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.
Growing evidence from in vitro studies suggests that spinal serotonin (5‐HT) receptor subtypes 5‐HTR1A and 5‐HTR7 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‐HTR1A/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‐HTR1A 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‐HTR7 antagonist. Moreover, a near complete blockade of 8‐OH‐DPAT‐induced movement was obtained in wild‐type mice pretreated with 5‐HTR1A and 5‐HTR7 antagonists, and in 5‐HTR7–/– mice pretreated with 5‐HTR1A 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.
The 5-HT
7 receptor was among a group of 5-HT receptors that were discovered using targeted cloning strategies 12 years ago. This receptor is a seven-transmembrane-domain G-protein-coupled receptor ...that is positively linked to adenylyl cyclase. The distributions of 5-HT
7 receptor mRNA, immunolabeling and radioligand binding exhibit strong similarities, with the highest receptor densities present in the thalamus and hypothalamus and significant densities present in the hippocampus and cortex. The recent availability of selective antagonists and knockout mice strains has dramatically increased our knowledge about this receptor. Together with unselective agonists, these new tools have helped to reveal the 5-HT
7 receptor distribution in more detail. Important functional roles for the 5-HT
7 receptor in thermoregulation, circadian rhythm, learning and memory, hippocampal signaling and sleep have also been established. Hypotheses driving current research indicate that this receptor might be involved in mood regulation, suggesting that the 5-HT
7 receptor is a putative target in the treatment of depression.
Using 5‐HT7 receptor knockout mice it has been shown that the 5‐HT7 receptor is the main mediator of serotonin‐induced hypothermia but very little is known about the relevance of 5‐HT7 receptors in ...behaviour. We here report that lack of 5‐HT7 receptors leads to a specific learning deficit that is not due to general sensory or behavioural deficits. The knockout mice show impaired contextual fear conditioning but no significant deficits in motor and spatial learning or cued and operant conditioning. In addition, we demonstrate that 5‐HT7 receptor knockout mice display decreased long‐term synaptic plasticity within the CA1 region of the hippocampus. The results indicate an important role for the 5‐HT7 receptor in contextual hippocampal‐dependent learning and suggest a possible neuronal correlate for such a role is present within the CA1 region of the hippocampus.
The 5-HT7 receptor was among a group of 5-HT receptors that were discovered using targeted cloning strategies 12 years ago. This receptor is a seven-transmembrane-domain G-protein-coupled receptor ...that is positively linked to adenylyl cyclase. The distributions of 5-HT7 receptor mRNA, immunolabeling and radioligand binding exhibit strong similarities, with the highest receptor densities present in the thalamus and hypothalamus and significant densities present in the hippocampus and cortex. The recent availability of selective antagonists and knockout mice strains has dramatically increased our knowledge about this receptor. Together with unselective agonists, these new tools have helped to reveal the 5-HT7 receptor distribution in more detail. Important functional roles for the 5-HT7 receptor in thermoregulation, circadian rhythm, learning and memory, hippocampal signaling and sleep have also been established. Hypotheses driving current research indicate that this receptor might be involved in mood regulation, suggesting that the 5-HT7 receptor is a putative target in the treatment of depression.
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 (K i = 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.
Quality control and harmonization of data is a vital and challenging undertaking for any successful data coordination center and a responsibility shared between the multiple sites that produce, ...integrate, and utilize the data. Here we describe a coordinated effort between scientists and data managers in the Cancer Family Registries to implement a data governance infrastructure consisting of both organizational and technical solutions. The technical solution uses a rule-based validation system that facilitates error detection and correction for data centers submitting data to a central informatics database. Validation rules comprise both standard checks on allowable values and a crosscheck of related database elements for logical and scientific consistency. Evaluation over a 2-year timeframe showed a significant decrease in the number of errors in the database and a concurrent increase in data consistency and accuracy.
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 (MCL) dopamine 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-HT-7 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-HT-7 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-HT-7 receptor as a novel target for treating addiction.
Rationale: The 5-HT sub(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 sub(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 sub(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 sub(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 sub(7) receptor antagonists. The antidepressant effect of amisulpride has been shown to most likely be mediated by the 5-HT sub(7) receptor. Conclusions: The use of pharmacological and genetic tools in preclinical animal models strongly supports a role for the 5-HT sub(7) receptor in depression. Indirect evidence exists showing that 5-HT sub(7) receptor antagonism is clinically useful in the treatment of depression. Available data also indicate a possible involvement of the 5-HT sub(7) receptor in anxiety, epilepsy, pain, and schizophrenia.
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