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Acepromazine and Chlorpromazine As Pharmaceutical-Grade Alternatives to Chlorprothixene for Pupillary Light Reflex Imaging in Mice

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Acepromazine and Chlorpromazine As Pharmaceutical-Grade Alternatives to Chlorprothixene for Pupillary Light Reflex Imaging in Mice Journal of the American Association for Laboratory Animal Science Vol 59, No 2 Copyright 2020 March 2020 by the American Association for Laboratory Animal Science Pages 197–203 Acepromazine and Chlorpromazine as Pharmaceutical-grade Alternatives to Chlorprothixene for Pupillary Light Reflex Imaging in Mice Samantha S Eckley,1 Jason S Villano,1 Nora S Kuo,1 and Kwoon Y Wong2,* Studies of visual responses in isoflurane-anesthetized mice often use the sedative chlorprothixene to decrease the amount of isoflurane used because excessive isoflurane could adversely affect light-evoked responses. However, data are not available to justify the use of this nonpharmaceutical-grade chemical. The current study tested whether pharmaceutical-grade sedatives would be appropriate alternatives for imaging pupillary light reflexes. Male 15-wk-old mice were injected intraperitoneally with 1 mg/kg chlorprothixene, 5 mg/kg acepromazine, 10 mg/kg chlorpromazine, or saline. After anesthetic induction, anes- thesia maintenance used 0.5% and 1% isoflurane for sedative- and saline-injected mice, respectively. A photostimulus (16.0 log photons cm−2 s−1; 470 nm) was presented to the right eye for 20 min, during which the left eye was imaged for consensual pupillary constriction and involuntary pupil drift. Time to immobilization, loss of righting reflex, physiologic parameters, gain of righting reflex, and degree of recovery were assessed also. The sedative groups were statistically indistinguishable for all measures. By contrast, pupillary drift occurred far more often in saline-treated mice than in the sedative groups. Fur- thermore, saline-treated mice took longer to reach maximal pupil constriction than all sedative groups and had lower heart rates compared with chlorpromazine- and chlorprothixene-sedated mice. Full recovery (as defined by purposeful movement, response to tactile stimuli, and full alertness) was not regularly achieved in any sedative group. In conclusion, at the doses tested, acepromazine and chlorpromazine are suitable pharmaceutical-grade alternatives to chlorprothixene for pupil imaging and conceivably other in vivo photoresponse measurements; however, given the lack of full recovery, lower dosages should be investigated further for use in survival procedures. Abbreviations: GORR, gain of righting reflex; LORR, loss of righting reflex; PLR, pupillary light reflex DOI: 10.30802/AALAS-JAALAS-19-000094 Light-evoked pupillary constriction, also known as the pupil- conjunction with a sedative so that the level of isoflurane can be lary light reflex (PLR), is mediated by melanopsin-expressing, reduced considerably. A commonly used anesthetic approach intrinsically photosensitive retinal ganglion cells that drive for in vivo electrophysiologic studies of light-evoked responses various nonimage-forming visual responses as well as regu- is premedication with chlorprothixene, an antipsychotic drug of late conscious visual perception.21,24,26,34 Thus, PLR imaging the thioxanthene class, followed by isoflurane levels maintained is useful for assessing the properties and functions of these at or below 0.5%.11,27,39,44 Chlorprothixene is an antagonist at ganglion cells.18,20,34,35,49,52 PLR studies in mice sometimes use dopamine, serotonin, histamine, muscarinic acetylcholine, and anesthesia to immobilize the animals, but conventional veteri- α-adrenergic receptors.17,38 Chlorprothixene has been discontin- nary anesthetic regimens have presented various challenges. ued in the United States as a pharmaceutical-grade compound The inhalant anesthetic isoflurane has been shown to suppress but is still available in Europe.1,12,28 the PLR in humans.3,32 Meanwhile, xylazine, an α2 adrenergic According to The Guide for the Care and Use of Laboratory Ani- agonist typically used as a sedative and in combination with mals, pharmaceutical-grade chemicals “should…be used, when ketamine, can cause acute reversible lens opacities8 that interfere available, for all animal-related procedures” and “[t]he use of with pupillary imaging. nonpharmaceutical-grade chemicals or substances should be In PLR imaging studies, most of the stated complications may described and justified in the animal use protocol…”.30 The 2 be circumvented by hand-restraining unanesthetized mice,48 but primary concerns of using reagent-grade chemicals are steril- this method is infeasible for prolonged continuous imaging51 ity and efficacy. Sterility can be achieved through appropriate and could trigger anxiety and other autonomic responses that handling and filtration but is difficult to maintain when dosing alter the pupil size.5,7 Another strategy is to apply isoflurane in multiple animals. Efficacy is especially important for anesthetics and analgesics, because a decline in efficacy can immediately compromise animal welfare. The main advantage of using Received: 01 Jul 2019. Revision requested: 03 Sept 2019. Accepted: 09 Sept 2019. pharmaceutical-grade compounds is that they are formulated 1 2 Unit for Laboratory Animal Medicine, Department of Ophthalmology and Visual Sci- to account for such properties as purity, sterility, biocompat- ences, and Department of Molecular,Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan ibility, osmolality, and pH so that they are suitable for in vivo *Corresponding author. Email: [email protected] 197 Vol 59, No 2 Journal of the American Association for Laboratory Animal Science March 2020 use. In the United States, chlorprothixene is available only in suppression of involuntary pupillary drift during PLR imaging reagent-grade form, necessitating justification in the animal (see later section). Chlorprothixene powder was made to 8 mg/ protocol and extra precautions for use. To provide such justi- mL in 100% dimethylsulfoxide, and then diluted in saline to its fication, there should be clear benefits to using chloprothixene final concentration of 0.2 mg/mL and sterile-filtered through over other pharmaceutical-grade options, but no such benefits a 0.22-µm hydrophilic PVDF filter (Thermo Fisher Scientific, have been reported in the literature. Therefore, an appropriate Waltham, MA). Acepromazine and chlorpromazine liquid pharmaceutical-grade substitute needed to be identified. Two stocks were diluted with saline to their final concentrations of potential pharmaceutical-grade alternatives are acepromazine 1 and 2 mg/mL, respectively. The final concentrations of all and chlorpromazine, which are both phenothiazines with a drugs were determined such that the injection volume would similar chemical backbone structure and mechanism of action be the same, regardless of the drug. Each mouse was weighed to chlorprothixene. Acepromazine is an antipsychotic medica- shortly before dosing, and the injection volume was calculated tion, but its current use is mainly in animals as a sedative and according to the weight. antiemetic.41,47 Chlorpromazine has been used as an antipsy- After injection, mice were observed for 1 min for the chotic and antiemetic in humans.4,37 absence of adverse effects, such as hunching, jumping, uri- Here, we compared the use of chlorprothixene, acepromazine, nation, defecation, and increased activity. Anesthesia was and chlorpromazine as premedications when measuring murine then induced by using 4% isoflurane (VetOne) and a portable PLR. We hypothesized that acepromazine and chlorpromazine, anesthesia machine (Patterson Scientific, Waukesha, WI), and like chlorprothixene, would enable us to reduce the isoflurane times to recumbency and loss of righting reflex (LORR) were level needed to immobilize a mouse to 0.5% and that all 3 seda- determined. Time to recumbency was defined as the moment tives would yield quantitatively comparable PLR. In addition, when the animal’s body and head were in full contact with we examined PLR in nonsedative-treated mice that were im- the chamber floor. The onset of recumbency triggered the as- mobilized by using the lowest isoflurane level needed (1%), to sessment of LORR, which was determined by manually tilting learn whether this fairly low level would avoid suppressing the the chamber to place the animal on its back and assessing its PLR, thereby obviating the need for sedatives. ability to right itself within 10 s. When the mouse righted itself, then the next assessment was made when recumbency was Materials and Methods again achieved. After LORR was attained (at approximately Animals. All procedures were approved by the University 2.4 min after injection), the isoflurane level was lowered to of Michigan IACUC. Male 15-wk-old B6129SF2/J mice (The 1% until 5 min postinjection, when it was reduced further to Jackson Laboratory, Bar Harbor, ME) were group-housed in 0.5% for the sedative groups for the remainder of the study; IVC (Allentown, Allentown, NJ) on Pure-o’Cel bedding (The isoflurane was kept at 1% for mice injected with saline, to Andersons Lab Bedding, Maumee, OH) with unrestricted maintain immobilization. access to triple-filtered city water; we tested just one sex and Imaging. Pupil imaging was performed between 0900 and one age to minimize the number of animals required and the 1600. Mice were placed sternally on a recirculating water blan- number of variables. Animal rooms were maintained on a ket (K-Mod 100 Heat Therapy Pump, Baxter, Deerfield, IL) set 12:12-h light:dark cycle, relative humidity of 30% to 70%, and at 41 °C. The right pupil of each mouse was dilated by using temperature of 72 ± 2 °F (22.2 ± 1.1 °C). Health surveillance drops of 2.5% phenylephrine
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