The extracellular entrance provides selectivity to serotonin 5-HT7 receptor antagonists with antidepressant-like behavior in vivo.

The finding that ergotamine binds serotonin receptors in a less conserved extended binding pocket close to the extracellular entrance, in addition to the orthosteric site, allowed us to obtain 5-HT7R antagonist 6 endowed with high affinity (Ki=0.7 nM) and significant 5-HT1AR selectivity (ratio>1428). Compound 6 exhibits in vivo antidepressant-like effect (1 mg/kg, ip) mediated by the 5-HT7R, which reveals its interest as a putative research tool or pharmaceutical in depression disorders.

The 5-HT7 receptor as a potential target for treating drug and alcohol abuse.

Alcohol and drug abuse take a large toll on society and affected individuals. However, very few effective treatments are currently available to treat alcohol and drug addiction. Basic and clinical research has begun to provide some insights into the underlying neurobiological systems involved in the addiction process. Several neurotransmitter pathways have been implicated and distinct reward neurocircuitry have been proposed-including the mesocorticolimbic dopamine (MCL-DA) system and the extended amygdala. The serotonin (5-HT) neurotransmitter system is of particular interest and multiple 5-HT receptors are thought to play significant roles in alcohol and drug self-administration and the development of drug dependence. Among the 5-HT receptors, the 5-HT7 receptor is currently undergoing characterization as a potential target for the treatment of several psychiatric disorders. Although this receptor has received only limited research regarding addictive behaviors, aspects of its neuroanatomical, biochemical, physiological, pharmacological, and behavioral profiles suggest that it could play a key role in the addiction process. For instance, genomic studies in humans have suggested a link between variants in the gene encoding the 5-HT7 receptor and alcoholism. Recent behavioral testing using high-affinity antagonists in mice and preliminary tests with alcohol-preferring rats suggest that this receptor could mediate alcohol consumption and/or reinforcement and play a role in seeking/craving behavior. Interest in the development of new and more selective pharmacological agents for this receptor will aid in examining the 5-HT7 receptor as a novel target for treating addiction.

Targeted inhibition of serotonin type 7 (5-HT7) receptor function modulates immune responses and reduces the severity of intestinal inflammation.

Mucosal inflammation in conditions ranging from infective acute enteritis or colitis to inflammatory bowel disease is accompanied by alteration in serotonin (5-hydroxytryptamine [5-HT]) content in the gut. Recently, we have identified an important role of 5-HT in the pathogenesis of experimental colitis. 5-HT type 7 (5-HT7) receptor is one of the most recently identified members of the 5-HT receptor family, and dendritic cells express this receptor. In this study, we investigated the effect of blocking 5-HT7 receptor signaling in experimental colitis with a view to develop an improved therapeutic strategy in intestinal inflammatory disorders. Colitis was induced with dextran sulfate sodium (DSS) or dinitrobenzene sulfonic acid (DNBS) in mice treated with selective 5-HT7 receptor antagonist SB-269970, as well as in mice lacking 5-HT7 receptor (5-HT7(-/-)) and irradiated wild-type mice reconstituted with bone marrow cells harvested from 5-HT7(-/-) mice. Inhibition of 5-HT7 receptor signaling with SB-269970 ameliorated both acute and chronic colitis induced by DSS. Treatment with SB-269970 resulted in lower clinical disease, histological damage, and proinflammatory cytokine levels compared with vehicle-treated mice post-DSS. Colitis severity was significantly lower in 5-HT7(-/-) mice and in mice reconstituted with bone marrow cells from 5-HT7(-/-) mice compared with control mice after DSS colitis. 5-HT7(-/-) mice also had significantly reduced DNBS-induced colitis. These observations provide us with novel information on the critical role of the 5-HT7 receptor in immune response and inflammation in the gut, and highlight the potential benefit of targeting this receptor to alleviate the severity of intestinal inflammatory disorders such as inflammatory bowel disease.

Effects of lurasidone in behavioral models of depression. Role of the 5-HT7 receptor subtype.

Major depression is a common psychiatric disorder associated with high symptomatic and functional burdens. Pharmacological treatment is often effective, but there remain substantial unmet needs in the form of non-responders, delayed onset of clinical effect, and side effects. Recent studies have positioned the serotonin 5-HT7 receptor as a new target for the treatment of depression. Preclinical studies have shown that antagonists induce an antidepressant-like response, a phenotype that can also be observed in mice lacking the receptor. Lurasidone is a new atypical antipsychotic agent with very high affinity for the 5-HT7 receptor. Patients in clinical trials have reported improved scores in depression ratings. We have tested lurasidone in both acute and chronic mouse models of depression. In the tail suspension and forced swim tests lurasidone decreased immobility, an antidepressant-like response. The effect required functional 5-HT7 receptors as it was absent in mice lacking the receptor. In the repeated open-space swim test lurasidone was able to reverse the despair induced by repeated swims in a manner similar to the commonly used antidepressant citalopram. The results provide evidence that lurasidone can act as a 5-HT7 receptor antagonist and provide a possible explanation for the antidepressant effect data currently emerging from lurasidone clinical trials. Additionally, the results give further support for targeting the 5-HT7 receptor in the treatment of depression. It will be of interest to clinically evaluate lurasidone as an antidepressant either as monotherapy or as an adjunctive therapy to available drugs.

Investigations on the 1-(2-biphenyl)piperazine motif: identification of new potent and selective ligands for the serotonin(7) (5-HT(7)) receptor with agonist or antagonist action in vitro or ex vivo.

Here we report the design, synthesis, and 5-HT(7) receptor affinity of a set of 1-(3-biphenyl)- and 1-(2-biphenyl)piperazines. The effect on 5-HT(7) affinity of various substituents on the second (distal) phenyl ring was analyzed. Several compounds showed 5-HT(7) affinities in the nanomolar range and >100-fold selectivity over 5-HT(1A) and adrenergic α(1) receptors. 1-[2-(4-Methoxyphenyl)phenyl]piperazine (9a) showed 5-HT(7) agonist properties in a guinea pig ileum assay but blocked 5-HT-mediated cAMP accumulation in 5-HT(7)-expressing HeLa cells.

The 5-HT(7) receptor in learning and memory.

The 5-HT(7) receptor is a more recently discovered G-protein-coupled receptor for serotonin. The functions and possible clinical relevance of this receptor are not yet fully understood. The present paper reviews to what extent the use of animal models of learning and memory and other techniques have implicated the 5-HT(7) receptor in such processes. The studies have used a combination of pharmacological and genetic tools targeting the receptor to evaluate effects on behavior and cellular mechanisms. In tests such as the Barnes maze, contextual fear conditioning and novel location recognition that involve spatial learning and memory there is a considerable amount of evidence supporting an involvement of the 5-HT(7) receptor. Supporting evidence has also been obtained in studies of mRNA expression and cellular signaling as well as in electrophysiological experiments. Especially interesting are the subtle but distinct effects observed in hippocampus-dependent models of place learning where impairments have been described in mice lacking the 5-HT(7) receptor or after administration of a selective antagonist. While more work is required, it appears that 5-HT(7) receptors are particularly important in allocentric representation processes. In instrumental learning tasks both procognitive effects and impairments in memory have been observed using pharmacological tools targeting the 5-HT(7) receptor. In conclusion, the use of pharmacological and genetic tools in animal studies of learning and memory suggest a potentially important role for the 5-HT(7) receptor in cognitive processes.

Peripheral reduction of ß-amyloid is sufficient to reduce brain ß-amyloid: implications for Alzheimer's disease.

Three loci that modify ß-amyloid (Aß) accumulation and deposition in the brains of a mouse model of Alzheimer's disease have been previously described. One encompasses the Psen2 gene encoding presenilin 2, a component of the γ-secretase activity responsible for generating Aß by proteolysis. We show that the activity of mouse Psen2, as measured by levels of mRNA accumulation, unexpectedly is heritable in the liver but not the brain, suggesting liver as the origin of brain Aß deposits. Administration of STI571, a cancer therapeutic that does not cross the blood-brain barrier, reduced accumulation of Aß in both the blood and the brain, confirming brain Aß's peripheral origin and suggesting that STI571 and related compounds might have therapeutic/prophylactic value in human Alzheimer's disease. The genes Cib1 and Zfhx1b reside within the other modifier loci and also exhibit heritable expression in the liver, suggesting that they too contribute to Aß accumulation.

Serotonin 5-HT7 receptor agents: Structure-activity relationships and potential therapeutic applications in central nervous system disorders.

Since its discovery in the 1940s in serum, the mammalian intestinal mucosa, and in the central nervous system, serotonin (5-HT) has been shown to be involved in virtually all cognitive and behavioral human functions, and alterations in its neurochemistry have been implicated in the etiology of a plethora of neuropsychiatric disorders. The cloning of 5-HT receptor subtypes has been of importance in enabling them to be classified as specific protein molecules encoded by specific genes. The 5-HT(7) receptor is the most recently classified member of the serotonin receptor family. Since its identification, it has been the subject of intense research efforts driven by its presence in functionally relevant regions of the brain. The availability of some selective antagonists and agonists, in combination with genetically modified mice lacking the 5-HT(7) receptor, has allowed for a better understanding of the pathophysiological role of this receptor. This paper reviews data on localization and pharmacological properties of the 5-HT(7) receptor, and summarizes the results of structure-activity relationship studies aimed at the discovery of selective 5-HT(7) receptor ligands. Additionally, an overview of the potential therapeutic applications of 5-HT(7) receptor agonists and antagonists in central nervous system disorders is presented.

LP-211 is a brain penetrant selective agonist for the serotonin 5-HT(7) receptor.

We have determined the pharmacological profile of the new serotonin 5-HT(7) receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211). Radioligand binding assays were performed on a panel of 5-HT receptor subtypes. The compound was also evaluated in vivo by examining its effect on body temperature regulation in mice lacking the 5-HT(7) receptor (5-HT(7)(-/-)) and their 5-HT(7)(+/+) sibling controls. Disposition studies were performed in mice of both genotypes. It was found that LP-211 was brain penetrant and underwent metabolic degradation to 1-(2-diphenyl)piperazine (RA-7). In vitro binding assays revealed that RA-7 possessed higher 5-HT(7) receptor affinity than LP-211 and a better selectivity profile over a panel of 5-HT receptor subtypes. In vivo it was demonstrated that LP-211, and to a lesser degree RA-7, induced hypothermia in 5-HT(7)(+/+) but not in 5-HT(7)(-/-) mice. Our results suggest that LP-211 can be used as a 5-HT(7) receptor agonist in vivo.

The 5-HT(7) receptor as a mediator and modulator of antidepressant-like behavior.

The 5-HT(7) 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-HT(7) receptor. Immobility despair in the tail suspension test and the forced swim test was evaluated in mice lacking the 5-HT(7) receptor (5-HT(7)(-/-)) and in wild-type controls (5-HT(7)(+/+)) 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-HT(7)(+/+) and 5-HT(7)(-/-) mice. Combining doses of citalopram and the 5-HT(7) receptor antagonist SB-269970 that by themselves did not affect behavior, reduced immobility in 5-HT(7)(+/+) mice in both the tail suspension test and the forced swim test. No effect was seen in 5-HT(7)(-/-) mice. Desipramine and reboxetine, two norepinephrine reuptake inhibitors, dose-dependently reduced immobility in the tail suspension test in 5-HT(7)(+/+) mice, but had no effect in 5-HT(7)(-/-) mice. A synergistic effect between desipramine and SB-269970 was found in both behavioral tests in 5-HT(7)(+/+) 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-HT(7)(+/+) mice, but not in 5-HT(7)(-/-) mice. The results show that the 5-HT(7) receptor is required for the observed interaction between this receptor and antidepressants such as citalopram. The data furthermore support the hypothesis that the 5-HT(7) receptor might be a suitable target for treating depression.

The 5-HT7 receptor and disorders of the nervous system: an overview.

RATIONALE: The 5-HT(7) receptor is a more recently discovered G-protein-coupled receptor for serotonin. The functions and possible clinical relevance of this receptor are not yet fully understood. OBJECTIVE: The present paper reviews to what extent the use of animal models of human psychiatric and neurological disorders have implicated the 5-HT(7) receptor in such disorders. The studies have used a combination of pharmacological and genetic tools targeting the receptor to evaluate effects on behavior. RESULTS: Models of anxiety and schizophrenia have yielded mixed results with no clear role for the 5-HT(7) receptor described in these disorders. Some data are available for epilepsy, migraine, and pain but it is still very early to draw any definitive conclusions. There is a considerable amount of evidence supporting a role for the 5-HT(7) receptor in depression. Both blockade and inactivation of the receptor have resulted in an antidepressant-like profile in models of depression. Supporting evidence has also been obtained in sleep studies. Especially interesting are the augmented effects achieved by combining antidepressants and 5-HT(7) receptor antagonists. The antidepressant effect of amisulpride has been shown to most likely be mediated by the 5-HT(7) receptor. CONCLUSIONS: The use of pharmacological and genetic tools in preclinical animal models strongly supports a role for the 5-HT(7) receptor in depression. Indirect evidence exists showing that 5-HT(7) receptor antagonism is clinically useful in the treatment of depression. Available data also indicate a possible involvement of the 5-HT(7) receptor in anxiety, epilepsy, pain, and schizophrenia.

The 5-HT7 receptor is involved in allocentric spatial memory information processing.

The hippocampus has been implicated in aspects of spatial memory. Its ability to generate new neurons has been suggested to play a role in memory formation. Hippocampal serotonin (5-HT) neurotransmission has also been proposed as a contributor to memory processing. Studies have shown that the 5-HT(7) receptor is present in the hippocampus in relatively high abundance. Thus the aim of the present study was to investigate the possible role of the 5-HT(7) receptor in spatial memory using 5-HT(7) receptor-deficient mice (5-HT(7)(-/-)). A hippocampus-associated spatial memory deficit in 5-HT(7)(-/-) mice was demonstrated using a novel location/novel object test. A similar reduction in novel location exploration was observed in C57BL/6J mice treated with the selective 5-HT(7) receptor antagonist SB-269970. These findings prompted an extended analysis using the Barnes maze demonstrating that 5-HT(7)(-/-) mice were less efficient in accommodating to changes in spatial arrangement than 5-HT(7)(+/+) mice. 5-HT(7)(-/-) mice had specific impairments in memory compilation required for resolving spatial tasks, which resulted in impaired allocentric spatial memory whereas egocentric spatial memory remained intact after the mice were forced to switch back from striatum-dependent egocentric to hippocampus-dependent allocentric memory. To further investigate the physiological bases underlining these behaviors we compared hippocampal neurogenesis in 5-HT(7)(+/+) and 5-HT(7)(-/-) mice employing BrdU immunohistochemistry. The rate of cell proliferation in the dentate gyrus was identical in the two genotypes. From the current data we conclude that the 5-HT(7)(-/-) mice performed by remembering a simple sequence of actions that resulted in successfully locating a hidden target in a static environment.

Spinal 5-HT7 receptors are critical for alternating activity during locomotion: in vitro neonatal and in vivo adult studies using 5-HT7 receptor knockout mice.

5-HT7 receptors have been implicated in the control of locomotion. Here we use 5-HT7 receptor knockout mice to rigorously test whether 5-HT acts at the 5-HT7 receptor to control locomotor-like activity in the neonatal mouse spinal cord in vitro and voluntary locomotion in adult mice. We found that 5-HT applied onto in vitro spinal cords of 5-HT7+/+ mice produced locomotor-like activity that was disrupted and subsequently blocked by the 5-HT7 receptor antagonist SB-269970. In spinal cords isolated from 5-HT7-/- mice, 5-HT produced either uncoordinated rhythmic activity or resulted in synchronous discharges of the ventral roots. SB-269970 had no effect on 5-HT-induced rhythmic activity in the 5-HT7-/- mice. In adult in vivo experiments, SB-269970 applied directly to the spinal cord consistently disrupted locomotion and produced prolonged-extension of the hindlimbs in 5-HT7+/+ but not 5-HT7-/- mice. Disrupted EMG activity produced by SB-269970 in vivo was similar to the uncoordinated rhythmic activity produced by the drug in vitro. Moreover, 5-HT7-/- mice displayed greater maximal extension at the hip and ankle joints than 5-HT7+/+ animals during voluntary locomotion. These results suggest that spinal 5-HT7 receptors are required for the production and coordination of 5-HT-induced locomotor-like activity in the neonatal mouse and are important for the coordination of voluntary locomotion in adult mice. We conclude that spinal 5-HT7 receptors are critical for alternating activity during locomotion.

Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo.

RATIONALE: Amisulpride is approved for clinical use in treating schizophrenia in a number of European countries and also for treating dysthymia, a mild form of depression, in Italy. Amisulpride has also been demonstrated to be an antidepressant for patients with major depression in many clinical trials. In part because of the selective D(2)/D(3) receptor antagonist properties of amisulpride, it has long been widely assumed that dopaminergic modulation is the proximal event responsible for mediating its antidepressant and antipsychotic properties. OBJECTIVES: The purpose of these studies was to determine if amisulpride's antidepressant actions are mediated by off-target interactions with other receptors. MATERIALS AND METHODS: We performed experiments that: (1) examined the pharmacological profile of amisulpride at a large number of central nervous system (CNS) molecular targets and, (2) after finding high potency antagonist affinity for human 5-HT(7a) serotonin receptors, characterized the actions of amisulpride as an antidepressant in wild-type and 5-HT(7) receptor knockout mice. RESULTS: We discovered that amisulpride was a potent competitive antagonist at 5-HT(7a) receptors and that interactions with no other molecular target investigated in this paper could explain its antidepressant actions in vivo. Significantly, and in contrast to their wild-type littermates, 5-HT(7) receptor knockout mice did not respond to amisulpride in two widely used rodent models of depression, the tail suspension test and the forced swim test. CONCLUSIONS: These results indicate that 5-HT(7a) receptor antagonism, and not D(2)/D(3) receptor antagonism, likely underlies the antidepressant actions of amisulpride.

Descending command systems for the initiation of locomotion in mammals.

Neurons in the brainstem implicated in the initiation of locomotion include glutamatergic, noradrenergic (NA), dopaminergic (DA), and serotonergic (5-HT) neurons giving rise to descending tracts. Glutamate antagonists block mesencephalic locomotor region-induced and spontaneous locomotion, and glutamatergic agonists induce locomotion in spinal animals. NA and 5-HT inputs to the spinal cord originate in the brainstem, while the descending dopaminergic pathway originates in the hypothalamus. Agonists acting at NA, DA or 5-HT receptors facilitate or induce locomotion in spinal animals. 5-HT neurons located in the parapyramidal region (PPR) produce locomotion when stimulated in the isolated neonatal rat brainstem-spinal cord preparation, and they constitute the first anatomically discrete group of spinally-projecting neurons demonstrated to be involved in the initiation of locomotion in mammals. Neurons in the PPR are activated during treadmill locomotion in adult rats. Locomotion evoked from the PPR is mediated by 5-HT(7) and 5-HT(2A) receptors, and 5-HT(7) antagonists block locomotion in cat, rat and mouse preparations, but have little effect in mice lacking 5-HT(7) receptors. 5-HT induced activity in 5-HT(7) knockout mice is rhythmic, but coordination among flexor and extensor motor nuclei and left and right sides of the spinal cord is disrupted. In the adult wild-type mouse, 5-HT(7) receptor antagonists impair locomotion, producing patterns of activity resembling those induced by 5-HT in 5-HT(7) knockout mice. 5-HT(7) receptor antagonists have a reduced effect on locomotion in adult 5-HT(7) receptor knockout mice. We conclude that the PPR is the source of a descending 5-HT command pathway that activates the CPG via 5-HT(7) and 5-HT(2A) receptors. Further experiments are necessary to define the putative glutamatergic, DA, and NA command pathways.

Inactivation of the 5-HT(7) receptor partially blocks phencyclidine-induced disruption of prepulse inhibition.

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-HT(7) receptor. METHODS: We examined the role of 5-HT(7) 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-HT(7) receptor due to a targeted inactivation of this receptor gene and the selective 5-HT(7) receptor antagonist SB-269970. RESULTS: SB-269970 did not affect either baseline PPI or PCP-disrupted PPI. There was no difference between 5-HT(7)(+/+) and 5-HT(7)(-/-) 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-HT(7)(-/-) mice, although it was not affected by the 5-HT(7) 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-HT(7) 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-HT(7)(-/-) mice may provide a useful tool to study the role of 5-HT(7) receptor in the action of atypical antipsychotic drugs and schizophrenia.

The 5-HT7 receptor influences stereotypic behavior in a model of obsessive-compulsive disorder.

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.

Contribution of spinal 5-HT1A and 5-HT7 receptors to locomotor-like movement induced by 8-OH-DPAT in spinal cord-transected mice.

Growing evidence from in vitro studies suggests that spinal serotonin (5-HT) receptor subtypes 5-HTR(1A) and 5-HTR(7) are associated with an induction of central pattern generator activity. However, the possibility of a specific role for these receptor subtypes in locomotor rhythmogenesis in vivo remains unclear. Here, we studied the effects of a single dose (1 mg/kg, i.p.) of 8-hydroxy-2-(di-N-propylamino)-tetralin (8-OH-DPAT), a potent and selective 5-HTR(1A/7) agonist, in mice spinal cord transected at the low-thoracic level (Th9/10). The results show that 8-OH-DPAT acutely induced, within 15 min, hindlimb movements that share some characteristics with normal locomotion. Paraplegic mice pretreated with the selective 5-HTR(1A) antagonists, WAY100,135 or WAY100,635, displayed significantly less 8-OH-DPAT-induced movement. A similar reduction of 8-OH-DPAT-induced movements was found in animals pretreated with SB269970, a selective 5-HTR(7) antagonist. Moreover, a near complete blockade of 8-OH-DPAT-induced movement was obtained in wild-type mice pretreated with 5-HTR(1A) and 5-HTR(7) antagonists, and in 5-HTR(7)-/- mice pretreated with 5-HTR(1A) antagonists. Overall, these results clearly demonstrate that 8-OH-DPAT potently induces locomotor-like movement in the previously paralysed hindlimbs of low-thoracic-transected mice. The results, with selective antagonists and knockout animals, provide compelling evidence of a specific contribution of both receptor subtypes to spinal locomotor rhythmogenesis in vivo.

5-HT7 receptor inhibition and inactivation induce antidepressantlike behavior and sleep pattern.

BACKGROUND: The 5-hydroxytryptamine7 receptor (5-HT7) is implicated in circadian rhythm phase resetting, and 5-HT7 receptor-selective antagonists alter rapid eye movement (REM) sleep parameters in a pattern opposite from those in patients with clinical depression. METHODS: As sleep, circadian rhythm, and mood regulation are related, we examined 5-HT7 receptor knockout mice in two behavioral models of depression. The forced swim and tail suspension tests are highly predictive for antidepressant drug activity. RESULTS: Unmedicated 5-HT7-/- mice showed decreased immobility in both tests, consistent with an antidepressantlike behavior. The selective 5-HT7 receptor antagonist SB-269970 also decreased immobility. The selective serotonin reuptake inhibitor citalopram, a widely used antidepressant, decreased immobility in both 5-HT7+/+ and 5-HT7-/- mice in the tail suspension test, suggesting that it utilizes an independent mechanism. The 5-HT7-/- mice spent less time in and had less frequent episodes of REM sleep, also consistent with an antidepressantlike state. CONCLUSIONS: The 5-HT7 receptor might have a role in mood disorders and antagonists might have therapeutic value as antidepressants.

Z-analysis: a new approach to analyze stimulation curves with intrinsic basal stimulation.

In the study of receptor biology it is of considerable importance to describe the stimulatory properties of an agonist according to mathematically defined models. However, the presently used models are insufficient if the experimental preparation contains an intrinsic basal stimulation. We have developed a novel approach, tentatively named Z-analysis. In this approach, the concentration of endogenous agonist is calculated by extending the stimulation curve to zero effect. The concentration of endogenous agonist is then combined with the concentration of added agonist to estimate the true EC(50) value. We developed a new model, the Z-model, specifically for this purpose, but in addition, we describe how Z-analysis can be applied to the traditional E(0)-model. Models were applied to computer-generated curves with different Hill coefficients, using iterative curve fitting procedures. In addition to applying the models to ideal cases, we also used Monte Carlo-simulated data. Specific transformations were used to enable comparisons between parameters determined from these models. Both models were able to provide estimates of all eight parameters analyzed, both using ideal data and on Monte Carlo-simulated data. The Z-model was found to provide better estimates of the concentration of endogenous agonist, the EC(50) values, and the Hill value, in curves with Hill coefficient deviating from one. In conclusion, Z-analysis was suitable both to determine the concentration of endogenous agonists and to determine true EC(50) values. We found several advantages with the Z-model compared to traditional E(0)-model for analysis of stimulation curves that contain basic intrinsic stimulation.