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Objectives This study aimed to investigate the effects of ketanserin on micturition mediated via the 5-HT2A receptor in the motoneuron nucleus of the Lumbosacral cord, as reflected in high frequency oscillations (HFOs) of intravesical pressure and the external urethral sphincter electromyogram (EUS-EMG) in anesthetized male rats. Methods： Male Sprague-Dawley rats were used. Cystometry and EUS-EMG were performed in all rats under urethane anesthesia to examine the variations after successive intrathecal (i.t.) administration of various doses of ketanserin into the lumbosacral cord. Immunofluorescence staining and Western blotting were made to observe the distribution of 5-HT2 A and −2C receptors in the lumbosacral cord motor neurons. Results Compared to the controls, ketanserin-treated rats showed a declined trend of dose-dependent manner in the HFOs, in accordance with the variation of EUS-EMG, while decreased micturition volume, voiding efficiency, and increased post-void residual volume was only observed at the dose of 0.1 mg/kg. The effects of ketanserin on the HFO and EUS-EMG activity were partially or completely reversed by the 5-HT2A/2C receptor agonist, DOI. Meanwhile, immunofluorescence staining and Western blot analysis showed that immunoreactivity of 5-HT2A receptor was higher than that of 5-HT2C, labeling in the lumbosacral cord motoneurons. Conclusions The intrathecally administrated 5-HT2A receptor antagonist ketanserin can weaken the EUS bursting activity, decrease HFOs, and reduce voiding efficiency as dose dependently. The effects of ketanserin on micturition may be mainly mediated via the 5-HT2A receptors in the motoneuron nucleus of the lumbosacral cord.

This study aimed to investigate the effects of ketanserin on micturition mediated via the 5-HTCompared to the controls, ketanserin-treated rats showed a declined trend of dose-dependent manner in the HFOs, in accordance with the variation of EUS-EMG, while decreased micturition volume, voiding efficiency, and increased post-void residual volume was only observed at the dose of 0.1 mg/kg. The effects of ketanserin on the HFO and EUS-EMG activity were partially or completely reversed by the 5-HTThe intrathecally administrated 5-HT

In this work we evaluated antidepressant-like effect of E. uniflora leaves EO employing the tail suspension test. The involvement of serotonergic and adrenergic systems was appraised. EO was administered by oral route (p.o.) in mice and the doses of 10 and 50mg/kg exhibited antidepressant-like action in the TST. The effect of EO (10mg/kg) was prevented by the pretreatment of mice with ketanserin (5mg/kg, intraperitoneal), prazosin (0.1mg/kg, i.p.) and yohimbine (0.1mg/kg, i.p.). In addition, further analysis of the in vitro antioxidant effect of the EO was made against lipid oxidation. The results revealed that EO has a potent antioxidant activity and therapeutic potential for the development of phytomedicines with antidepressant and antioxidant properties.

Hallucinogenic drugs, such as lysergic acid diethylamide (LSD), mescaline and psilocybin, alter perception and cognitive processes. All hallucinogenic drugs have in common a high affinity for the serotonin 5-HT(2A) receptor. Metabotropic glutamate 2/3 (mGlu2/3) receptor ligands show efficacy in modulating the cellular and behavioral responses induced by hallucinogenic drugs. Here, we explored the effect of chronic treatment with the mGlu2/3 receptor antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)-propionic acid (LY341495) on the hallucinogenic-like effects induced by LSD (0.24mg/kg). Mice were chronically (21 days) treated with LY341495 (1.5mg/kg), or vehicle, and experiments were carried out one day after the last injection. Chronic treatment with LY341495 down-regulated [(3)H]ketanserin binding in somatosensory cortex of wild-type, but not mGlu2 knockout (KO), mice. Head-twitch behavior, and expression of c-fos, egr-1 and egr-2, which are responses induced by hallucinogenic 5-HT(2A) agonists, were found to be significantly decreased by chronic treatment with LY341495. These findings suggest that repeated blockade of the mGlu2 receptor by LY341495 results in reduced 5-HT(2A) receptor-dependent hallucinogenic effects of LSD.

Mesobuthus tamulus (MBT) venom is shown to depress the spinal reflexes through a mechanism unrelated to the NMDA receptors. 5-Hydroxytryptamine (5-HT) is another excitatory transmitter in the spinal cord therefore, the present study was undertaken to examine the involvement of 5-HT in the venom-induced depression of reflexes. The experiments were performed on isolated hemisected spinal cords from 4 to 6-day-old rats. Stimulation of a dorsal root with supramaximal strength evoked monosynaptic reflex (MSR) and polysynaptic reflex (PSR) potentials in the corresponding segmental ventral root. MBT venom (0.3 microg/ml) depressed the spinal reflexes in a time-dependent manner and the maximal depression was seen at 10 min. The time to produce 50% depression (T-50) of MSR and PSR was 8.1+/-1.41 and 6.8+/-0.5 min, respectively. Pretreatment with pindolol (1 microM; 5-HT(1A/1B) receptor antagonist) blocked the reflexes up to 15 min. On the other hand, ketanserin (10 microM; 5-HT(2A/2C) receptor antagonist) or ondansetron (0.1 microM; 5-HT(3) receptor antagonist) blocked the venom-induced depression of MSR and PSR during entire exposure time (30 min). The 5-HT concentration of the cords exposed to venom (1.6+/-0.04 microg/g tissue) was significantly greater than the control group (0.98+/-0.08 microg/g tissue). The results indicate that venom-induced depression of spinal reflexes is mediated via 5-HTergic transmission involving 5-HT(1A/1B), 5-HT(2A/2C) and 5-HT(3) receptors.

The involvement of 5-hydroxytryptaminergic (5-HTergic) system for the 3-nitropropionic acid (3-NPA)-induced depression of spinal reflexes was evaluated and compared with other energy deficiency condition (ischemia; glucose-free and O 2 -free). The monosynaptic (MSR) and polysynaptic reflex (PSR) potentials were recorded at ventral root by stimulating the corresponding dorsal root in neonatal rat spinal cord in vitro . Superfusion of 3-NPA (3.4 mM) or ischemic solution depressed the reflexes in a time-dependent manner abolishing them by 35 min. Pretreatment with pindolol (1 μM), ketanserin (10 μM) or ondansetron (0.1 μM); 5-HT 1 , 5-HT 2 , or 5-HT 3 receptor antagonist, respectively, did not block the 3-NPA-induced depression of reflexes whereas, ischemia-induced depression was blocked by ondansetron. 5-HT content of the spinal cords incubated with 3-NPA (3.4 mM) for 30 min was decreased significantly (33 ng/g tissue) while increased (286 ng/g) in cords exposed to ischemic solution as compared to saline-treated cords (161 ng/g). Thus, 3-NPA-induced depression of spinal reflexes does not involve 5-HTergic pathway unlike ischemia-induced depression.

We investigated the role of 5-HT 2A and 5-HT 2C receptors in atypical absence seizures (AAS) induced by trans-1,4-bis[2-chloro-benzylaminomethyl] cyclohexane, dihydrocholoride (AY-9944). The total duration and number and mean duration of the spontaneous bursts of slow spike-and-wave discharges (SSWD) that characterize the AY model were measured using electrocorticographic (ECoG) recordings in freely moving animals. In a randomized counterbalanced dose response design, rats were treated with either the 5-HT 2A agonist 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI, 0.5, 1 or 2 mg/kg), the 5-HT 2C preferring agonist m -chlorophenylpiperazine ( m CPP, 1, 2, or 4 mg/kg), the 5-HT 2A antagonist ketanserin (2.5 or 5 mg/kg), or vehicle. DOI significantly reduced the total duration and number of SSWD. In contrast, m CPP had no effect on total duration or number of SSWD. Ketanserin exacerbated the number of SSWD at 2.5 mg/kg but produced mixed results at 5.0 mg/kg. However, none of the treatments affected the mean SSWD duration. These data support the hypothesis that 5HT 2A receptors are involved in the pathology of experimental atypical absence seizures.

In the present study, we examined serotonin (5-HT)-induced intracellular Ca(2+) ([Ca(2+)]i) responses to hypoxia in glomus cells isolated from carotid body (CB) of the rat. 5-HT did not induce any [Ca(2+)]i responses in clustered glomus cells during normoxia (21% O2), whereas, the perfusion of hypoxic solution (1% O2) induced repetitive increases in [Ca(2+)]i in the same specimens. The frequency and magnitude of hypoxia-induced [Ca(2+)]i changes observed in the glomus cells were enhanced in the presence of 5-HT, and this response was inhibited by the 5-HT2 receptor antagonist, ketanserin. Furthermore, RT-PCR analysis detected the expression of 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT3A, and 5-HT3B receptor mRNAs in extracts of the CB. These results suggest that 5-HT increases hypoxia-induced [Ca(2+)]i responses in glomus cells. 5-HT may elevate hypoxic responses in glomus cells in order to increase chemosensory activity of the CB.

The involvement of 5-hydroxytryptaminergic (5-HT) system for the Ptychodiscus brevis toxin (PbTx)-induced depression of spinal reflexes was evaluated. The reflex potentials were recorded at ventral root by stimulating the corresponding dorsal root in neonatal rat spinal cord in vitro . Superfusion of PbTx (2.8–84 μM) depressed the monosynaptic (MSR) and polysynaptic (PSR) reflexes in a concentration-dependent manner. The depression of the reflexes was maximal with 84 μM of the toxin. Ondansetron (0.1 μM), a 5-HT 3 receptor antagonist, blocked the PbTx-induced depression of MSR and PSR. Spiperone (a 5-HT 2A antagonist) or ketanserin (5-HT 2A/2C antagonist and also at 5-HT 1B/1D ) failed to block the PbTx-induced depression of the reflexes. The 5-HT concentration of the cords was increased by four-fold after exposure to PbTx (28 μM) and the increase was not seen in the cords pretreated with dl -2 amino-5-phosphonovaleric acid (APV, a NMDA receptor antagonist). Superfusion of 5-HT or phenylbiguanide (PBG, a 5-HT 3 receptor agonist) also produced depression of the spinal reflexes in a concentration-dependent manner. The 5-HT-induced depression of reflexes was blocked by ondansetron but not by spiperone. The results demonstrate that the PbTx-induced depression of spinal reflexes involves 5-hydroxytryptamine via 5-HT 3 receptors modulated by NMDA receptor.

Direct administration of interleukin-1beta (IL-1beta) into the lateral cerebral ventricle of rat brain, in addition to inducing febrile responses, upregulated the immunoreactivity of tryptophan hydroxylase in the preoptic anterior hypothalamus. The fever induced by IL-1beta was significantly attenuated by pretreatment with intracerebroventricular injection of 5-HT2A receptor antagonists including cyproheptadine, ketanserin, or mianserin. In addition, the IL-1beta-induced fever was mimicked by intracerebroventricular administration of a 5-HT2A receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-amionpropane (DOI). The DOI-induced (present results) or IL-1beta-induced (previous results) fever was further attenuated by pretreatment with an intracerebroventricular dose of mu-opioid receptor antagonists (e.g., buprenorphine or cyclic d-phe-cys-Try-d-Arg-Thr-pen-Thr-NH2) or 5-HT receptor antagonists (e.g., ketanserin or cyproheptadine). These findings suggest that a 5-HT2A-mu opioid receptor mechanism in the hypothalamus may mediate the IL-1beta fever.

Although evidence suggests that 5-HT 2A and muscarinic M1/M4 receptors are implicated in the pathology of schizophrenia, the results are not conclusive. In the present study we tested the hypothesis that binding of 5-HT 2A and M1/M4 receptors is altered in the postmortem brain of schizophrenia subjects. Quantitative autoradiography was employed to measure [ 3 H]ketanserin binding to 5-HT 2A receptors and [ 3 H]pirenzepine binding to both M1 and M4 receptors in Brodmann's area 9 (BA9), caudate/putamen, and the hippocampal formation from six schizophrenic and six control subjects. A significant reduction in the density of 5HT 2A receptors in BA 9 of schizophrenic subjects was observed ( p = 0.036). No significant difference was observed in the density of 5HT 2A receptors in the hippocampus or caudate/putamen between the two groups. No significant changes in the density of M1/M4 receptors was observed in these three regions between the two groups. These findings support a possible involvement of the serotonergic system in the pathology of schizophrenia.

In the present study we examined the effect of prolonged treatment with cocaine (a sensitization and discrimination paradigm) on the expression of serotonin (5-HT) 1B receptors in rat brain structures using a quantitative autoradiographic analysis. To estimate the distribution of 5-HT 1B receptors in several brain coronal sections, we used [ N -methyl- 3 H]GR 125743, a 5-HT 1B/1D receptor antagonist, in the presence of ketanserin (a drug used to block 5-HT 1D receptors). The binding of [ N -methyl- 3 H]GR 125743 in the areas containing dopamine cell bodies (the ventral tegmental area, the substantia nigra) and terminals (the nucleus accumbens shell and core, but not in the caudate-putamen) and in the subiculum of the hippocampus was increased after withdrawal from repeated cocaine in both the discrimination and the sensitization paradigms, either being effective as confirmed by behavioral experiments. Neither acute cocaine injection nor the psychostimulant challenge following its repeated administration affected the binding of [ N -methyl- 3 H]GR 125743 in the above brain areas. Our results indicate that withdrawal from chronic cocaine induces up-regulation of 5-HT 1B receptors in a number of rat brain structures.

One promising strategy to prevent the chronicity of post-operative pain (POP) is to attenuate acute POP during the early phase by efficacious medications with fewer side effects. Duloxetine, one of the serotonin (5-HT)-norepinephrine (NE) reuptake inhibitors (SNRI), is used to treat a wide range of acute and chronic pain. However, its effect on POP has not been investigated. In the present study, we investigated the anti-hypersensitivity effect of duloxetine using a rat model of POP. The possible involvement of spinal 5-HT2A and α2-noradrenergic receptors were also evaluated by using antagonists for 5-HT2A (ketanserin) or α2-noradrenergic receptors (idazoxan). Finally, with the method of in vivo microdialysis, the increase in spinal NA and 5-HT levels after intraperitoneal (i.p.) delivery of duloxetine were investigated. The results showed that intrathecal (i.t.) or i.p. delivery of duloxetine produced an anti-hyperalgesic effect in a dose-dependent manner. The anti-hypersensitivity effect of duloxetine was partly attenuated by pretreatment with ketanserin or idazoxane. Microdialysis study revealed that 5-HT and NA concentrations at the spinal dorsal horn were increased, peaking at 30min after i.p. injection of 20mg/kg duloxetine. These findings indicate that duloxetine inhibits POP by increasing spinal NA and 5-HT levels and activating spinal 5-HT2A or α2-noradrenergic receptors.

A common intronic single nucleotide polymorphism (T102C) in the 5-HT2A receptor gene is associated with the development of different neuropsychiatric symptoms, including hallucinations and depressive symptoms in Alzheimer's disease (AD). Differential 5-HT2A receptor binding has also been associated with the development of these symptoms in AD. However, the relationship between 5-HT2A (T102C) genotype and 5-HT2A receptor binding in AD and control human brains has not been examined. We examined the association between different 5-HT2A (T102C) genotypes and [(3)H] ketanserin binding in the temporal and frontal cortex of 20 AD and 14 control human brains. In homozygotes, but not heterozygotes, there was a significant reduction in B(max) values for [(3)H] ketanserin binding in both areas of cortex in AD compared with control subjects. This study suggests a mechanism for the generation of different neuropsychiatric symptoms in AD from a single nucleotide polymorphism with reduced receptor binding in T102C 5-HT2A receptor gene homozygotes correlating with susceptibility to depressive symptoms, whereas the relative preservation of receptor binding in heterozygotes with AD correlating with susceptibility to hallucinations.

Serotonergic modulation of spontaneous and reflexive blinking was studied in four cats and one monkey. In cats, facial nucleus injections of the type-2 serotonin receptor (5-HT2) antagonist ketanserin tended to increase the latency of the first (R1) and second (R2) components of the blink reflex to supraorbital nerve stimulation. Injections of serotonin tended to increase and of ketanserin, to decrease the duration and amplitude of R2. Serotonin also produced unilateral blepharospasm and hemifacial spasm. In the monkey, the 5-HT2 agonist 2,5-dimethoxy-4-iodoamphetamine increased spontaneous blink frequency while ketanserin decreased both peak blink velocity and spontaneous blink frequency. These findings in cat and monkey indicate that serotonergic innervation of the facial nucleus has a behaviorally important role in modulation of spontaneous and reflexive blinks and suggest that dysfunction of serotonergic systems could be important to the pathophysiology of some cases of blepharospasm.

The present study examined the effect of 5-hydroxytraptamine (5-HT) on the feeding behavior of transgenic mice with neuropeptide Y (NPY) overexpression. Solution of 5-HT (1, 2.5 or 5 mg/kg) was administered intraperitoneally into (1) NPY-overexpressing mice, and (2) wild-type mice with 2-deoxy- d -glucose (2-DG) induced hyperphagia. The NPY-overexpressing mice were further divided into five groups: (1) control mice, (2) mice treated with 5-HT (5 mg/kg), (3) mice treated with 5-HT (5 mg/kg) and ketanserin (0.5 or 1 mg/kg), a 5-HT2A receptor antagonist, (4) mice treated with insulin (1 IU/kg), and (5) mice treated with insulin (1 IU/kg) and 5-HT (5 mg/kg). Food intake and plasma glucose levels were measured. The results showed that 5-HT reduced hyperphagia in both NPY-overexpressing mice and 2-DG-treated mice in dose-dependent manner. Hyperglycemia was induced by 5-HT administration. Ketanserin antagonized the 5-HT induced hypophagia and hyperglycemia. Insulin, on the other hand, prevented 5-HT induced hyperglycemia but not the hypophagic effect. In conclusion, 5-HT reduces hyperphagia in the NPY-overexpressing rat through action on 5-HT2A receptors and this hypophagic effect of 5-HT does not depend on the hyperglycemia.

Serotonergic mechanisms are involved in gender-related behaviors and psychiatric conditions like aggression, eating disorders, depression, impulsivity or suicide. We studied gender differences in the living human brain type-2 serotonin receptor (5HT2r). Twenty-two healthy age-matched men and women were investigated using positron emission tomography and the selective radiotracer, 18F-labeled altanserin. Binding was quantified using a non-linear least-squares minimization procedure. We found significantly higher 5HT2r binding capacity in men than in women, especially in the frontal and cingulate cortices. Distinct liability for men and women to suffer from some psychiatric disorders responding to serotonergic agents may be related to differences in brain serotonin receptors.

In this study, it has been clearly demonstrated that a selective 5-hydroxytryptamine (5-HT) 1A agonist, 8-OH-2-(di- n -propylamino)-tetraline (8-OH-DPAT, 1 μM) significantly inhibited forskolin (10 μM)-stimulated cyclic AMP (cAMP) accumulation in the C6BU-1 cells transfected with 5-HT 1A receptor gene. Further, this 8-OH-DPAT-induced inhibition of forskolin-stimulated activity was significantly attenuated after pre-exposure to 5-HT (10μM) for 12 h. Spiperone (l0μM), a 5-HT 1A and 5-HT 2A antagonist, prevented 5-HT-induced desensitization of 5-HT 1A receptor, but a selective 5-HT 2A receptor antagonist, ketanserin, did not. In addition, pre-exposure to a selective 5-HT 2A agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 10μM), for 24 h did not alter the inhibitory effect of 8-OH-DPAT on forskolin-stimulated cAMP accumulation in these transfected cells, suggesting that prolonged exposure to 5-HT induced 5-HT 1A receptor desensitization, mediated by 5-HT 1A receptor but not 5-HT 2A receptors.

Identification of mechanisms that regulate the number of synapses in the brain has been a key issue for understanding the mechanism of plasticity. Here, we report that the density of synapses can be changed using an antagonist and/or an agonist of serotonin (5-HT) type 2A receptors in the chicken spinal cord. Because of the widespread distribution pattern of 5-HT fibers and 5-HT2A receptors in the central nervous system, 5-HT is thought to play a role in the formation and maintenance of synapses that are involved in normal brain function and mechanism of plasticity.

Affinities and densities of binding sites for the 5HT1A receptor ligand [3H]8-hydroxy(di-n-propylamino)tetralin ([3H]8-OH-DPAT) and the 5HT2 receptor ligand [3H]ketanserin were measured using a rapid filtration assay in crude membrane preparations from frontal cortex and hippocampus of nine cirrhotic patients who died in hepatic encephalopathy and from an equal number of age-matched subjects free from hepatic, neurological or psychiatric disorders. Binding site densities (Bmax) obtained by Scatchard analysis of saturation binding isotherms for [3H]8-OH-DPAT were decreased in frontal cortex (by 56%, P < 0.05) and hippocampus (by 30%, P < 0.05). [3H]ketanserin binding sites were concomitantly increased (by 55%, P < 0.05) in hippocampus of cirrhotic patients. Ligand binding affinities were within normal ranges in all cases. Previous reports have described the accumulation of the 5HT metabolite 5-hydroxyindoleacetic acid and increased activities of the 5HT-metabolizing enzyme MAOA in this same material from patients with hepatic encephalopathy. Taken together, these findings suggest that alterations of serotoninergic function in brain could be responsible for some of the neuropsychiatric symptoms of hepatic encephalopathy observed in humans with chronic liver disease.

The presence and abundance of 5-HT1A and 5-HT2A receptor mRNAs in post mortem human hippocampus was investigated using a novel quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) technique using cyclophilin mRNA as an internal standard. 5-HT1A and 5-HT2A receptor mRNAs were each co-amplified with varying dilutions of cyclophilin primers, and their abundance expressed as a ratio of cyclophilin mRNA. Using this technique in combination with quantitative autoradiography we have investigated the effect of aging on hippocampal 5-HT1A and 5-HT2A receptor mRNA abundance and binding site densities. There was a significant negative correlation between hippocampal 5-HT1A receptor binding site densities and age and a similar trend for 5-HT1A receptor mRNA abundance. Neither 5-HT2A receptor binding site densities nor mRNA abundance were affected by age. Both 5-HT1A and 5-HT2A receptor binding site densities in individual subjects correlated significantly with abundance of their encoding mRNA. This study demonstrates that 5-HT1A and 5-HT2A receptor mRNAs can be measured in small samples of human brain. Combining studies of mRNA with those directed at binding sites will help reveal mechanisms underlying changes in expression of these receptors in various neuropsychiatric disorders.

The central interaction between 5-HT and exogenous and endogenous thyrotropin-releasing hormone (TRH)-induced gastric lesions was investigated in conscious rats. Intracisternal injection (i.c.) of the TRH analog, RX 77368, (2.5 nmol) in indomethacin (2 mg/kg, i.p.)-treated rats produced 1.4 ± 0.1% of gastric corpus mucosal lesions which were aggravated by 30 and 208% by simultaneous i.c. injection 5-HT at 10 and 100 nmol, respectively, whereas i.v. 5-HT (100 nmol) had no effect. The 5- HT 2 1 c antagonist, ketanserin, given i.c. at 10 or 100 nmol reduced by 44 and 76%, respectively, cold restraint stress-induced 3.4 ± 0.6% gastric lesions in indomethacin-pretreated rats whereas, when given i.v. (100 nmol), it was inactive. Ketanserin or 5-HT (100 nmol, i.c.) alone did not modify the gastric mucosa. The present data suggest a potentiating interaction between endogenous 5-HT and TRH which has implication in the understanding of medullary mechanisms involved in gastric lesion formation induced by cold restraint.

The effects of serotonergic anxiolytics on the development of physical dependence on diazepam were examined in mice. Co-administration of buspirone (5-HT1A agonist) or ondansetron (5-HT3 antagonist), but not mianserin (5-HT1C antagonist) or ketanserin (5-HT2 antagonist) with diazepam potentiated the hypersensitivity to FG 7142 following chronic treatment with diazepam. This potentiation was not ascribable to pharmacokinetic interactions between diazepam and buspirone or ondansetron. These results suggest that co-administration of buspirone or ondansetron with diazepam may potentiate the development of physical dependence on diazepam; 5-HT1A and 5-HT3 receptors may be partially involved in the development of physical dependence on diazepam.

The effect of the 10-day dexamethasone administration on serotonin-2 (5-HT2) and beta-adrenergic receptor binding sites was evaluated in rat cerebral cortex and hippocampus. The dexamethasone treatment (1, 2 and 5 mg/kg) significantly increased the density of the 5-HT2 receptor binding sites in a dose-dependent manner, whereas a decreased density of beta-adrenergic receptor binding sites was observed in rat cortex. In contrast, there were no significant differences in the densities of the 5-HT2 or beta-adrenergic receptor binding sites in rat hippocampus using dexamethasone. The results suggest that dexamethasone differentially modulates the 5-HT2 and beta-adrenergic receptor binding sites in rat brain.

Ritanserin (0.5 and 1 mg/kg) and ketanserin (2.5 mg/kg), two antagonists with high affinity for 5-HT2 receptors, attenuated restraint stress-induced hypophagia in rats. Two injections of the 5-HT2 receptor antagonist cinanserin ( 30 nmol 0.5 μ l ) in the paraventricular nucleus of the hypothalamus completely reversed the effect of stress on food intake. (±)Cyanopindolol (3 and 8 mg/kg), an antagonist at 5-HT1A and 5-HT1B receptors, had no effect whereas 8-hydroxy-2-di-n-propylamino) tetralin (30–300 μg/kg), an agonist at 5-HT1A receptors, significantly attenuated the hypophagia. The results suggest that restraint stress-induced hypophagia is mediated by 5-HT2 receptors in the paraventricular nucleus of the hypothalamus. The potential utility of this model in anorexia nervosa is discussed.

Warm ambient temperature facilitates hyperthermia and other neurotoxic responses elicited by psychogenic drugs such as MDMA and methamphetamine. However, little is known about the neural mechanism underlying such effects. In the present study, we tested the hypothesis that a warm ambient temperature may enhance the responsivity of 5-HT(2A) receptors in the central nervous system and thereafter cause an augmented response to 5-HT(₂A) receptor agonists. This hypothesis was tested by measuring changes in body-core temperature in response to the 5-HT(2A) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) administered at four different ambient temperature levels: 12 °C (cold), 22 °C (standard), 27 °C (thermoneutral zone) and 32 °C (warm). It was found that DOI only evoked a small increase in body-core temperature at the standard (22 °C) or thermoneutral ambient temperature (27 °C). In contrast, there was a large increase in body-core temperature when the experiments were conducted at the warmer ambient temperature (32 °C). Interestingly, the effect of DOI at the cold ambient temperature of 12 °C was significantly reduced. Moreover, the ambient temperature-dependent response to DOI was completely blocked by pretreatment with the 5-HT(₂A) receptor antagonist ketanserin. Taken together, these findings support the hypothesis that 5-HT(₂A) receptors may be responsible for some neurotoxic effects of psychogenic drugs in the central nervous system, the activity of which is functionally inhibited at cold but enhanced at warm ambient temperature in contrast to that at standard experimental conditions.

Hallucinogenic drugs, including mescaline, psilocybin and lysergic acid diethylamide (LSD), act at serotonin 5-HT2A receptors (5-HT2ARs). Metabotropic glutamate receptor 2/3 (mGluR2/3) ligands show efficacy in modulating the responses induced by activation of 5-HT2ARs. The formation of a 5-HT2AR-mGluR2 complex suggests a functional interaction that affects the hallucinogen-regulated cellular signaling pathways. Here, we tested the cellular and behavioral effects of hallucinogenic 5-HT2AR agonists in mGluR2 knockout (mGluR2-KO) mice. Mice were intraperitoneally injected with the hallucinogens DOI (2 mg/kg) and LSD (0.24 mg/kg), or vehicle. Head-twitch behavioral response, expression of c-fos, which is induced by all 5-HT2AR agonists, and expression of egr-2, which is hallucinogen-specific, were determined in wild type and mGluR2-KO mice. [(3)H]Ketanserin binding displacement curves by DOI were performed in mouse frontal cortex membrane preparations. Head twitch behavior was abolished in mGluR2-KO mice. The high-affinity binding site of DOI was undetected in mGluR2-KO mice. The hallucinogen DOI induced c-fos in both wild type and mGluR2-KO mice. However, the induction of egr-2 by DOI was eliminated in mGlu2-KO mice. These findings suggest that the 5-HT2AR-mGluR2 complex is necessary for the neuropsychological responses induced by hallucinogens.

3N-(2′-[ 18 F]Fluoroethyl)benperidol ([ 18 F]FEB) an 18 F-labeled analogue of the D 2 antagonist benperidol, was evaluated as a tracer for positron emission tomography (PET). PET imaging of a living baboon showed that the fluorinated ligand rapidly localized in vivo within D 2 receptor-rich brain tissue, with selective retention lasting over 2 h after tracer injection. Pretreatment of the animal with unlabeled D 2 -specific antagonist eticlopride (4 mg/kg, i.v.) 1 h before [ 18 F]FEB completely abolished the selective disposition of the radioligand, whereas the regional cerebral blood flow, blood volume and peripheral metabolism/protein binding of [ 18 F]FEB were not changed. Tracer localization when the baboon was pretreated with unlabeled ketanserin (0.55 mg/kg, i.v.) or SCH 23390 (1.1 mg/kg, i.v.) was identical to that for the control case, indicating that the [ 18 F]FEB did not bind to S 2 of D 1 receptors in vivo. [ 18 F]FEB has advantages compared to previously used PET tracers, and may be an excellent radioligand for non-invasive study of D 2 receptor binding.

This study assessed the effects of a serotonin (5-HT)1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and a 5-HT2 antagonist ketanserin on fully kindled seizures from the hippocampus. 8-OH-DPAT produced a marked suppression in hippocampal kindled seizures, while producing behavioral signs similar to those seen in the 5-HT syndrome. Although DOI and ketanserin did not affect kindled focal epileptic activity, DOI shortened and ketanserin prolonged the latency to onset of generalized convulsions. Our data suggest that 5-HT1A receptors play an inhibitory role in the generation of hippocampal seizures, whereas 5-HT2 receptors may participate in kindled seizure generalization from this region.

In decerebrate, paralyzed, vagotomized and artificially ventilated cats, serotonin (5-HT) and its analogues, microinjected into the hypoglossal (XII) motor nucleus, altered the activity of the genioglossal branch of XII nerve. 5-HT, carboxamidotryptamine malcate (5-CT) and DOI (1–5 mM) increased the activity by over 200%. Methysergide reversed this increase. Methysergide, mianserin, or ketanserin (100–250 nl, 1 mM) reduced the spontaneous hypoglossal activity by 20–50%. Buspirone, 8-OH-DPAT and (−)-propranolol were without effect. Thus, 5-HT provides a substantial tonic excitatory drive to XII motoneurons. The 5-HT receptors involved are likely to be type 1C or 2, but uncertainty regarding the affinity profiles of the drugs used in in vivo conditions in the cat precludes a definite identification.

Serotonin (5HT), a major platelet secretory product, has been shown to suppress CNS function in vivo. As part of an ongoing project to study interactions between neuron and platelet, we used organotypic explant cultures of rat spinal cord to study if 5HT had a morphologically demonstrable neurotoxic effect. The results suggest that serotonin may be neurotoxic, and that this effect may be prevented by ketanserin, a specific 5HT2 antagonist. Related experiments, using acetylcholinesterase (AChE) enzyme activity as a biochemical parameter, indicate that 5HT hastens the decline of enzyme activity. The concentrations of 5HT at which neurotoxicity was demonstrated were comparable to the calculated 5HT concentration potentially present in the vicinity of an acute cerebral thrombus. These findings could provide new insight into the mechanism of ischemic neuronal injury.

Various receptor ligands were investigated for their effects on the uptake of the antiepileptic drug valproic acid (VPA) in primary astroglial cultures from cerebral cortex of neonatal rats. After stimulation with the α 1 -adrenoceptor agonist phenylephrine, 5-hydroxytryptamine (5-HT) or the glutamate receptor agonists glutamate, quisqualate and kainate, the V max and K m values for the drug transport increased. On the contrary, after exposure to the α 2 -adrenoceptor agonist clonidine, V max and K m decreased. The effects were reversed in comparison to the control level in the presence of selective receptor antagonists. The data indicate a specific coupling between receptors and the uptake system for VPA. Furthermore, the results may have significant implications, as they suggest that receptors on astrocytes can be involved in the local regulation of drug transport in brain.

We studied binding of [ 125 I]SCH 23982 in two regions of human brain, the caudate and the dorsolateral prefrontal cortex. Binding characteristics of [ 125 I]SCH 23982 and of the non-iodinated tritiated analogue, [ 3 H]SCH 23390, were compared. In caudate, binding of [ 125 I]SCH 23982 was consistent with binding to D 1 dopamine receptors while in frontal cortex, [ 125 I]SCH 23982 bound mostly to serotonergic 5HT 2 receptors. In contrast to [ 3 H]SCH 23390, no evidence of binding of [ 125 I]SCH 23982 to D 1 receptors could be found in human frontal cortex. This indicates that iodination of SCH 23390 induces a decrease in its relative D 1 verus 5HT 2 selectivity that prohibits the use of [ 125 I]SCH 23982 to label D 1 receptors in human cortex.

N-omega-[18F]fluoroethylketanserin ([18F]FEK), an 18F-labeled analogue of the serotonin S2 antagonist ketanserin, was evaluated for use with positron emission tomography (PET). PET imaging of a baboon brain following injection of [18F]FEK indicated that the fluorinated ligand rapidly localized in vivo within S2 receptor-rich tissues (frontal cortex/cerebellum radioactivity ratio = 2.5 after 15 min), and selective localization was retained for as long as 3 h post injection. Pretreatment with unlabeled ketanserin (15 mg/kg, i.v.) 1 h prior to [18F]FEK completely abolished selective localization of the radiotracer, whereas regional cerebral blood flow, cerebral blood volume, and the free fraction of [18F]FEK in arterial blood were unaltered. [18F]FEK has several advantages compared to previously used PET radiopharmaceuticals, and may be an excellent radioligand for non-invasive evaluation of S2 binding in vivo.

The interaction between thyrotropin-releasing hormone (TRH) and methysergide (MeSG) on reflex activity was examined in spinal cords from neonatal rats. MeSG depressed the monosynaptic reflex (MSR) by nearly 90% at 0.03 μM but had no effect on the dorsal root reflex at 0.003–3.0 μM. Neither spiperone, ketanserin, cyproheptadine nor ICS 205–930 (3-tropanyl-indole-3-carboxylate) depressed the MSR nor did they affect the potentiation elicited by TRH. TRH reversed the depression of the MSR by MeSG in a concentration-dependent manner without affecting the dorsal root reflex. MeSG-induced depression of the MSR was also reversed by 3,4-diaminopyridine which simultaneously increased the magnitude and duration of both reflexes. It appears that neither MeSG-induced depression nor TRH-induced potentiation of the MSR involves the spinal serotonergic system or blockade of K + channels.

The level of cyclic AMP in NCB-20 cells was increased by serotonin (5-HT), 5-methoxytryptamine and 2-methyl-5-HT with EC 50 of 0.5 ± 0.1, 1.0 ± 0.1, 10 ± 0.1 μ M, respectively. The 5-HT-mediated increase of cyclic AMP content was completely blocked by metergoline but unaffected by 5-HT 3 antagonists, ICS 205–930, MDL 72222, quipazine and 5-HT 2 antagonist, ketanserin. Putative 5-HT 1A agonists (8-OH-DPAT, ipsapirone, and buspirone) and 5-HT 1B agonists (TFMPP and m -CPP) affected neither basal nor forskolin-dependent cyclic AMP accumulation. Receptor binding studies suggest that NCB-20 cells are devoid of 5-HT 1A and 5-HT 1B receptor sites. Application of 5-HT onto NCB-20 cells resulted in membrane depolarization by an evoked inward current which displayed rapid desensitization. 5-HT-mediated current had a reversal potential around 0 mV and was potently and reversibly inhibited by ICS 205–930. Our data suggest that in NCB-20 cells the 5-HT 3 receptor is involved in the generation of inward currents, while the 5-HT receptor coupled to adenylate cyclase does not seem to correspond to any of the known receptor subtypes.

Adult hippocampal neurogenesis is reported to be a target of antidepressants, drugs of abuse and animal models of depression, suggesting a role for this form of structural plasticity in psychopathology. Serotonergic neurotransmission, which is implicated in several psychiatric diseases, has been reported to regulate adult hippocampal neurogenesis. Amongst the serotonergic receptors, the serotonin2A/2C (5-HT2A/2C) receptors play an important role in the actions of antidepressants and the effects of hallucinogenic drugs of abuse. We have used the mitotic marker 5'-bromo-2-deoxyuridine to address the effects of the 5-HT2A/2C receptors on the proliferation of adult hippocampal progenitors following acute or chronic treatment with the hallucinogenic partial agonists, (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and lysergic acid diethylamide (LSD) and the antagonist, Ketanserin. Acute, and chronic, DOI and LSD treatments induced a strong behavioral activation, but did not alter adult hippocampal progenitor proliferation. In striking contrast, Ketanserin treatment resulted in a biphasic regulation with a significant decline (22%) in progenitor proliferation following a single treatment, and a robust increase (46%) observed following chronic administration. These results indicate that hallucinogenic drugs that primarily target the 5-HT2A/2C receptors, in contrast to other drugs of abuse, may not alter adult hippocampal neurogenesis. In addition, our results that enhanced adult hippocampal progenitor proliferation results from a sustained blockade of the 5-HT2A/2C receptors suggest that the 5-HT2A/2C receptors may be an important target for the neurogenic effects of antidepressant treatment.

Involvement of 5-hydroxytryptaminergic (5-HT) system for aglycemia- and ischemia-induced depression of the spinal reflexes was evaluated. The monosynaptic (MSR) and polysynaptic (PSR) reflex potentials were elicited in the ventral root by stimulating the corresponding dorsal root in an isolated spinal cord from neonatal rat. Superfusion of aglycemic (glucose-free) or ischemic (glucose- and O(2)-free) solution produced a time-dependent depression of the spinal reflexes and abolished them within 35 min. The time required to produce 50% depression of the reflexes (T-50) was around 19 and 13 min for aglycemia and ischemia, respectively. Spiperone (5-HT(2A) antagonist) and ketanserin, (5-HT(2A/2C) antagonist) blocked the aglycemia-induced depression of the reflexes completely while ondansetron (5-HT(3) antagonist) attenuated it partially (as abolition times were around 50 min). Ischemia-induced depression was blocked up to 50 min by ketanserin or ondansetron but not by spiperone. In the presence of ketanserin or ondansetron, the reflexes were abolished by 60 min while in spiperone the reflexes were abolished by 30 min. In 5,7-dihydroxytryptamine treated rats, aglycemia depressed the reflexes by 45 min (greater than control, P

Effects of leptin on milk consumption in food-deprived mice were investigated. In this feeding model, systemic administration of leptin reduced milk intake of mice dose-dependently. Decreases in milk intake elicited by leptin were significantly reduced by the serotonin (5-HT) synthesis inhibitor p-chlorophenylalanine (PCPA). The suppressive effects of leptin on milk intake were antagonized by the 5-HT 2B/2C receptor antagonist SB206553, while the 5-HT 1B receptor antagonist GR55562 and the 5-HT 2A receptor antagonist ketanserin did not affect it. Our results indicated that the 5-HT depleter PCPA and the 5-HT 2B/2C receptor antagonist SB206553 attenuated leptin-induced suppression of milk intake. Therefore, leptin-induced hypophagic effects may be mediated by enhancement of serotonergic neurons, resulting in activation of the 5-HT 2B/2C receptor.

Modulation of the serotonin (5HT) system via 5HT1A or 5HT2A receptors exerts a neuroprotective effect on delayed neuronal death after transient forebrain ischemia. We tested the hypothesis that a 5HT1A agonist (Ipsapirone) in combination with a 5HT2A receptor antagonist (Ketanserin) could improve the neuroprotection. Starting 15 min prior to transient forebrain ischemia in the gerbil model, different doses of Ipsapirone (1, 2, 3 mg) and Ketanserin (5 mg/kg) were applied intraperitoneally. Seven days after ischemia, surviving pyramidal cells of the CA1 sector of the hippocampus were counted. The significance of the differences between the means was assessed by an analysis of variance according to the Scheffe test. The hippocampal cell damage was analyzed by histological evaluation. Combined application of Ipsapirone and Ketanserin led to a dose-dependent additive effect with up to 83% preservation of hippocampal CA1 neurons (P

Clozapine is an atypical antipsychotic with high affinity for several serotonin receptors. This drug causes paradoxical downregulation of 5-hydroxytryptamine(2A) (5-HT)(2A) receptors, but its modulation of other serotonin receptors has not been studied. We examined the effects of clozapine and several other drugs on the regulation of rat 5-HT(6) and 5-HT(7) receptors individually expressed in transfected HeLa cells. Both 5-HT(6) and 5-HT(7) receptor densities (B(max)) were reduced by 5-carboxamidotryptamine, an agonist, and methiothepin, an inverse agonist. Clozapine reduced 5-HT(6) B(max). This suggests that 5-HT(6) receptors are also paradoxically downregulated by the antagonist clozapine. 5-Hydroxytryptamine(7) receptor B(max), on the other hand, was increased by clozapine. Clozapine's modulation of the 5-HT(6) and 5-HT(7) receptor levels may be important in the action of this atypical antipsychotic.

Modulation of central 5-HT receptor sensitivity is implicated in the therapeutic response to electroconvulsive shock (ECS). Altered 5-HT receptor expression may play a role in this process. We have measured the mRNAs encoding 5-HT1A, 5-HT2A, 5-HT2C and 5-HT7 receptors, and the 5-HT transporter, in rat brain after single ECS, repeated ECS, and 3 weeks after repeated ECS. Hippocampal 5-HT1A receptor mRNA was decreased in CA4 and increased in dentate gyrus by single or repeated ECS, with parallel alterations in [3H]8-OH-DPAT binding site densities. Repeated ECS increased cortical [3H]ketanserin binding and 5-HT2A receptor mRNA. The other mRNAs were unchanged. The results show that ECS has subtype specific, anatomically discrete, and temporally selective effects on 5-HT receptor expression.

Serotonin (5-HT) may inhibit glutamate release in the dorsal facial area (DFA) of the medulla and decrease common carotid arterial (CCA) blood flow. We attempted to clarify which subtype(s) of 5-HT receptor was involved. A microdialysis probe was inserted in DFA. The concentration of glutamate in dialysates were determined by chromatography. Glutamate concentration was dose-dependently decreased by perfusion of 5-HT or DOI, a 5-HT2 agonist, but not by 5-CT, a 5-HT1 agonist. The 5-HT-induced decrease in glutamate was reversed by co-perfusion of ketanserin, a 5-HT2 antagonist, but not by propranolol, a 5-HT1 antagonist. CCA blood flow was decreased when 5-HT or DOI was perfused, and was reversed by co-perfusing ketanserin. In conclusion, 5-HT may inhibit glutamate release via 5-HT2 receptor in DFA, resulting in the reduction of CCA blood flow.

Microinjection of serotonin and 5-hydroxytryptamine 2 (5-HT 2) agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) in nucleus ambiguus caused excitation of posterior cricoarytenoid (PCA) muscles of the larynx in anesthetized, spontaneously breathing cats. Intravenous administration of 5-HT 2 antagonist ketanserin produced complete block of excitatory effect of DOM injection. Electrical stimulation of nucleus raphe pallidus caused excitation of PCA activity, that was blocked by pretreatment of ketanserin. These results indicate that serotonergic cells in the-raphe pallidus provide tonic drive to medullary PCA motoneurons through 5-HT 2 receptors.