Authors: Grigorios Oikonomou, Michael Altermatt, Rong-Wei Zhang...

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

Review

Authors: Adam L Halberstadt, Mark A Geyer

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

Authors: Mario de la Fuente Revenga, Urjita H Shah, Nima Nassehi...

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

Authors: David R Maguire

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

Review

Authors: Michele R Brumley, Sierra D Kauer, Hillary E Swann...

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

Authors: Yury P Gerasimenko, Ronaldo M Ichiyama, Igor A Lavrov...

We hypothesized that epidural spinal cord stimulation (ES) and quipazine (a serotonergic agonist) modulates the excitability of flexor and extensor related intraspinal neural networks in qualitatively unique, but complementary, ways to facilitate locomotion in spinal cord-injured rats. To test this hypothesis, we stimulated (40 Hz) the S(1) spinal segment before and after quipazine administration (0.3 mg/kg, ip) in bipedally step-trained and nontrained, adult, complete spinal (mid-thoracic) rats. The stepping pattern of these rats was compared with control rats. At the stimulation levels used, stepping was elicited only when the hindlimbs were placed on a moving treadmill. In nontrained rats, the stepping induced by ES and quipazine administration was non-weight bearing, and the cycle period was shorter than in controls. In contrast, the stepping induced by ES and quipazine in step-trained rats was highly coordinated with clear plantar foot placement and partial weight bearing. The effect of ES and quipazine on EMG burst amplitude and duration was greater in flexor than extensor motor pools. Using fast Fourier transformation analysis of EMG bursts during ES, we observed one dominant peak at 40 Hz in the medial gastrocnemius (ankle extensor), whereas there was less of dominant spectral peak in the tibialis anterior (ankle flexor). We suggest that these frequency distributions reflect amplitude modulation of predominantly monosynaptic potentials in the extensor and predominantly polysynaptic pathways in the flexor muscle. Quipazine potentiated the amplitude of these responses. The data suggest that there are fundamental differences in the circuitry that generates flexion and extension during locomotion.

Topics: Animals; Behavior, Animal; Biomechanical Phenomena; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation Therapy; Electrodes, Implanted; Electromyography; Epidural Space; Female; Locomotion; Motor Activity; Quipazine; Rats; Rats, Sprague-Dawley; Reflex; Serotonin Receptor Agonists; Spectrum Analysis; Spinal Cord; Spinal Cord Injuries

PubMed: 17855582
DOI: 10.1152/jn.00836.2007

A combination therapy of neural and glial restricted precursor cells and chronic quipazine treatment paired with passive cycling promotes quipazine-induced stepping in adult spinalized rats.

Authors: Elizabeth A Dugan, Jed S Shumsky

INTRODUCTION

In order to develop optimal treatments to promote recovery from complete spinal cord injury (SCI), we examined the combination of: (1) a cellular graft of neural and glial restricted precursor (NRP/GRP) cells, (2) passive exercise, and (3) chronic quipazine treatment on behavioral outcomes and compared them with the individual treatment elements. NRP/GRP cells were transplanted at the time of spinalization.

METHODS

Daily passive exercise began 1 week after injury to give sufficient time for the animals to recover. Chronic quipazine administration began 2 weeks after spinalization to allow for sufficient receptor upregulation permitting the expression of its behavioral effects. Behavioral measures consisted of the Basso, Beattie, and Bresnahan (BBB) locomotor score and percent of weight-supported steps and hops on a treadmill.

RESULTS

Rats displayed an increased response to quipazine (BBB ≥ 9) beginning at 8 weeks post-injury in all the animals that received the combination therapy. This increase in BBB score was persistent through the end of the study (12 weeks post-injury).

CONCLUSION

Unlike the individual treatment groups which never achieved weight support, the combination therapy animals were able to perform uncoordinated weight-supported stepping without a body weight support system while on a moving treadmill (6.5 m per minute) and were capable of supporting their own weight in stance during open field locomotion testing. No regeneration of descending serotonergic projections into and through the lesion cavity was observed. Furthermore, these results are a testament to the capacity of the lumbar spinal cord, when properly stimulated, to sustain functioning locomotor circuitry following complete SCI.

Topics: Animals; Exercise Therapy; Female; Neural Stem Cells; Neuroglia; Quipazine; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Stem Cell Transplantation; Walking

PubMed: 25329574
DOI: 10.1179/2045772314Y.0000000274

Authors: David R Maguire, Jun-Xu Li, Wouter Koek...

RATIONALE

The serotonin (5-HT) system is involved in pain modulation, and 5-HT receptor agonists can enhance antinociceptive effects of mu opioid receptor agonists. Less is known about the actions of 5-HT receptor agonists on other effects of opioids.

OBJECTIVE

This study examined the effects of non-contingent and contingent administration of the 5-HT(2A) receptor agonists DOM and quipazine on i.v. heroin self-administration in rhesus monkeys.

RESULTS

Heroin (0.0001-0.1 mg/kg/infusion) generated an inverted U-shaped dose-response function. Non-contingent administration of DOM (0.1-0.32 mg/kg) flattened the dose-response function in three monkeys and eliminated heroin self-administration in a fourth monkey. Contingent DOM (0.0032-0.032 mg/kg/infusion) alone did not maintain responding above that maintained by saline, and, when added to self-administered heroin, monkeys responded less than for the same unit doses of heroin alone. Non-contingent (0.32-3.2 mg/kg) and contingent (0.0032-0.56 mg/kg/infusion) administration of quipazine flattened the dose-response function in two monkeys, increasing responding maintained by small unit doses of heroin and saline, but failed to enhance responding for heroin in two other monkeys.

CONCLUSION

This study shows that DOM does not enhance, and might attenuate, the positive reinforcing effects of the mu opioid receptor agonist heroin. Quipazine increased responding for saline and small doses of heroin; those effects were modest and observed in only two subjects. Taken together, these data suggest that 5-HT(2A) receptor agonists do not significantly enhance the reinforcing effectiveness of mu opioid receptor agonists and support the view that administering 5-HT drugs in combination with opioids to treat pain might not enhance abuse liability.

Topics: DOM 2,5-Dimethoxy-4-Methylamphetamine; Animals; Dose-Response Relationship, Drug; Female; Heroin; Macaca mulatta; Male; Quipazine; Reinforcement Schedule; Self Administration; Serotonin 5-HT2 Receptor Agonists

PubMed: 22836370
DOI: 10.1007/s00213-012-2803-0

Authors: N A Sharif, E H Wong, D N Loury...

1. The biochemical and pharmacological properties of 5-HT3 receptors in homogenates of NG108-15 and NCB-20 neuroblastoma cells and rat cerebral cortex have been ascertained by the use of [3H]-quipazine and [3H]-GR65630 binding. 2. In NG108-15 and NCB-20 cell homogenates, [3H]-quipazine bound to a single class of high affinity (NG108-15: Kd = 6.2 +/- 1.1 nM, n = 4; NCB-20: Kd = 3.0 +/- 0.9 nM, n = 4; means +/- s.e.means) saturable (NG108-15: Bmax = 1340 +/- 220 fmol mg-1 protein; NCB-20: Bmax = 2300 +/- 200 fmol mg-1 protein) binding sites. In rat cortical homogenates, [3H]-quipazine bound to two populations of binding sites in the absence of the 5-hydroxytryptamine (5-HT) uptake inhibitor, paroxetine (Kd1 = 1.6 +/- 0.5 nM, Bmax1 = 75 +/- 14 fmol mg-1 protein; Kd2 = 500 +/- 300 nM, Bmax2 = 1840 +/- 1040 fmol mg-1 protein, n = 3), and to a single class of high affinity binding sites (Kd = 2.0 +/- 0.5 nM, n = 3; Bmax = 73 +/- 6 fmol mg-1 protein) in the presence of paroxetine. The high affinity (nanomolar) component probably represented 5-HT3 binding sites and the low affinity component represented 5-HT uptake sites. 3. [3H]-paroxetine bound with high affinity (Kd = 0.02 +/- 0.003 nM, n = 3) to a site in rat cortical homogenates in a saturable (Bmax = 323 +/- 45 fmol mg-1 protein, n = 3) and reversible manner. Binding to this site was potently inhibited by 5-HT uptake blockers such as paroxetine and fluoxetine (pKi s = 8.6-9.9), while 5-HT3 receptor ligands exhibited only low affinity (pK; < 7). No detectable specific [3H]-paroxetine binding was observed in NG108-15 or NCB-20 cell homogenates. 4. [3H]-quipazine binding to homogenates of NG108-15, NCB-20 cells and rat cortex (in the presence of 0.1 microM paroxetine) exhibited similar pharmacological characteristics. 5-HT3 receptor antagonists competed for [3H]-quipazine binding with high nanomolar affinities in the three preparations and the rank order of affinity was: (S)-zacopride > quarternized ICS 205-930 2 granisetron > ondansetron > ICS 205-209 (R)-zacopride > quipazine > renzapride > MDL-72222 > butanopride > metoclopramide. 5. [3H]-GR65630 labelled a site in NCB-20 cell homogenates with an affinity (Kd = 0.7 + 0.1 nms n = 4) and density (B__ = 1800 + 1000 fmol mg- protein) comparable to that observed with [3H]-quipazine. Competition studies also indicated a good correlation between the pharmacology of 5-HT3 binding sites when [3H]-GR65630 and [3H]-quipazine were used in these cells. 6. In conclusion, [3H]-quipazine labelled 5-HT3 receptor sites in homogenates of NG108-15 cells, NCB-20 cells and rat cerebral cortex. In rat cortical homogenates, [3H]-quipazine also bound to 5-HT uptake sites, which could be blocked by 0.1 microM paroxetine. The pharmacological specificity of the 5-HT3 receptor labelled by [3H]-quipazine was similar in the neuroblastoma cells and rat cortex and was substantiated in NCB-20 cells by the binding profile of the selective 5-HT3 receptor antagonist, [3H]-GR65630.

Topics: Animals; Binding, Competitive; Cell Line; Cerebral Cortex; Imidazoles; Indoles; Kinetics; Ligands; Mice; Nervous System Neoplasms; Neuroblastoma; Paroxetine; Piperidines; Quipazine; Rats; Receptors, Serotonin; Serotonin Antagonists; Tumor Cells, Cultured

PubMed: 1830236
DOI: 10.1111/j.1476-5381.1991.tb12277.x

Authors: Hillary E Swann-Thomsen, Derek D Viall, Michele R Brumley...

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