusion, strains with different anxiety vulnerability express different behavioral responses toward the same aversive stimulus, and the anxiolytic-like effects of clomipramine and 8-OH-DPAT are both behavior and strain dependent.