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Recently, studies have demonstrated that serotonin type 7 receptors (5-HT7) have conflincting effects on neuronal excitability in different brain regions. However, the effect of 5-HT7 on seizures has not been exactly elucidated yet. Therefore, our aim in this study was to investigate the effects of 5-HT7 antagonist SB-269970 on pentylenetetrazole (PTZ) induced fully kindled rats. In the study, 32 adult male Wistar Albino rats (weighing 220–260 g) were used. Rats were injected with PTZ (35 mg/kg) intraperitoneally every other day to generate kindling model. 5-CT (0.1 mg/kg) and SB-269970 (1 mg/kg) were administered 30 min before acute seizure induction with PTZ (35 mg/kg). Seizure stages were determined according to the Racine scale. After electrocorticography (ECoG) recordings of seizure-induced rats were obtained, the animals were sacrificed by decapitation. The hippocampal GABA levels were determined by ELISA kit and the number of c-Fos positive neurons in the hippocampal dentate gyrus (DG), CA1 and CA3 areas were measured by immunohistochemical method. The results showed that SB-269970 reduced the number of spikes, percent seizure duration and duration of generalized tonic-clonic seizures (dGTCS), while increasing the onset time of generalized tonic-clonic seizures (oGTCS). The hippocampal GABA levels were significantly increased in the SB-269970 group compared with the PTZ group. In addition, SB-269970 reduced the number of c-Fos positive cells in hippocampal CA1 area. 5-HT7 antagonist SB-269970 displays anticonvulsant effects on PTZ-induced seizures in fully kindled rats and these effects may be related to GABAergic activity in the hippocampus. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is one of the most common types of cancer seen among men worldwide. Previous studies have demonstrated that serotonin regulates cell proliferation, migration, and invasion in vitro; the presence of 5-HT receptors in cancer cells; and the role of serotonin in tumor development. The most recently discovered of these receptors is 5-HT7 but also least characterized receptors of serotonin. The aim of this study is to investigate the existence and possible role of 5-HT7 receptors in healthy and cancerous prostate tissues and also investigate effects of receptor agonists and antagonists on PC-3 cells to evaluate potential therapeutic effects. PC-3 cells were cultured and effects of 5-HT7 receptor agonist (LP-44) and antagonist (SB-269970) were evaluated on these cells. After proliferation analyses, relative expression of apoptotic markers and 5-HT7 receptor mRNA expression levels were determined through real-time PCR. Annexin V-FITC/PI double staining and Hoechst 33258 staining assay methods were applied to determine apoptosis. Additional PCR studies were performed on healthy and cancerous prostate tissue to see existence of receptors in human samples. The viability of PC-3 cells was decreased by SB-269970 after 48 and 72 h of incubation. However, LP-44 increased PC-3 cell proliferation at all time points. In 10-6 M SB-269970 treated PC-3 cells, there was significant increase in the expression of CAS-3 (4-fold), CAS-9 (2.5-fold), BAX (1.9-fold), and Tp-53 (4.8-fold) gene mRNA levels when compared to non-treated control group. Conversely, there was a significant decrease in NF-κB (2.9-fold) and 5-HT7 receptor (3.6-fold) mRNA expression in cells treated with SB-269970 when compared to control. SB-269970 that antagonized 5-HT7 receptors also induced apoptosis in Annexin V-FITC/PI double staining assay and Hoechst 33258 staining assays when compared with other groups. In human samples, 5-HT7 receptor mRNA expression was approximately 200-fold higher than that of heathy ones. In this study, for the first time, the 5-HT7 receptor antagonist SB-269970 has been shown to inhibit proliferation in PC-3 cells and to be associated with an apoptosis-inducing effect. These results suggest blocking 5-HT7 receptors can be a novel therapeutic target for the treatment of prostate cancer. [ABSTRACT FROM AUTHOR]

Abstract 5-HT 7 receptors have been suggested to play a role in the regulation of psychiatric disorders. The experimental literature however is not fully consistent on this possibility. Two selective 5-HT 7 receptor antagonists, DR-4004 and SB-269970, were evaluated in mouse models used to detect drugs used to treat anxiety, depression, or schizophrenia. A 5-HT-induced hypothermia assay was used to define the doses of DR-4004 and SB-269970 predicted to impact 5-HT 7 receptors in the brain in vivo. 5-HT produced hypothermia in wildtype mice by either i.p. or i.c.v. routes but did not in 5-HT 7 receptor knockout mice. 5-HT-induced hypothermia was not attenuated by drugs selectively blocking alpha1 or 5-HT 1A receptors. Doses of DR-4004 and SB-269970 that blocked 5-HT-induced hypothermia, did not display significant anxiolytic-like (elevated plus maze; vogel conflict) or antidepressant-like efficacy (tail-suspension test) in mouse models. These compounds did demonstrate some antipsychotic-like properties in the PCP-induced hyperactivity assay and anxiolytic/anti-stress effects in the stress-induced cGMP assay. Negative findings were substantiated by positive control drugs that were active in each assay system. We conclude that 5-HT-induced hypothermia can be used to estimate blockade of central 5-HT 7 receptors. Effects of DR-4004 and SB-269970 in animal models are generally consistent with the experimental literature that the evidence is mixed or not robust regarding the potential efficacy of 5-HT 7 receptor antagonism in the treatment of anxiety, depression, or schizophrenia. [ABSTRACT FROM AUTHOR]

Rationale: The effect of atypical antipsychotic drugs (AAPDs), e.g., lurasidone, to improve cognitive impairment associated with schizophrenia (CIAS), has been suggested to be due, in part, to enhancing release of dopamine (DA), acetylcholine (ACh), and glutamate (Glu) in cortex and hippocampus.Results: The present study found acute lurasidone reversed the cognitive deficit in novel object recognition (NOR) in subchronic (sc) phencyclidine (PCP)-treated mice, an animal model for CIAS. This effect of lurasidone was blocked by pretreatment with the 5-HT1AR antagonist, WAY-100635, or the 5-HT7R agonist, AS 19. Lurasidone significantly increased medial prefrontal cortex (mPFC) ACh, DA, and Glu efflux, all of which were blocked by WAY-100635, with similar effects in the dorsal striatum (dSTR), except for the absence of an effect on Glu increase. AS 19 inhibited Glu, but not DA efflux, in the dSTR. The selective 5-HT7R antagonist, SB-26970, increased mPFC DA, 5-HT, Glu, and, importantly, also GABA efflux and striatal DA, NE, 5-HT, and Glu efflux, indicating tonic inhibition of the release of these neurotransmitters by 5-HT7R stimulation. These results provide new evidence that GABA release in the mPFC is tonically inhibited by 5-HT7R stimulation and suggest that a selective 5-HT7R antagonist might be clinically useful to enhance cortical GABAergic release. All SB-269970 effects were blocked by AS 19 or WAY-100635, suggesting 5-HT1AR agonism is necessary for the release of these neurotransmitters by SB-269970. Lurasidone increased ACh, DA, and NE but not Glu efflux in mPFC and dSTR DA and Glu efflux in 5-HT7 KO mice.Conclusion: We conclude that lurasidone-induced Glu efflux in mPFC requires 5-HT7R antagonism while its effects on cortical ACh and DA efflux are mainly due to 5-HT1AR stimulation. [ABSTRACT FROM AUTHOR]

The neurotransmitter 5-hydroxytryptamine (5-HT) is involved in regulation of local tissue inflammation and repair through a set of receptors (5-HT1-7 receptors), which are expressed in the lung. Considering the protective importance of 5-HT receptor antagonists against development of pulmonary fibrosis, we evaluated whether 5-HT7 receptor antagonist (SB-269970) modulates lung inflammatory and fibrogenic processes in comparison with 5-HT2A/B receptor antagonist (terguride), in bleomycin (BLM)-induced idiopathic pulmonary fibrosis (IPF) model. IPF model induced by a single dose of intra-tracheal BLM instillation (5 mg/kg), and rats were treated with intraperitoneal injection of SB-269970 (1 mg/kg day) or terguride (1.2 mg/kg/d). The experiment was carried out on two separate sets of rats that were killed at day 7th and day 21st to evaluate the endpoint of the IPF inflammatory and fibrogenic phases, respectively. During the inflammatory phase 5-HT2A/B and 5-HT7 receptor antagonists attenuated the BLM-induced increase in the lung fluid content, the inflammatory cytokines levels and oxidative stress burden. In the fibrogenic phase, both SB-269970 and terguride reduced the serotonin concentrations in lung homogenates and significantly protected against IPF fibrogenic phase by attenuating collagen deposition and mRNA expression of both transforming growth factor-β1 (TGF- β1), and procollagen type Ӏ (PINP). 5-hydroxytryptamine 5-HT7 receptor antagonist showed more benefits than 5-HT2A/B receptor antagonist on the deleterious effects accompanied BLM instillation. The present study showed involvement of 5-HT7 receptor in the pathophysiology of BLM-induced IPF in rats and identified it as a potential therapeutic target in lung fibrotic disorders. [ABSTRACT FROM AUTHOR]

A series of 39 arylsulfonamide/amide derivatives of (aryloxy)ethyl alkyl amines, was designed with the support of the Virtual Combinatorial Library-Virtual Screening protocol, and synthesized using solid-phase methodologies. Representative compounds were biologically evaluated for their affinity for 5-HT 7 Rs and for their selectivity over related 5-HTRs (5-HT 1A Rs, 5-HT 2A Rs, 5-HT 6 Rs), dopamine D 2 Rs and adrenergic α 1 Rs. The study identified the derivatives 27 (3-fluoro-N-{1-[2-(2-cyclopentylphenoxy)ethyl]piperidin-4-yl}-benzenesulfonamide; PZ-1417) and 35 (4-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}-8-azabicyclo[3.2.1]octan-3-yl)-benzenesulfonamide; PZ-1150) as being potent 5-HT 7 R antagonists with antidepressant and anxiolytic properties in the forced swim test (0.625–5 mg/kg and 0.625 mg/kg, respectively), the tail suspension test (0.625 mg/kg and 0.625 mg/kg, respectively), and in four plate test (0.625 mg/kg and 1.25–2.5 mg/kg, respectively) in mice. It has to be stressed that new compounds displayed higher activity than that of SB-269970, a reference 5-HT 7 R antagonist. Finally, the study provided valuable insight into the development of potential therapeutic agents for the treatment of CNS disorders. [ABSTRACT FROM AUTHOR]

The antagonists of serotonin 5-HT7 receptors have been demonstrated to ameliorate cognitive impairments in pharmacological animal models of schizophrenia that involve blockade of N-methyl- d -aspartate receptors (NMDARs). The administration of NMDAR antagonists evokes a broad range of cognitive deficits, including a loss of impulse control. The involvement of 5-HT7 receptors in the modulation of impulsivity has been recently suggested but has not been studied in great detail. The aim of the present study was to examine the effect of a selective 5-HT7 receptor antagonist SB-269970 on a measure of impulsive action, i.e., premature responding on the five-choice serial reaction time task (5-CSRTT) in rats. The antagonist of 5-HT2A receptor M100,907 was used as a positive control. The efficacies of both compounds were assessed in conditions of increased impulsivity that were produced by the administration of the NMDAR antagonist MK-801 or/and non-drug stimuli, i.e., using variable inter-trial intervals (vITIs). To examine the general ability of SB-269970 to counteract the MK-801-induced impairments, a discrete paired-trial delayed alternation task in a T-maze was employed. MK-801 significantly increased the number of premature responses in 5-CSRTT, and this effect was abolished by the administration of M100,907 (0.5 mg/kg) and SB-269970 (1 mg/kg). In addition, M100,907, but not SB-269970, reduced premature responding in the prolonged ITI trials. Both M100,907 and SB-269970 attenuated MK-801-induced working memory impairment in a T-maze. The present study demonstrated the efficacy of SB-269970 against MK-801-induced premature responding in the 5-CSRTT. This anti-impulsive action may offer additional benefits to the cognitive-enhancing effects of pharmacological blockade of 5-HT7 receptors. [ABSTRACT FROM AUTHOR]

Background: Serotonin exhibits a vast repertoire of actions including cell proliferation and differentiation. The effect of serotonin, as an incomplete mitogen, on liver regeneration has recently been unveiled and is mediated through 5-HT2 receptor. The aim of the present study was to investigate the effect of 5-HT7 receptor blockade on liver regeneration after partial hepatectomy. Methods: Male Wistar rats were subjected to 60-70% partial hepatectomy. 5-HT7 receptor blockade was applied by intraperitoneal administration of SB-269970 hydrochloride two hours prior to and sixteen hours after partial hepatectomy and by intraperitoneal administration of SB-258719 sixteen hours after partial hepatectomy. Animals were sacrificed at different time points until 72 h after partial hepatectomy. Liver regeneration was evaluated by [3H]-thymidine incorporation into hepatic DNA, the mitotic index in hematoxylin-eosin (HE) sections and by immunochemical detection of Ki67 nuclear antigen. Reversion of 5-HT7 blockade was performed by intraperitoneal administration of AS-19. Serum and liver tissue lipids were also quantified. Results: Liver regeneration peaked at 24 h ([3H]-thymidine incorporation into hepatic DNA and mitotic index by immunochemical detection of Ki67) and at 32 h (mitotic index in HE sections) in the control group of rats. 5-HT7 receptor blockade had no effect on liver regeneration when applied 2 h prior to partial hepatectomy. Liver regeneration was greatly attenuated when blockade of 5-HT7 receptor was applied (by SB-258719 and SB-269970) at 16 h after partial hepatectomy and peaked at 32 h ([3H]-thymidine incorporation into hepatic DNA and mitotic index by immunochemical detection of Ki67) and 40 h (mitotic index in HE sections) after partial hepatectomy. AS-19 administration totally reversed the observed attenuation of liver regeneration. Conclusions: In conclusion, 5-HT7 receptor is a novel type of serotonin receptor implicated in hepatocyte proliferation. [ABSTRACT FROM AUTHOR]

Abstract: In the search for a novel serotonin 7 (5-HT7) receptor PET radioligand we synthesized and evaluated a new series of biphenylpiperazine derivatives in vitro. Among the studied compounds, (R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol ((R)-16), showed the best combination of affinity, selectivity, and lipophilicity, and was thus chosen for carbon-11 labelling and evaluation in pigs. After intravenous injection, [11C](R)-16 entered the pig brain and displayed reversible tracer kinetics. Pretreatment with the 5-HT7 receptor selective antagonist SB-269970 (1) resulted in limited decrease in the binding of [11C](R)-16, suggesting that this radioligand is not optimal for imaging the brain 5-HT7 receptor in vivo but it may serve as a lead compound for the design of novel 5-HT7 receptor PET radioligands. [Copyright &y& Elsevier]

Abstract: The effects of SB-269970, a selective 5-HT7 receptor antagonist, on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. The 5-HT7 receptor ligand was microinjected into the horizontal limb of the diagonal band of Broca (HDB) and the laterodorsal tegmental nucleus (LDT) during the light period of the 12-h light/12-h dark cycle. For comparative purposes the compound was administered systemically and, in addition, injected directly into the dorsal raphe nucleus (DRN). Microinjection of SB-269970 into the HDB and the DRN induced a significant reduction of rapid-eye-movement sleep (REMS). Similar effects were observed after systemic administration of the 5-HT7 receptor antagonist. On the other hand, local infusion of the compound into the LDT provoked the opposite effect. It is proposed that the deactivation of GABAergic cells located in the HDB, DRN and LDT is responsible for the changes induced by SB-269970 on REM sleep values. It is suggested that the antidepressant effect of the 5-HT7 receptor antagonist could partly depend on the involvement of neuronal systems located in the DRN and the HDB. [Copyright &y& Elsevier]

Abstract: This study assessed the role of systemic and spinal 5-HT7 receptors on rats submitted to spinal nerve injury. In addition, the 5-HT7 receptors level in dorsal root ganglion and spinal cord was also determined. Tactile allodynia was induced by L5/L6 spinal nerve ligation. Systemic (0.01–10mg/kg) or spinal (0.3–30μg) administration of the selective 5-HT7 receptor antagonist SB-269970 but not vehicle reduced in a dose-dependent manner established tactile allodynia. This effect was maintained for about 6h. SB-269970 was more potent and effective by the spinal administration route than through systemic injection. Spinal nerve ligation reduced expression of 5-HT7 receptors in the ipsilateral but not contralateral dorsal root ganglia. Moreover, 5-HT7 receptor levels were lower in the ipsilateral dorsal spinal cord of neuropathic rats compared to naïve and sham rats. No changes in the receptor levels were observed in the contralateral dorsal spinal cord and in both regions of the ventral spinal cord. Data suggest that spinal 5-HT7 receptors play a pronociceptive role in neuropathic rats. Results also indicate that spinal nerve injury leads to a reduced 5-HT7 receptors level in pain processing-related areas which may result from its nociceptive role in this model. Data suggest that selective 5-HT7 receptor antagonists may function as analgesics in nerve injury pain states. [Copyright &y& Elsevier]

Abstract: The 5-HT7 receptor has been suggested as a target for treating depression since inactivation or blockade of the receptor has an antidepressant-like behavioral effect. The present study investigated possible interactions between various classes of drugs with antidepressant properties and blockade or inactivation of the 5-HT7 receptor. Immobility despair in the tail suspension test and the forced swim test was evaluated in mice lacking the 5-HT7 receptor (5-HT7 −/−) and in wild-type controls (5-HT7 +/+) following acute drug treatments. Citalopram, a selective serotonin reuptake inhibitor and widely used antidepressant, dose-dependently reduced immobility in the tail suspension test in both 5-HT7 +/+ and 5-HT7 −/− mice. Combining doses of citalopram and the 5-HT7 receptor antagonist SB-269970 that by themselves did not affect behavior, reduced immobility in 5-HT7 +/+ mice in both the tail suspension test and the forced swim test. No effect was seen in 5-HT7 −/− mice. Desipramine and reboxetine, two norepinephrine reuptake inhibitors, dose-dependently reduced immobility in the tail suspension test in 5-HT7 +/+ mice, but had no effect in 5-HT7 −/− mice. A synergistic effect between desipramine and SB-269970 was found in both behavioral tests in 5-HT7 +/+ mice. Reboxetine combined with SB-269970 had effect only in the forced swim test. GBR 12909, a dopamine reuptake inhibitor, dose-dependently reduced tail suspension test immobility in both genotypes. There was no interaction between GBR 12909 and SB-269970. Aripiprazole, an antipsychotic, reduced immobility in both tests in 5-HT7 +/+ mice, but not in 5-HT7 −/− mice. The results show that the 5-HT7 receptor is required for the observed interaction between this receptor and antidepressants such as citalopram. The data furthermore support the hypothesis that the 5-HT7 receptor might be a suitable target for treating depression. [Copyright &y& Elsevier]

• Long-term exposure to isoflurane anesthesia induced memory impairment and upregulation of 5-HT 7 R in the hippocampus of mice. • Prior activation of 5-HT 7 R with selective agonist LP-211 fails to alleviate the anesthesia-induced memory impairment. • Prior blockade of 5-HT 7 R with selective antagonist SB-269970 can alleviate the anesthesia-induced memory impairment. • SB-269970 pretreatment probably protected anesthesia-induced memory impairment via its action on the gene expression of Slc6a11, Itpka, Arf3, Srcin1, and Epb41l2, and the synapse organization process in hippocampus of mice. General anesthesia is widely utilized in the clinic for surgical and diagnostic procedures. However, growing evidence suggests that anesthetic exposure may affect cognitive function negatively. Unfortunately, little is known about the underlying mechanisms and efficient prevention and therapeutic strategies for the anesthesia-induced cognitive dysfunction. 5-HT 7 R, a serotonin receptor family member, is functionally associated with learning and memory. It has recently become a potential therapeutic target in various neurological diseases as its ligands have a wide range of neuropharmacological effects. However, it remains unknown the role of 5-HT 7 R in the long-term isoflurane anesthesia-induced memory impairment and whether prior activation or blockade of 5-HT 7 R before anesthesia has modulating effects on this memory impairment. In this study, 5-HT 7 R selective agonist LP-211 and 5-HT 7 R selective antagonist SB-269970 were pretreated intraperitoneally to mice before anesthesia; their effects on the cognitive performance of mice were assessed using fear conditioning test and novel object recognition test. Furthermore, the transcriptional level of 5-HT 7 R in the hippocampus was detected using qRT-PCR, and proteomics was conducted to probe the underlying mechanisms. As a result, long-term exposure to isoflurane anesthesia caused memory impairment and an increase in hippocampal 5-HT 7 R mRNA expression, which could be attenuated by SB-269970 pretreatment but not LP-211pretreatment. According to the proteomics results, the antiamnestic effect of SB-269970 pretreatment was probably attributed to its action on the gene expression of Slc6a11, Itpka, Arf3, Srcin1, and Epb41l2, and synapse organization in the hippocampus. In conclusion, 5-HT 7 R is involved in the memory impairment induced by long-term isoflurane anesthesia, and the prior blockade of 5-HT 7 R with SB-269970 protects the memory impairment. This finding may help to improve the understanding of the long-term isoflurane anesthesia-induced memory impairment and to construct potential preventive and therapeutic strategies for the adverse effects after long-term isoflurane exposure. [ABSTRACT FROM AUTHOR]

Abstract: The effects of LP-44, a selective 5-HT7 receptor agonist, and of SB-269970, a selective 5-HT7 receptor antagonist, on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. The 5-HT7 receptor ligands were microinjected directly into the dorsal raphe nucleus (DRN) during the light period of the 12-h light/12-h dark cycle. Infusion of LP-44 (1.25–5.0mM) into the DRN induced a significant reduction of rapid-eye-movement sleep (REMS) and of the number of REM periods. Similar effects were observed after the direct administration into the DRN of SB-269970 (0.5–1.0mM). Pretreatment with a dose of SB-269970 (0.5mM) that significantly affects sleep variables antagonized the LP-44 (2.5mM)-induced suppression of REMS and of the number of REM periods. It is proposed that the suppression of REMS after microinjection of LP-44 into the DRN is related, at least in part, to the activation of GABAergic neurons in the DRN that contribute to long projections that reach, among others, the laterodorsal and pedunculopontine tegmental nuclei involved in the promotion of REMS. [Copyright &y& Elsevier]

Background: Studies have implicated the serotonin (5-HT)7 receptor in physiological and pathophysiological phenomena, including thermoregulation, central control of micturition and locomotion, regulation of circadian rhythm, sleep, and depression. Further, several antidepressant and antipsychotic drugs have high affinity for the 5-HT7 receptor. Methods: We examined the role of 5-HT7 receptors in a rodent analogue of sensorimotor gating deficits in schizophrenia: phencyclidine (PCP)-induced disruption of prepulse inhibition (PPI) of acoustic startle. We used mice lacking the 5-HT7 receptor due to a targeted inactivation of this receptor gene and the selective 5-HT7 receptor antagonist SB-269970. Results: SB-269970 did not affect either baseline PPI or PCP-disrupted PPI. There was no difference between 5-HT7 +/+ and 5-HT7 −/− mice in startle reactivity or PPI regardless of prepulse intensity (74–82 dB), interstimulus interval (25–500 msec), or pulse intensity (90–120 dB). Nevertheless, disruption of PPI produced by PCP (10 mg/kg) in wild-type mice was reduced in 5-HT7 −/− mice, although it was not affected by the 5-HT7 antagonist SB-269970. By contrast, the PPI-disruptive effects of apomorphine (5 mg/kg) and amphetamine (7.5 mg/kg) were comparable in both genotypes. Conclusions: The results indicate a partial role for the 5-HT7 receptor in the glutamatergic PPI model of sensorimotor gating deficits in schizophrenia that is sensitive to atypical antipsychotics and no involvement of this receptor in the dopaminergic PPI model that is sensitive to typical antipsychotics. Thus, the 5-HT7 −/− mice may provide a useful tool to study the role of 5-HT7 receptor in the action of atypical antipsychotic drugs and schizophrenia. [Copyright &y& Elsevier]

Abstract: Using extracellular unitary recordings in anaesthetized rats, this study examined the implication of the serotonin 7 (5-HT7) receptors in the inhibitory effect of amphetamine on ventral tegmental area and substantia nigra pars compacta dopamine neuronal activity. The acute administration of the selective 5-HT7 receptor antagonist, SB-269970 (0.1, 0.5 and 1 mg/kg, i.p.), did not alter the firing activity of dopamine neurons. Interestingly, this antagonist prevented significantly the inhibition of dopamine neuronal firing activity induced by amphetamine (1 mg/kg, i.v.) in the ventral tegmental area, but not in the substantia nigra pars compacta. The present results suggest that 5-HT7 receptors modulate the dopamine firing activity in the ventral tegmental area, thus affecting preferentially the mesocorticolimbic pathway. [Copyright &y& Elsevier]

Abstract: Serotonin exerts its effects via at least 14 different receptor subtypes, but the role of only a few of them has been studied in relation to the control of seizures. A negative role of 5-HT7 receptors has recently been proposed. To evaluate further in unstressed and stressed animals the possible role of this receptor subtype in the control of brain excitability, we treated mice with antagonists and agonists of these receptors prior to exposure to swim stress and the intravenous infusion of picrotoxin, a non-competitive GABAA receptor antagonist. In accordance with the previous studies, swim stress increased the doses of picrotoxin producing two convulsant signs (running/bouncing clonus, tonic hindlimb extension) and death, i.e., swim stress increased the seizure threshold for picrotoxin. SB-269970 (10–30 mg/kg ip), a selective antagonist of 5-HT7 receptors, and ritanserin (1 mg/kg ip), a nonselective 5-HT 2/7 antagonist, failed to affect, while 5-carboxamidotryptamine (5-CT), a potent 5-HT 1/7 receptor agonist, increased in unstressed and swim-stressed mice the doses of picrotoxin producing convulsions and death. The anticonvulsant effect obtained with 5-CT 0.5 mg/kg was not greater than that obtained with 0.1 mg/kg. The 5-CT (0.1 mg/kg ip)-induced increase of the seizure threshold for picrotoxin in stressed mice was abolished with SB-269970 (10 mg/kg), but not with WAY-100635 (0.3 mg/kg), a selective antagonist of 5-HT1A receptors, suggesting that the anticonvulsant effect of 5-CT against convulsions produced by picrotoxin was achieved via 5-HT7 receptors. The results suggest a positive role of 5-HT7 receptors in the control of seizures. [Copyright &y& Elsevier]

Abstract: The 5-HT7 receptor has been suggested as a new putative target for the treatment of neuropsychiatric disorders, especially depression. This hypothesis is based on the finding that antidepressant drugs have relatively high affinity for the 5-HT7 receptor, and that inactivation or blockade of the receptor leads to an antidepressant-like profile in behavioral models and sleep parameters. Obsessive-compulsive disorder is also believed to involve the serotonergic system and is treated using antidepressants, thus it is of interest to study the possible role of the 5-HT7 receptor in this disorder. We have evaluated the effect of inactivation or pharmacological blockade of the 5-HT7 receptor in three mouse behavioral models that are believed to mimic some of the stereotypic aspects of obsessive-compulsive disorder. In the most well-established behavioral model, marble burying, both inactivation and blockade of the 5-HT7 receptor reduced stereotypic behavior in that the number of marbles buried decreased. In two newer, less well-characterized models, head dipping and plastic-mesh screen chewing, there was no difference between wild-type mice and mice lacking the 5-HT7 receptor. Taken together the data confirms and expands on previous findings that the 5-HT7 receptor is of importance for behaviors affected by antidepressants, and suggests that the 5-HT7 receptor might be of relevance as a target for the treatment of obsessive-compulsive disorder. [Copyright &y& Elsevier]

Abstract: The physiological function of 5-HT7 receptors is not yet fully determined. This study was designed to characterize the involvement of 5-HT7 receptor in rat body temperature regulation and in adrenocorticotropic hormone (ACTH) and corticosterone secretion. In the first part of our study, acute administration of SB-269970 (0.1–1mg/kg, i.p.), a potent and selective 5-HT7 receptors antagonist, dose-dependently prevented 5-HT1A/7 receptor agonist 8-OH-DPAT (0.1mg/kg, s.c.)-induced hypothermia and when the 5-HT1A receptor antagonist WAY-100,635 was co-injected with SB-269970, a reduction of the latter hypothermia was obtained in an additive manner. In contrast, 1mg/kg (i.p.) of SB-269970 failed to prevent 8-OH-DPAT (0.5mg/kg, s.c.)-induced increase of ACTH and corticosterone plasma levels. In conclusion, the present results unveil an additive effect of both 5-HT1A and 5-HT7 receptors in core body temperature regulation. [Copyright &y& Elsevier]

Abstract: The effects of SB-269970, a selective 5-HT7 receptor antagonist, on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. SB-269970 was infused directly into the dorsal raphe nucleus (DRN) during the light phase. The 5-HT7 receptor antagonist (0.25–1.0mM) induced a significant reduction of REM sleep and of the number of REM periods whereas REM sleep latency was augmented. Pretreatment with the GABAA receptor agonist muscimol (1.0–2.0mM), which by itself did not affect sleep variables, prevented the decrease of REM sleep induced by SB-269970 (1.0mM). Our results indicate that the 5-HT7 receptor is involved in the effect of DRN serotonergic (5-HT) neurons on brainstem structures that act to promote and induce REM sleep. We propose that the SB-269970-induced suppression of REM sleep is dependent upon the inhibition of GABA release in the DRN. [Copyright &y& Elsevier]

Abstract: The possible pronociceptive role of peripheral and spinal 5-HT7 receptors in the formalin test was assessed. Local administration of 5-HT7 (SB-269970, 2.5–77.1nmol/paw), but not 5-HT1A (WAY-100635, 1–60nmol/paw), receptor antagonist significantly reduced formalin-induced flinching. Local 5-hydroxytryptamine (5-HT, 3–100nmol/paw) or 5-carboxamidotryptamine (5-CT, 0.3–3nmol/paw) (a 5-HT7/1A receptor agonist) augmented, in a dose-dependent manner, 0.5% formalin-induced nociceptive behavior. The local pronociceptive effect of 5-HT or 5-CT was significantly reduced by SB-269970 (25 and 77.1nmol/paw), but not by WAY-100635 (10nmol/paw). 5-HT7 receptors were observed in myelinated and unmyelinated axons of the digital nerves in rat hindpaw. Intrathecal SB-269970 (2.5–77.1nmol/rat) or WAY-100635 (1–50nmol/rat) did not modify 1% formalin-induced nociceptive behavior. Spinal 5-HT (25–200nmol/rat) significantly reduced formalin-induced flinching behavior during phase 2. At lower doses (0.1–3nmol/rat) intrathecal 5-CT dose-dependently increased flinching during phase 2. In contrast, higher doses (10–30nmol/rat) of 5-CT reduced formalin-induced nociceptive behavior during both phases. The spinal pronociceptive effect of 5-CT was reduced by SB-269970 (7.7–77nmol/rat), but not by WAY-100635 (10nmol/rat). In addition, the spinal antinociceptive effect of 5-CT was partially reversed by WAY-100635 (10nmol/rat). The spinal antinociceptive effect of 5-HT was unaffected either by SB-269970 (77nmol/rat) or WAY-100635 (10nmol/rat). Data suggest that 5-HT7, but not 5-HT1A, receptors play a pronociceptive role in peripheral and spinal sites in the rat formalin test. [Copyright &y& Elsevier]

Abstract: Brain serotonin 5-HT7 receptors are known to be expressed in neurons and astrocytes. We now report the presence of these receptors in a third type of cell, microglial cells. 5-Hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) induced concentration-dependent stimulations of cAMP accumulation in the human microglial MC-3 cell line. The maximal effect of 5-HT was 3.4±0.3-fold stimulation (mean±S.E.M., ) above basal levels. The rank order of agonist potency (pEC50 values) was 5-CT (7.09)>5-HT (6.13)≥5-MeOT (5.78)≫8-OH-DPAT (ca. 5). The effect of 5-CT was inhibited in a concentration-dependent manner by the selective 5-HT7 receptor antagonist SB-269970 (pA 2 value 9.03). Western blot analysis revealed the presence of immunoreactive bands corresponding to the human 5-HT7 receptor in extracts of MC-3 cells. The presence of two splice variants of the 5-HT7 receptor (5-HT7(a/b)) was visualized by reverse transcriptase–polymerase chain reaction (RT–PCR) analysis with specific primers. In real-time PCR studies, the mRNA for interleukin-6 (IL-6) was found to be increased by 2.5-fold in MC-3 cells after 1 h incubation with 5-CT (1 μM) and this effect was fully blocked by the 5-HT7 receptor antagonist SB-269970 (1 μM). These data show that functional 5-HT7 receptors are present in human microglial MC-3 cells, suggesting that they are involved in neuroinflammatory processes. [Copyright &y& Elsevier]

Abstract: The antinociceptive effects of the serotonin (5-HT)1A/7 receptor agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) administered into the medial thalamus were evaluated. Pain behaviors organized at spinal (spinal motor reflexes, SMRs), medullary (vocalizations during shock, VDSs), and forebrain (vocalization after discharges, VADs) levels of the neuraxis were elicited by tailshock. Administration of 8-OH-DPAT (5, 10, and 20μg/side) into nucleus parafascicularis (nPf) produced dose-dependent increases in VDS and VAD thresholds, but failed to elevate SMR threshold. The increase in VAD threshold was significantly greater than that of VDS threshold. Similar effects were observed with administration of 8-OH-DPAT (20μg/side) into the rostral portion of the central lateral thalamic nucleus. The bilateral or unilateral administration of 8-OH-DPAT (20μg) into other thalamic nuclei, or into sites dorsal to nPf, did not elevate vocalization thresholds. Increases in vocalization thresholds produced by nPf-administered 8-OH-DPAT were mediated by both 5-HT1A and 5-HT7 receptors. Intra-nPf administration of the 5-HT1A receptor antagonist WAY-100635 (0.05 or 0.5μg/side), or the 5-HT7 receptor antagonist SB-269970 (1 or 2μg/side), but not the dopamine D2 receptor antagonist raclopride (10μg/side), reversed 8-OH-DPAT induced elevations in vocalization thresholds. These results provide the first reported evidence of behavioral antinociception following the administration of a 5-HT agonist into the medial thalamus. [Copyright &y& Elsevier]

This study evaluated the possible involvement of 5-HT2B receptors in long-lasting hypotension to 5-hydroxytryptamine (5-HT), which is predominantly mediated by 5-HT7 receptors, in anaesthetised vagosympathectomized rats. Intravenous injections of 5-HT and 5-carboxamidotryptamine (5-CT) elicited a dose-dependent hypotension that was dose-dependently antagonised by (R)-1-{(3-hydroxyphenyl)sulfonyl}-2-{2-(4-methyl-1-piperidinyl) ethyl} pyrrolidine (SB-269970; a selective 5-HT7 receptor antagonist), but not by saline. Interestingly, α-methyl-5-(2-thienylmethoxy)-1H-indole-3-ethanamine (BW723C86; a 5-HT2B receptor agonist) produced vasopressor responses without affecting hypotension to 5-HT. These results suggest that hypotension to 5-HT and 5-CT is mainly mediated by 5-HT7 receptors, whilst the role of 5-HT2B receptors seems unlikely. [Copyright &y& Elsevier]

1. Serotonin 5-HT7 receptors are present in astrocytes. Understanding their role in this type of cell would greatly benefit from the identification of astrological cell lines expressing this receptor type. 2. The aim of the present study was to assess the expression of native 5-HT7 receptors and 5-HT7 receptor mRNA in a number of human glioblastoma cell lines, by means of camp measurements. Western blot analysis and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. 3. 5-Hydroxytryptamine (5-HT)7 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) induced concentration-dependent stimulations of camp accumulation in the human glioblastoma cell lines, U-373 MG, U-138 MG, U-87 MG, DBTRG-05MG, T98G, H4, CCF-STTG1 and Hs 683. The rank order of potency was 5-CT > 5-HT = 5-MeOT ... 8-OH-DPAT. 4. The effect of 5-CT was inhibited in a concentration-dependent manner by the selective 5-HT7 receptor antagonist SB-269970 in all human glioblastoma cells. Schild analysis yielded slope factors close to unity (0.89-1.13) and pA2 values of 8.69-9.05. 5. Western blot analysis revealed the presence of immunoreactive bands corresponding to the human 5-HT7 receptor in extracts of all human glioblastoma cell lines. 6. The presence of the three splice variants of the 5-HT7 receptor (5-HT ... ) was visualized by RT-PCR analysis with specific primers in all human glioblastoma cell lines. 7. In conclusion, human glioblastoma cell lines express functional 5-HT7 receptors and the three splice variants of the corresponding mRNA. These cell lines could serve as model systems of native 5-HT7 receptors in glial cells to investigate their putative role in process like release of neurotrophic factors or inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Recombinant 5-hydroxytryptamine 5-HT7 receptors are known to express constitutive, i.e., agonist-independent activity. Nonselective ligands, like methiothepin, ritanserin or clozapine behave as full inverse agonists at 5-HT7 receptors. The aim of the present study was to evaluate the degree of inverse agonist activity of three selective 5-HT7 receptor antagonists ((R)-3,N-dimethyl-N-[1-methyl-3-(4-methyl-piperidin-1-yl)propyl]benzene sulfonamide or SB-258719, R-(+)-1-(toluene-3-sulfonyl)-2-[2-(4-methylpiperidin-1-yl)ethyl]-pyrrolidine or SB-258741 and (R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)-pyrrolidine-1-sulfonyl)-phenol or SB-269970) in the same model. cAMP accumulation was measured in intact Chinese hamster ovary (CHO) cells expressing human recombinant 5-HT7a receptors. In these cells, 5-HT stimulated cAMP levels and a series of ligands antagonized the effect of 5-HT with a 5-HT7 receptor-like profile. SB-258719 had no inverse agonist activity, SB-258741 behaved as a partial inverse agonist and SB-269970 was a quasi-full inverse agonist (as compared to methiothepin). The inverse agonist effect of SB-269970 was antagonized in a concentration-dependent manner by SB-258719. The widespread spectrum of inverse agonist activities shown by these compounds should help assessing the physiological relevance of constitutive 5-HT7 receptor activity in native tissues. [Copyright &y& Elsevier]

1 We aimed to characterize 5-HT receptors mediating contraction and relaxation to 5-HT in dog proximal stomach longitudinal muscle (LM) strips. 2 Of the tryptamine analogues tested. 5-HT was the most potent contractile agent at basal length, while 5-CT was the most potent relaxant of PGF[sub2α]-induced contraction. Neither the contractions to 5-HT. nor the relaxations to 5-CT were influenced by tetrodotoxin. illustrating that action potential propagation is not involved. 3 The 5-HT-induced contraction was antagonized by mesulergine (0.03 to 0.3 μM) and ketanserin (2-20 nM). but the antagonism was not of a simple competitive nature. indicating multiple receptor involvement. Ketanserin (3 to 30 nM) and mesulergine (30 nM) competitively antagonized the α-Me-5-HT-induced contraction (pK[subB]: 8.83±0.09 and pA[sub2]: 8.257plusmn;0.06 respectively), These affinity values are in line with literature affinities of ketanserin and mesulergine at 5-HT[sub2A] receptors in various bioassays. 4 The 5-CT-induced inhibition of PGF[sub2α]-induced contraction was competitively antagonized by mesulergine (pK[sub B] estimate: 8.52 ±] 0.12) and by the selective 5-HT[sub 7] receptor antagonist SB-269970 (pK[sub B] estimate; 9.36 ± 0.14). Both pK[sub B]estimates are in line with literature affinities of these compounds for 5-HT[sub7] receptors. Mesulergine (3d nM) and SB-269970 (10 nM) shifted the relaxant curve to 5-HT parallel to the right in the presence of ketanserin (0.3 μM) (pA[sub2] estimates of 8.08±0.10 and 8.75± 0.14 respectively), indicative of 5-HT[sub7] receptor involvement. 5 It is concluded that 5-HT induces dog proximal stomach (LM) contraction via smooth muscle 5-HT[sub2A] receptors and relaxation via smooth muscle 5-HT[sub7] receptors. [ABSTRACT FROM AUTHOR]

5-HT7 receptor antagonism has been shown to ameliorate ketamine-induced schizophrenia-like deficits in extradimensional set-shifting using the attentional set-shifting task (ASST). However, this rodent paradigm distinguishes between several types of cognitive rigidity associated with neuropsychiatric conditions. The goal of this study was to test 5-HT7 receptor involvement in the reversal learning component of the ASST because this ability depends primarily on the orbito-frontal cortex, which shows strong 5-HT7 receptor expression. We found that impaired performance on the ASST induced by NMDA receptor blockade (MK-801, 0.2 mg/kg) in 14 rats was reversed by coadministration of the 5-HT7 receptor antagonist SB-269970. The strongest effect was found on the reversal phases of ASST, whereas injection of SB-269970 alone had no effect. These results indicate that 5-HT7 receptor mechanisms may have a specific contribution to the complex cognitive deficits, increasing perseverative responding, in psychiatric diseases, including schizophrenia, depression, and anorexia nervosa, which express different forms of cognitive inflexibility.