The head-twitch response in the least shrew (Cryptotis parva) is a 5-HT2− and not a 5-HT1C-mediated phenomenon

Darmani, Nissar A.; Mock, Orin B.; Towns, Lex C.; Gerdes, C

doi:10.1016/0091-3057(94)90542-8

Cited by 35 publications

(27 citation statements)

References 23 publications

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“…Moreover, i.p. administration of the selective 5-HT 2A R agonist, DOI, produces the head-twitch response in the least shrew [61] but not emesis [Darmani, unpublished observation]. Likewise, at diverse doses, we tested the antiemetic potential of two selective 5-HT 6 R antagonists (Ro-046790 and Ro-04368554).…”

Section: Discussionmentioning

confidence: 99%

Serotonin 5-HT3 Receptor-Mediated Vomiting Occurs via the Activation of Ca2+/CaMKII-Dependent ERK1/2 Signaling in the Least Shrew (Cryptotis parva)

et al. 2014

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Stimulation of 5-HT3 receptors (5-HT3Rs) by 2-methylserotonin (2-Me-5-HT), a selective 5-HT3 receptor agonist, can induce vomiting. However, downstream signaling pathways for the induced emesis remain unknown. The 5-HT3R channel has high permeability to extracellular calcium (Ca2+) and upon stimulation allows increased Ca2+ influx. We examined the contribution of Ca2+/calmodulin-dependent protein kinase IIα (Ca2+/CaMKIIα), interaction of 5-HT3R with calmodulin, and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling to 2-Me-5-HT-induced emesis in the least shrew. Using fluo-4 AM dye, we found that 2-Me-5-HT augments intracellular Ca2+ levels in brainstem slices and that the selective 5-HT3R antagonist palonosetron, can abolish the induced Ca2+ signaling. Pre-treatment of shrews with either: i) amlodipine, an antagonist of L-type Ca2+ channels present on the cell membrane; ii) dantrolene, an inhibitor of ryanodine receptors (RyRs) Ca2+-release channels located on the endoplasmic reticulum (ER); iii) a combination of their less-effective doses; or iv) inhibitors of CaMKII (KN93) and ERK1/2 (PD98059); dose-dependently suppressed emesis caused by 2-Me-5-HT. Administration of 2-Me-5-HT also significantly: i) enhanced the interaction of 5-HT3R with calmodulin in the brainstem as revealed by immunoprecipitation, as well as their colocalization in the area postrema (brainstem) and small intestine by immunohistochemistry; and ii) activated CaMKIIα in brainstem and in isolated enterochromaffin cells of the small intestine as shown by Western blot and immunocytochemistry. These effects were suppressed by palonosetron. 2-Me-5-HT also activated ERK1/2 in brainstem, which was abrogated by palonosetron, KN93, PD98059, amlodipine, dantrolene, or a combination of amlodipine plus dantrolene. However, blockade of ER inositol-1, 4, 5-triphosphate receptors by 2-APB, had no significant effect on the discussed behavioral and biochemical parameters. This study demonstrates that Ca2+ mobilization via extracellular Ca2+ influx through 5-HT3Rs/L-type Ca2+ channels, and intracellular Ca2+ release via RyRs on ER, initiate Ca2+-dependent sequential activation of CaMKIIα and ERK1/2, which contribute to the 5-HT3R-mediated, 2-Me-5-HT-evoked emesis.

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Section: Discussionmentioning

confidence: 99%

Serotonin 5-HT3 Receptor-Mediated Vomiting Occurs via the Activation of Ca2+/CaMKII-Dependent ERK1/2 Signaling in the Least Shrew (Cryptotis parva)

et al. 2014

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“…In rodent models, central administration of NK 1 receptor agonists induces a specific behavior analogous to foot-tapping in gerbils called scratching [43]. We had previously observed in the least shrew that the serotonergic 5-HT 2A receptor agonist DOI also induced centrally-mediated head-twitch and scratching behaviors analogous to those seen in DOI-treated rodents [11,62], which were sensitive to both 5-HT 2A and NK 1 receptor antagonists [11,12,62], and our preliminary studies indicated that i.p. injection of the NK 1 receptor agonist GR73632 can rapidly induce both emesis and scratching behavior in the least shrew.…”

Section: Introductionmentioning

confidence: 97%

“…In the current study, in addition to emesis, systemic administration of the brain-penetrating NK 1 receptor agonist GR73632 [25] in the least shrew concomitantly produced scratching behavior in a dose-dependent manner. This behavior, analogous to mouse ear-scratching, is mediated centrally in both rodents and shrews via the stimulation of NK 1 or serotonergic 5-HT 2A receptors [11,12,16,62]. The crosstalk between the two neurotransmitter systems is demonstrable, in that blockade of NK 1 receptors prevents serotonergically induced scratching and head-twitching behavior in mice [12].…”

Section: Behavioral Effects Of Substance P Relate To Cns Penetrationmentioning

confidence: 99%

“…of both vomiting (oral ejections of food or liquid, or the act of vomiting which did not result in actual ejection of food or liquid due to an empty stomach) and scratching behaviors were recorded for the next 30 min. Scratches within a bout were counted and scored cumulatively, with a new bout starting either: 1) after a 2 sec interval without scratching; or 2) after the shrew would switch to scratching with the opposing limb no matter how long an interval had passed since the previous bout (see also [11]). Based on these results, i.p.…”

Section: Dose-response Emesis and Scratching Studies With Tachykinin mentioning

confidence: 99%

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Utilization of the least shrew as a rapid and selective screening model for the antiemetic potential and brain penetration of substance P and NK1 receptor antagonists

et al. 2008

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Substance P (SP) is thought to play a cardinal role in emesis via the activation of central tachykinin NK 1 receptors during the delayed phase of vomiting produced by chemotherapeutics. Although the existing supportive evidence is significant, due to lack of an appropriate animal model, the evidence is indirect. As yet, no study has confirmed that emesis produced by SP or a selective NK 1 receptor agonist is sensitive to brain penetrating antagonists of either NK 1 , NK 2 , or NK 3 receptors. The goals of this investigation were to demonstrate: 1) whether intraperitoneal (i.p.) administration of either SP, a brain penetrating (GR73632) or non-penetrating (e.g. SarMet -SP) NK 1 receptor agonist, an NK 2 receptor agonist (GR64349), or an NK 3 receptor agonist (Pro 7 -NKB), would induce vomiting and/or scratching in the least shrew (Cryptotis parva) in a dose-dependent manner; and whether these effects are sensitive to the above selective receptor antagonists; 2) whether an exogenous emetic dose of SP (50 mg/kg, i.p.) can penetrate into the shrew brain stem and frontal cortex; 3) whether GR73632 (2.5 mg/kg, i.p.)-induced activation of NK 1 receptors increases Fos-measured neuronal activity in the neurons of both brain stem emetic nuclei and the enteric nervous system of the gut; and 4) whether selective ablation of peripheral NK 1 receptors can affect emesis produced by GR73632. The results clearly demonstrated that while SP produced vomiting only, GR73632 caused both emesis and scratching behavior dose-dependently in shrews, and these effects were sensitive to NK 1 -, but not NK 2 -or NK 3 -receptor antagonists. Neither the selective, non-penetrating NK 1 receptor agonists, nor the selective NK 2 -or NK 3 -receptor agonists, caused a significant dose-dependent behavioral effect. An emetic dose of SP selectively and rapidly penetrated the brain stem but not the frontal cortex. Systemic GR73632 increased Fos expression in the enteric nerve plexi, the medial subnucleus of nucleus tractus solitarius, and the dorsal motor nucleus of the vagus, but not the area postrema. Ablation of peripheral NK 1 receptors attenuated the ability of GR73632 to induce a maximal frequency of emesis and shifted its percent animals vomiting dose-response curve to the right. The NK 1 -ablated shrews exhibited scratching behavior after systemic GR73632-injection. These results, for the first time, affirm a cardinal role for central NK 1 receptors in SP-induced vomiting, and a Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. facilitatory role for gastrointestinal NK 1 receptors. In addition, the...

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“…Quipazine also binds at 5-HT 1A and 5-HT 1B receptors and behaves as an agonist at these populations (Peroutka 1985;Schoeffter and Hoyer 1989). [It might be parenthetically noted that MD-354 seems to lack 5-HT 2A and 5-HT 1A agonist actions, since it failed to produce either the head-twitch response or the serotonin syndrome, which are considered to be functional models of 5-HT 2A and 5-HT 1A receptor activation, respectively (Darmani et al 1994;Darmani and Zhao 1999).] mCPBG is known to facilitate norepinephrine release (Schlicker et al 1994) and to interact with the dopamine transporter (Campbell et al 1995); it is not known at this time if MD-354 shares these actions.…”

Section: Discussionmentioning

confidence: 97%

The 5-HT 3 agent N -(3-chlorophenyl)guanidine (MD-354) serves as a discriminative stimulus in rats and displays partial agonist character in a shrew emesis assay

et al. 2000

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The head-twitch response in the least shrew (Cryptotis parva) is a 5-HT2− and not a 5-HT1C-mediated phenomenon

Cited by 35 publications

References 23 publications

Serotonin 5-HT3 Receptor-Mediated Vomiting Occurs via the Activation of Ca2+/CaMKII-Dependent ERK1/2 Signaling in the Least Shrew (Cryptotis parva)

Serotonin 5-HT3 Receptor-Mediated Vomiting Occurs via the Activation of Ca2+/CaMKII-Dependent ERK1/2 Signaling in the Least Shrew (Cryptotis parva)

Utilization of the least shrew as a rapid and selective screening model for the antiemetic potential and brain penetration of substance P and NK1 receptor antagonists

The 5-HT 3 agent N -(3-chlorophenyl)guanidine (MD-354) serves as a discriminative stimulus in rats and displays partial agonist character in a shrew emesis assay

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