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Neuron Aug 2019The role of serotonin (5-HT) in sleep is controversial: early studies suggested a sleep-promoting role, but eventually the paradigm shifted toward a wake-promoting...
The role of serotonin (5-HT) in sleep is controversial: early studies suggested a sleep-promoting role, but eventually the paradigm shifted toward a wake-promoting function for the serotonergic raphe. Here, we provide evidence from zebrafish and mice that the raphe are critical for the initiation and maintenance of sleep. In zebrafish, genetic ablation of 5-HT production by the raphe reduces sleep, sleep depth, and the homeostatic response to sleep deprivation. Pharmacological inhibition or ablation of the raphe reduces sleep, while optogenetic stimulation increases sleep. Similarly, in mice, ablation of the raphe increases wakefulness and impairs the homeostatic response to sleep deprivation, whereas tonic optogenetic stimulation at a rate similar to baseline activity induces sleep. Interestingly, burst optogenetic stimulation induces wakefulness in accordance with previously described burst activity of the raphe during arousing stimuli. These results indicate that the serotonergic system promotes sleep in both diurnal zebrafish and nocturnal rodents. VIDEO ABSTRACT.
Topics: Animals; Arousal; Buspirone; Circadian Rhythm; Fenclonine; Homeostasis; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Optogenetics; Quipazine; Raphe Nuclei; Serotonergic Neurons; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sleep; Sleep Deprivation; Tryptophan Hydroxylase; Wakefulness; Zebrafish; Zebrafish Proteins
PubMed: 31248729
DOI: 10.1016/j.neuron.2019.05.038 -
ACS Chemical Neuroscience Mar 2021Known classic psychedelic serotonin 2A receptor (5-HTR) agonists retain a tryptamine or phenethylamine at their structural core. However, activation of the 5-HTR can be...
Known classic psychedelic serotonin 2A receptor (5-HTR) agonists retain a tryptamine or phenethylamine at their structural core. However, activation of the 5-HTR can be elicited by drugs lacking these fundamental scaffolds. Such is the case of the N-substituted piperazine quipazine. Here, we show that quipazine bound to and activated 5-HTR as measured by [H]ketanserin binding displacement, Ca mobilization, and accumulation of the canonical G signaling pathway mediator inositol monophosphate (IP) and . Additionally, quipazine induced via 5-HTR an expression pattern of immediate early genes (IEG) in the mouse somatosensory cortex consistent with that of classic psychedelics. In the mouse head-twitch response (HTR) model of psychedelic-like action, quipazine produced a lasting effect with high maximal responses during the peak effect that were successfully blocked by the 5-HTR antagonist M100907 and absent in 5-HTR knockout (KO) mice. The acute effect of quipazine on HTR appeared to be unaffected by serotonin depletion and was independent from 5-HTR activation. Interestingly, some of these features were shared by its deaza bioisostere 2-NP, but not by other closely related piperazine congeners, suggesting that quipazine might represent a distinct cluster within the family of psychoactive piperazines. Together, our results add to the mounting evidence that quipazine's profile matches that of classic psychedelic 5-HTR agonists at cellular signaling and behavioral pharmacology levels.
Topics: Animals; Hallucinogens; Ketanserin; Mice; Mice, Knockout; Quipazine; Receptor, Serotonin, 5-HT2A; Serotonin
PubMed: 33400504
DOI: 10.1021/acschemneuro.0c00291 -
Current Topics in Behavioral... 2018Because of the ethical and regulatory hurdles associated with human studies, much of what is known about the psychopharmacology of hallucinogens has been derived from... (Review)
Review
Because of the ethical and regulatory hurdles associated with human studies, much of what is known about the psychopharmacology of hallucinogens has been derived from animal models. However, developing reliable animal models has proven to be a challenging task due to the complexity and variability of hallucinogen effects in humans. This chapter focuses on three animal models that are frequently used to test the effects of hallucinogens on unconditioned behavior: head twitch response (HTR), prepulse inhibition of startle (PPI), and exploratory behavior. The HTR has demonstrated considerable utility in the neurochemical actions of hallucinogens. However, the latter two models have clearer conceptual bridges to human phenomenology. Consistent with the known mechanism of action of hallucinogens in humans, the behavioral effects of hallucinogens in rodents are mediated primarily by activation of 5-HT receptors. There is evidence, however, that other receptors may play secondary roles. The structure-activity relationships (SAR) of hallucinogens are reviewed in relation to each model, with a focus on the HTR in rats and mice.
Topics: Animals; Behavior; Behavior, Animal; Exploratory Behavior; Hallucinogens; Humans; Mice; Models, Animal; Rats; Sensory Gating; Serotonin 5-HT2 Receptor Agonists
PubMed: 28224459
DOI: 10.1007/7854_2016_466 -
Developmental Psychobiology May 2015Some of the most simple, stereotyped, reflexive, and spinal-mediated motor behaviors expressed by animals display a level of flexibility and plasticity that is not... (Review)
Review
Some of the most simple, stereotyped, reflexive, and spinal-mediated motor behaviors expressed by animals display a level of flexibility and plasticity that is not always recognized. We discuss several examples of how coordinated action patterns have been shown to be flexible and adaptive in response to sensory feedback. We focus on interlimb and intralimb coordination during the expression of two action patterns (stepping and the leg extension response) in newborn rats, as well as interlimb motor learning. We also discuss the idea that the spinal cord is a major site for supporting plasticity in the developing motor system. An implication of this research is that normally occurring sensory stimulation during the perinatal period influences the typical development and expression of action patterns, and that exploiting the developmental plasticity of the motor system may lead to improved strategies for promoting recovery of function in human infants with motor disorders.
Topics: Animals; Animals, Newborn; Behavior, Animal; Electromyography; Learning; Motor Activity; Neuronal Plasticity; Rats
PubMed: 25739742
DOI: 10.1002/dev.21280 -
Behavioural Pharmacology Jun 2021Serotonin plays a pivotal role in the initiation and modulation of locomotor behavior in the intact animal, as well as following spinal cord injury. Quipazine, a...
Serotonin plays a pivotal role in the initiation and modulation of locomotor behavior in the intact animal, as well as following spinal cord injury. Quipazine, a serotonin 2 receptor agonist, has been used successfully to initiate and restore motor behavior in rodents. Although evidence suggests that the effects of quipazine are spinally mediated, it is unclear whether intrathecal (IT) quipazine administration alone is enough to activate locomotor-like activity or whether additional stimulation is needed. Thus, the current study examined the effects of IT administration of quipazine in postnatal day 1 rats in two separate experiments. In experiment 1, quipazine (0.1, 0.3, or 1.0 mg/kg) was dissolved in saline and administered via IT injection to the thoracolumbar cord. There was no significant effect of drug on hindlimb alternating stepping. In experiment 2, quipazine (0.3 or 1.0 mg/kg) was dissolved in a polysorbate 80-saline solution (Tween 80) and administered via IT injection. Polysorbate 80 was used to disrupt the blood-brain barrier to facilitate absorption of quipazine. The injection was followed by tail pinch 5 minutes post-injection. A significant increase in the percentage of hindlimb alternating steps was found in subjects treated with 0.3 mg/kg quipazine, suggesting that IT quipazine when combined with sensory stimulation to the spinal cord, facilitates locomotor-like behavior. These findings indicate that dissolving the drug in polysorbate 80 rather than saline may heighten the effects of IT quipazine. Collectively, this study provides clarification on the role of quipazine in evoking spinally-mediated locomotor behavior.
Topics: Animals; Animals, Newborn; Biological Availability; Blood-Brain Barrier; Injections, Spinal; Kinesis; Motor Activity; Polysorbates; Quipazine; Rats; Receptors, Serotonin, 5-HT2; Serotonin 5-HT2 Receptor Agonists; Solvents; Spinal Cord Injuries
PubMed: 33595953
DOI: 10.1097/FBP.0000000000000608 -
Behavioural Brain Research Apr 2016The purpose of this study was to determine what dose of quipazine, a serotonergic agonist, facilitates air-stepping and induces postural control and patterns of...
The purpose of this study was to determine what dose of quipazine, a serotonergic agonist, facilitates air-stepping and induces postural control and patterns of locomotion in newborn rats. Subjects in both experiments were 1-day-old rat pups. In Experiment 1, pups were restrained and tested for air-stepping in a 35-min test session. Immediately following a 5-min baseline, pups were treated with quipazine (1.0, 3.0, or 10.0 mg/kg) or saline (vehicle control), administered intraperitoneally in a 50 μL injection. Bilateral alternating stepping occurred most frequently following treatment with 10.0 mg/kg quipazine, however the percentage of alternating steps, interlimb phase, and step period were very similar between the 3.0 and 10.0 mg/kg doses. For interlimb phase, the forelimbs and hindlimbs maintained a near perfect anti-phase pattern of coordination, with step period averaging about 1s. In Experiment 2, pups were treated with 3.0 or 10.0 mg/kg quipazine or saline, and then were placed on a surface (open field, unrestrained). Both doses of quipazine resulted in developmentally advanced postural control and locomotor patterns, including head elevation, postural stances, pivoting, crawling, and a few instances of quadrupedal walking. The 3.0 mg/kg dose of quipazine was the most effective at evoking sustained locomotion. Between the 2 experiments, behavior exhibited by the rat pup varied based on testing environment, emphasizing the role that environment and sensory cues exert over motor behavior. Overall, quipazine administered at a dose of 3.0 mg/kg was highly effective at promoting alternating limb coordination and inducing locomotor activity in both testing environments.
Topics: Analysis of Variance; Animals; Animals, Newborn; Dose-Response Relationship, Drug; Extremities; Female; Locomotion; Male; Posture; Psychomotor Performance; Quipazine; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Receptor Agonists; Time Factors
PubMed: 26795091
DOI: 10.1016/j.bbr.2016.01.006 -
Neurorehabilitation and Neural Repair Jun 2016In rat models of spinal cord injury, at least 3 different strategies can be used to promote long-term cortical reorganization: (1) active exercise above the level of the...
BACKGROUND
In rat models of spinal cord injury, at least 3 different strategies can be used to promote long-term cortical reorganization: (1) active exercise above the level of the lesion; (2) passive exercise below the level of the lesion; and (3) serotonergic pharmacotherapy. Whether and how these potential therapeutic strategies-and their underlying mechanisms of action-interact remains unknown. Methods In spinally transected adult rats, we compared the effects of active exercise above the level of the lesion (treadmill), passive exercise below the level of the lesion (bike), serotonergic pharmacotherapy (quipazine), and combinations of the above therapies (bike+quipazine, treadmill+quipazine, bike+treadmill+quipazine) on long-term cortical reorganization (9 weeks after the spinal transection). Cortical reorganization was measured as the percentage of cells recorded in the deafferented hindlimb cortex that responded to tactile stimulation of the contralateral forelimb. Results Bike and quipazine are "competing" therapies for cortical reorganization, in the sense that quipazine limits the cortical reorganization induced by bike, whereas treadmill and quipazine are "collaborative" therapies, in the sense that the reorganization induced by quipazine combined with treadmill is greater than the reorganization induced by either quipazine or treadmill.
CONCLUSIONS
These results uncover the interactive effects between active/passive exercise and serotonergic pharmacotherapy on cortical reorganization after spinal cord injury, emphasizing the importance of understanding the effects of therapeutic strategies in spinal cord injury (and in other forms of deafferentation) from an integrated system-level approach.
Topics: Action Potentials; Analysis of Variance; Animals; Cerebral Cortex; Disease Models, Animal; Exercise Test; Exercise Therapy; Exploratory Behavior; Male; Neurons; Quipazine; Rats; Rats, Sprague-Dawley; Serotonin Receptor Agonists; Spinal Cord Injuries
PubMed: 26338432
DOI: 10.1177/1545968315600523 -
The Journal of Pharmacology and... Jan 2023There has been increasing interest in the potential therapeutic effects of drugs with agonist properties at serotonin 2A subtype (5-HT) receptors (e.g., psychedelics),...
There has been increasing interest in the potential therapeutic effects of drugs with agonist properties at serotonin 2A subtype (5-HT) receptors (e.g., psychedelics), including treatment of substance use disorders. Studying interactions between 5-HT receptor agonists and other drugs is important for understanding potential therapeutic effects as well as adverse interactions. Direct-acting 5-HT receptor agonists such as 2,5-dimethoxy-4-methylamphetamine (DOM) and 2-piperazin-1-yl-quinoline (quipazine) enhance some (e.g., antinociceptive) effects of opioids; however, it is unclear whether they alter the abuse-related effects of opioids. This study examined whether DOM and quipazine alter the reinforcing effects of fentanyl in rhesus monkeys (n = 6) responding under a food versus drug choice procedure. Responding on one lever delivered sucrose pellets and responding on the other lever delivered intravenous (i.v.) infusions. In one set of experiments, fentanyl (0.1-3.2 g/kg/infusion) versus food choice sessions were preceded by noncontingent i.v. pretreatments with DOM (0032-0.32 mg/kg), quipazine (0.32-1.0 mg/kg), naltrexone (0.032 mg/kg), or heroin (0.1 mg/kg). In another set of experiments, fentanyl was available during choice sessions in combination with DOM (0.32-100 g/kg/infusion) or quipazine (3.2-320 g/kg/infusion) in varying dose ratios. Naltrexone decreased and heroin increased fentanyl choice, demonstrating sensitivity of responding to pharmacological manipulation. However, whether given as a pretreatment or made available in combination with fentanyl as a mixture, neither DOM nor quipazine significantly altered fentanyl choice. These results suggest that 5-HT receptor agonists do not enhance the reinforcing effects of opioids and, thus, will not likely enhance abuse potential. SIGNIFICANCE STATEMENT: Serotonin 2A subtype receptor agonists enhance some (e.g., antinociceptive) effects of opioids, suggesting they could be combined with opioids in some therapeutic contexts such as treating pain. However, it is unclear whether they also enhance adverse effects of opioids, including abuse. Results of this study indicate that serotonin 2A subtype receptor agonists do not reliably enhance opioid self-administration and, thus, are unlikely to enhance the abuse potential of opioids.
Topics: Animals; Quipazine; Fentanyl; DOM 2,5-Dimethoxy-4-Methylamphetamine; Macaca mulatta; Receptor, Serotonin, 5-HT2A; Heroin; Methamphetamine; Serotonin; Naltrexone; Quinolines; Analgesics, Opioid; Dose-Response Relationship, Drug
PubMed: 36272734
DOI: 10.1124/jpet.122.001318 -
Behavioral Neuroscience Feb 2017Quipazine is a 5-HT-receptor agonist that has been used to induce motor activity and promote recovery of function after spinal cord injury in neonatal and adult rodents....
Quipazine is a 5-HT-receptor agonist that has been used to induce motor activity and promote recovery of function after spinal cord injury in neonatal and adult rodents. Sensory stimulation also activates sensory and motor circuits and promotes recovery after spinal cord injury. In rats, tail pinching is an effective and robust method of sacrocaudal sensory afferent stimulation that induces motor activity, including alternating stepping. In this study, responsiveness to a tail pinch following treatment with quipazine (or saline vehicle control) was examined in spinal cord transected (at midthoracic level) and intact neonatal rats. Rat pups were secured in the supine posture with limbs unrestricted. Quipazine or saline was administered intraperitoneally and after a 10-min period, a tail pinch was administered. A 1-min baseline period prior to tail-pinch administration and a 1-min response period postpinch was observed and hind-limb motor activity, including locomotor-like stepping behavior, was recorded and analyzed. Neonatal rats showed an immediate and robust response to sensory stimulation induced by the tail pinch. Quipazine recovered hind-limb movement and step frequency in spinal rats back to intact levels, suggesting a synergistic, additive effect of 5-HT-receptor and sensory stimulation in spinal rats. Although levels of activity in spinal rats were restored with quipazine, movement quality (high vs. low amplitude) was only partially restored. (PsycINFO Database Record
Topics: Animals; Animals, Newborn; Female; Male; Motor Activity; Quipazine; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Agonists; Spinal Cord Injuries; Tail; Touch
PubMed: 28004950
DOI: 10.1037/bne0000176 -
Journal of Neurophysiology May 2015The spinal cord contains the circuitry to control posture and locomotion after complete paralysis, and this circuitry can be enabled with epidural stimulation...
The spinal cord contains the circuitry to control posture and locomotion after complete paralysis, and this circuitry can be enabled with epidural stimulation [electrical enabling motor control (eEmc)] and/or administration of pharmacological agents [pharmacological enabling motor control (fEmc)] when combined with motor training. We hypothesized that the characteristics of the spinally evoked potentials after chronic administration of both strychnine and quipazine under the influence of eEmc during standing and stepping can be used as biomarkers to predict successful motor performance. To test this hypothesis we trained rats to step bipedally for 7 wk after paralysis and characterized the motor potentials evoked in the soleus and tibialis anterior (TA) muscles with the rats in a non-weight-bearing position, standing and stepping. The middle responses (MRs) to spinally evoked stimuli were suppressed with either or both drugs when the rat was suspended, whereas the addition of either or both drugs resulted in an overall activation of the extensor muscles during stepping and/or standing and reduced the drag duration and cocontraction between the TA and soleus muscles during stepping. The administration of quipazine and strychnine in concert with eEmc and step training after injury resulted in larger-amplitude evoked potentials [MRs and late responses (LRs)] in flexors and extensors, with the LRs consisting of a more normal bursting pattern, i.e., randomly generated action potentials within the bursts. This pattern was linked to more successful standing and stepping. Thus it appears that selected features of the patterns of potentials evoked in specific muscles with stimulation can serve as effective biomarkers and predictors of motor performance.
Topics: Animals; Biomechanical Phenomena; Disease Models, Animal; Electric Stimulation Therapy; Electromyography; Evoked Potentials, Motor; Female; Glycine Agents; Hindlimb; Muscle, Skeletal; Quipazine; Rats; Rats, Sprague-Dawley; Recovery of Function; Serotonin Receptor Agonists; Spinal Cord Injuries; Strychnine; Time Factors
PubMed: 25695648
DOI: 10.1152/jn.00918.2014