Abstract
Background
Prepulse inhibition (PPI) of startle is a sensorimotor gating phenomenon perturbed in a variety of neuropsychiatric conditions. Psychedelics disrupt PPI in rats and humans, but their effects and involvement of the serotonin 5-HT2A receptor (5-HT2AR) in mice remain unexplored.
Methods
We tested the effect of the psychedelic 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.5 mg/kg, i.p.) on startle amplitude and %PPI in response to acoustic stimuli under up to four different experimental conditions that included changes in background and stimulus intensity, prepulse and pulse duration, and interstimulus interval in male and female 129S6/SvEv mice. We also evaluated the effect of the 5-HT2AR antagonist M100,907 (1 mg/kg, i.p.) on DOI-induced startle amplitude and %PPI, as well as the effect of the psychedelic LSD (0.24 mg/kg, i.p.) and the dopamine agonists apomorphine (5 mg/kg, s.c.) and SKF-82,958 (0.5 mg/kg, i.p.) in male 129S6/SvEv mice.
Results
DOI altered startle amplitude with either pulse alone or prepulse + pulse presentations in all PPI conditions, and increased %PPI in three out of four PPI conditions in male mice — an effect that was prevented by M100,907. In female mice, DOI increased %PPI without affecting startle amplitude. %PPI was positively correlated with startle amplitude in males while being negatively correlated in female mice. In male mice, LSD also increased %PPI, although it did not affect startle amplitude, whereas apomorphine and SKF-82,958 induced decreases in %PPI.
Conclusion
Our findings highlight a distinct effect of the psychedelic DOI on PPI in 129S6/SvEv mice, suggesting 5-HT2AR-dependent PPI improvement in a paradigm-dependent and sex-dependent manner.
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References
Allen JA, Yadav PN, Setola V, Farrell M, Roth BL (2011) Schizophrenia risk gene CAV1 is both pro-psychotic and required for atypical antipsychotic drug actions in vivo. Transl Psychiatry 1:e33. https://doi.org/10.1038/tp.2011.35
Aubert L, Reiss D, Ouagazzal A-M (2006) Auditory and visual prepulse inhibition in mice: parametric analysis and strain comparisons. Genes Brain Behav 5:423–431. https://doi.org/10.1111/j.1601-183X.2005.00178.x
Bershad AK, Schepers ST, Bremmer MP, Lee R, de Wit H (2019) Acute subjective and behavioral effects of microdoses of lysergic acid diethylamide in healthy human volunteers. Biol Psychiatry 86:792–800. https://doi.org/10.1016/j.biopsych.2019.05.019
Canal CE, Morgan D (2012) Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model. Drug Test Anal 4:556–576. https://doi.org/10.1002/dta.1333
de la Fuente Revenga M, Shin JM, Vohra HZ, Hideshima KS, Schneck M, Poklis JL, González-Maeso J (2019) Fully automated head-twitch detection system for the study of 5-HT2A receptor pharmacology in vivo. Sci Rep 9:14247. https://doi.org/10.1038/s41598-019-49913-4
de la Fuente Revenga M, Vohra HZ, González-Maeso J (2020) Automated quantification of head-twitch response in mice via ear tag reporter coupled with biphasic detection. J Neurosci Methods 334:108595. https://doi.org/10.1016/j.jneumeth.2020.108595
Dulawa SC, Geyer MA (2000) Effects of strain and serotonergic agents on prepulse inhibition and habituation in mice. Neuropharmacology 39:2170–2179. https://doi.org/10.1016/s0028-3908(00)00030-7
Dulawa SC, Gross C, Stark KL, Hen R, Geyer MA (2000) Knockout mice reveal opposite roles for serotonin 1A and 1B receptors in prepulse inhibition. Neuropsychopharmacology 22:650–659. https://doi.org/10.1016/S0893-133X(99)00164-5
Enga RM, Rice AC, Weller P, Subler MA, Lee D, Hall CP, Windle JJ, Beardsley PM, van den Oord EJ, McClay JL (2017) Initial characterization of behavior and ketamine response in a mouse knockout of the post-synaptic effector gene Anks1b. Neurosci Lett 641:26–32. https://doi.org/10.1016/j.neulet.2017.01.044
Farid M, Martinez ZA, Geyer MA, Swerdlow NR (2000) Regulation of sensorimotor gating of the startle reflex by serotonin 2A receptors. Ontogeny and strain differences Neuropsychopharmacology 23:623–632. https://doi.org/10.1016/S0893-133X(00)00163-9
Fendt M, Li L, Yeomans JS (2001) Brain stem circuits mediating prepulse inhibition of the startle reflex. Psychopharmacology 156:216–224. https://doi.org/10.1007/s002130100794
Freedland CS, Mansbach RS (1999) Behavioral profile of constituents in ayahuasca, an Amazonian psychoactive plant mixture. Drug Alcohol Depend 54:183–194. https://doi.org/10.1016/s0376-8716(98)00154-9
Geyer MA, Dulawa SC (2003) Assessment of murine startle reactivity, prepulse inhibition, and habituation. Curr Protoc Neurosci 24:8.17.1–8.17.15. https://doi.org/10.1002/0471142301.ns0817s24
Glennon RA (1994) Classical hallucinogens: an introductory overview. NIDA Res Monogr 146:4–32
Gogos A, Bogeski M, van den Buuse M (2008) Role of serotonin-1A receptors in the action of antipsychotic drugs: comparison of prepulse inhibition studies in mice and rats and relevance for human pharmacology. Behav Pharmacol 19:548–561. https://doi.org/10.1097/FBP.0b013e32830cd822
Gómez-Nieto R, Hormigo S, López DE (2020) Prepulse inhibition of the auditory startle reflex assessment as a hallmark of brainstem sensorimotor gating mechanisms. Brain Sciences 10:639. https://doi.org/10.3390/brainsci10090639
González-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, Lira A, Bradley-Moore M, Ge Y, Zhou Q, Sealfon SC, Gingrich JA (2007) Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron 53:439–452. https://doi.org/10.1016/j.neuron.2007.01.008
Gouzoulis-Mayfrank E, Heekeren K, Thelen B, Lindenblatt H, Kovar KA, Sass H, Geyer MA (1998) Effects of the hallucinogen psilocybin on habituation and prepulse inhibition of the startle reflex in humans. Behav Pharmacol 9:561–566. https://doi.org/10.1097/00008877-199811000-00011
Halberstadt AL (2020) Automated detection of the head-twitch response using wavelet scalograms and a deep convolutional neural network. Sci Rep 10:8344. https://doi.org/10.1038/s41598-020-65264-x
Halberstadt AL, Geyer MA (2010) LSD but not lisuride disrupts prepulse inhibition in rats by activating the 5-HT(2A) receptor. Psychopharmacology 208:179–189. https://doi.org/10.1007/s00213-009-1718-x
Halberstadt AL, Geyer MA (2011) Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology 61:364–381. https://doi.org/10.1016/j.neuropharm.2011.01.017
Halberstadt AL, Geyer MA (2018) Effect of hallucinogens on unconditioned behavior. Curr Top Behav Neurosci 36:159–199. https://doi.org/10.1007/7854_2016_466
Hanks JB, González-Maeso J (2013) Animal models of serotonergic psychedelics. ACS Chem Neurosci 4:33–42. https://doi.org/10.1021/cn300138m
Hanks JB, González-Maeso J (2016a) Hallucinogens: circuits, behavior and translational models. In: Preedy VR (ed) Neuropathology of drug addictions and substance misuse, volume 2. Elsevier, pp 813–820
Hanks JB, González-Maeso J (2016b) Molecular and cellular basis of hallucinogenic drug action. In: Preedy VR (ed) Neuropathology of drug addictions and substance misuse, volume 2. Elsevier, pp 803–812
Hazama K, Hayata-Takano A, Uetsuki K, Kasai A, Encho N, Shintani N, Nagayasu K, Hashimoto R, Reglodi D, Miyakawa T, Nakazawa T, Baba A, Hashimoto H (2014) Increased behavioral and neuronal responses to a hallucinogenic drug in PACAP heterozygous mutant mice. PLoS One 9:e89153. https://doi.org/10.1371/journal.pone.0089153
Ibarra-Lecue I, Mollinedo-Gajate I, Meana JJ, Callado LF, Diez-Alarcia R, Urigüen L (2018) Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway. Neuropsychopharmacology 43:2028–2035. https://doi.org/10.1038/s41386-018-0076-y
Jaggar M, Weisstaub N, Gingrich JA, Vaidya VA (2017) 5-HT2A receptor deficiency alters the metabolic and transcriptional, but not the behavioral, consequences of chronic unpredictable stress. Neurobiol Stress 7:89–102
Johansson C, Jackson DM, Zhang J, Svensson L (1995) Prepulse inhibition of acoustic startle, a measure of sensorimotor gating: effects of antipsychotics and other agents in rats. Pharmacol Biochem Behav 52:649–654. https://doi.org/10.1016/0091-3057(95)00160-x
Kurita M, Holloway T, García-Bea A, Kozlenkov A, Friedman AK, Moreno JL, Heshmati M, Golden SA, Kennedy PJ, Takahashi N, Dietz DM, Mocci G, Gabilondo AM, Hanks J, Umali A, Callado LF, Gallitano AL, Neve RL, Shen L, Buxbaum JD, Han M-H, Nestler EJ, Meana JJ, Russ SJ, González-Maeso J (2012) HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nat Neurosci 15:1245–1254. https://doi.org/10.1038/nn.3181
López-Giménez JF, Mengod G, Palacios JM, Vilaró MT (1997) Selective visualization of rat brain 5-HT2A receptors by autoradiography with [3H]MDL 100,907. Naunyn Schmiedeberg's Arch Pharmacol 356:446–454. https://doi.org/10.1007/pl00005075
López-Giménez JF, Vilaró MT, Palacios JM, Mengod G (1998) [3H]MDL100,907 labels 5-HT2A serotonin receptors selectively in primate brain. Neuropharmacology 37:1147–1158. https://doi.org/10.1016/S0028-3908(98)00102-6
López-Giménez JF, Vilaró MT, Palacios JM, Mengod G (2001) Mapping of 5-HT2A receptors and their mRNA in monkey brain: [3H]MDL100,907 autoradiography and in situ hybridization studies. The J of Comparative Neurology 429:571–589. https://doi.org/10.1002/1096-9861(20010122)429:4<571::aid-cne5>3.0.co;2-x
Ludewig K, Geyer MA, Etzensberger M, Vollenweider FX (2002) Stability of the acoustic startle reflex, prepulse inhibition, and habituation in schizophrenia. Schizophr Res 55:129–137. https://doi.org/10.1016/s0920-9964(01)00198-0
Miliano C, Marti M, Pintori N, Castelli MP, Tirri M, Arfe R, De Luca MA (2019) Neurochemical and behavioral profiling in male and female rats of the psychedelic agent 25I-NBOMe. Front Pharmacol 10:1406
Moreno JL, Holloway T, Albizu L, Sealfon SC, Gonzalez-Maeso J (2011) Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists. Neurosci Lett 493:76–79
Morici JF, Ciccia L, Malleret G, Gingrich JA, Bekinschtein P, Weisstaub NV (2015) Serotonin 2a receptor and serotonin 1a receptor interact within the medial prefrontal cortex during recognition memory in mice. Front Pharmacol 6:298
Morici JF, Miranda M, Gallo FT, Zanoni B, Bekinschtein P, Weisstaub NV (2018) 5-HT2a receptor in mPFC influences context-guided reconsolidation of object memory in perirhinal cortex. Elife 7:e33746
Nichols DE (2016) Psychedelics. Pharmacol Rev 68:264–355. https://doi.org/10.1124/pr.115.011478
Oliveras I, Sánchez-González A, Sampedro-Viana D, Piludu MA, Río-Alamos C, Giorgi O, Corda MG, Aznar S, González-Maeso J, Gerbolés C, Blázquez G, Cañete T, Tobeña A, Fernández-Teruel A (2017) Differential effects of antipsychotic and propsychotic drugs on prepulse inhibition and locomotor activity in Roman high- (RHA) and low-avoidance (RLA) rats. Psychopharmacology 234:957–975. https://doi.org/10.1007/s00213-017-4534-8
Ouagazzal A, Grottick AJ, Moreau J, Higgins GA (2001) Effect of LSD on prepulse inhibition and spontaneous behavior in the rat. A pharmacological analysis and comparison between two rat strains. Neuropsychopharmacology 25:565–575. https://doi.org/10.1016/S0893-133X(01)00282-2
Padich RA, McCloskey TC, Kehne JH (1996) 5-HT modulation of auditory and visual sensorimotor gating: II. Effects of the 5-HT2A antagonist MDL 100,907 on disruption of sound and light prepulse inhibition produced by 5-HT agonists in Wistar rats. Psychopharmacology 124:107–116. https://doi.org/10.1007/BF02245610
Páleníček T, Balíková M, Bubeníková-Valesová V, Horácek J (2008) Mescaline effects on rat behavior and its time profile in serum and brain tissue after a single subcutaneous dose. Psychopharmacology 196:51–62. https://doi.org/10.1007/s00213-007-0926-5
Páleníček T, Fujáková M, Brunovský M, Horáček J, Gorman I, Balíková M, Rambousek L, Syslová K, Kačer P, Zach P, Bubeníková-Valešová V, Tylš F, Kubešová A, Puskarčíková J, Höschl C (2013) Behavioral, neurochemical and pharmaco-EEG profiles of the psychedelic drug 4-bromo-2,5-dimethoxyphenethylamine (2C-B) in rats. Psychopharmacology 225:75–93. https://doi.org/10.1007/s00213-012-2797-7
Paylor R, Crawley JN (1997) Inbred strain differences in prepulse inhibition of the mouse startle response. Psychopharmacology 132:169–180. https://doi.org/10.1007/s002130050333
Ralph-Williams RJ, Lehmann-Masten V, Geyer MA (2003) Dopamine D1 rather than D2 receptor agonists disrupt prepulse inhibition of startle in mice. Neuropsychopharmacology 28:108–118. https://doi.org/10.1038/sj.npp.1300017
Reilly W, Koirala B, Devaud LL (2009) Sex differences in acoustic startle responses and seizure thresholds between ethanol-withdrawn male and female rats. Alcohol Alcohol 44:561–566. https://doi.org/10.1093/alcalc/agp049
Río-Álamos C, Piludu MA, Gerbolés C, Barroso D, Oliveras I, Sánchez-González A, Cañete T, Tapias-Espinosa C, Sampedro-Viana D, Torrubia R, Tobeña A, Fernández-Teruel A (2019) Volumetric brain differences between the Roman rat strains: neonatal handling effects, sensorimotor gating and working memory. Behav Brain Res 361:74–85. https://doi.org/10.1016/j.bbr.2018.12.033
Schmid Y, Enzler F, Gasser P, Grouzmann E, Preller KH, Vollenweider FX, Brenneisen R, Müller F, Borgwardt S, Liechti ME (2015) Acute effects of lysergic acid diethylamide in healthy subjects. Biol Psychiatry 78:544–553. https://doi.org/10.1016/j.biopsych.2014.11.015
Sipes TA, Geyer MA (1994) Multiple serotonin receptor subtypes modulate prepulse inhibition of the startle response in rats. Neuropharmacology 33:441–448. https://doi.org/10.1016/0028-3908(94)90074-4
Sipes TE, Geyer MA (1995) DOI disruption of prepulse inhibition of startle in the rat is mediated by 5-HT(2A) and not by 5-HT(2C) receptors. Behav Pharmacol 6:839–842
Swerdlow NR, Mansbach RS, Geyer MA, Pulvirenti L, Koob GF, Braff DL (1990) Amphetamine disruption of prepulse inhibition of acoustic startle is reversed by depletion of mesolimbic dopamine. Psychopharmacology 100:413–416. https://doi.org/10.1007/BF02244616
Swerdlow NR, Auerbach P, Monroe SM, Hartston H, Geyer MA, Braff DL (1993) Men are more inhibited than women by weak prepulses. Biol Psychiatry 34:253–260. https://doi.org/10.1016/0006-3223(93)90079-S
Swerdlow NR, Geyer MA, Braff DL (2001) Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology 156:194–215. https://doi.org/10.1007/s002130100799
Swerdlow NR, Braff DL, Geyer MA (2016) Sensorimotor gating of the startle reflex: what we said 25 years ago, what has happened since then, and what comes next. J Psychopharmacol 30:1072–1081. https://doi.org/10.1177/0269881116661075
Varty GB, Higgins GA, Higgins GA (1995) Examination of drug-induced and isolation-induced disruptions of prepulse inhibition as models to screen antipsychotic drugs. Psychopharmacology 122:15–26. https://doi.org/10.1007/BF02246437
Varty GB, Walters N, Cohen-Williams M, Carey GJ (2001) Comparison of apomorphine, amphetamine and dizocilpine disruptions of prepulse inhibition in inbred and outbred mice strains. Eur J Pharmacol 424:27–36. https://doi.org/10.1016/s0014-2999(01)01115-3
Vollenweider FX, Preller KH (2020) Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders. Nat Rev Neurosci 21:611–624. https://doi.org/10.1038/s41583-020-0367-2
Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Bäbler A, Vogel H, Hell D (1998) Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 9:3897–3902. https://doi.org/10.1097/00001756-199812010-00024
Vollenweider FX, Csomor PA, Knappe B, Geyer MA, Quednow BB (2007) The effects of the preferential 5-HT2A agonist psilocybin on prepulse inhibition of startle in healthy human volunteers depend on interstimulus interval. Neuropsychopharmacology 32:1876–1887. https://doi.org/10.1038/sj.npp.1301324
Weisstaub NV, Zhou M, Lira A, Lambe E, Gonzalez-Maeso J, Hornung JP, Sibille E, Underwood M, Itohara S, Dauer WT, Ansorge MS, Morelli E, Mann JJ, Toth M, Aghajanian G, Sealfon SC, Hen R, Gingrich JA (2006) Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice. Science 313:536–540
Zentner M, Grandjean D, Scherer KR (2008) Emotions evoked by the sound of music: characterization, classification, and measurement. Emotion 8:494–521. https://doi.org/10.1037/1528-3542.8.4.494
Funding
This work was supported in part by NIH-R01MH084894, NIH-R01MH111940, and NIHP30DA033934 (J.G.-M.), NIH-N01DA-17-8932 and NIH-N01DA-19-8949 (P.M.B.), NIH-P50AA022537 (J.T.W.), NIH-F30MH116550 (J.M.S), and NIH-T32MH020030 (M.d.l.F.R.). A.F.-T received support from grants PSI2017-82257-P (MINECO) and 2017SGR-1587.
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Conceived and designed the experiments, analyzed the data, and wrote the manuscript: H.Z.V., J.M.S., and J.G.-M. Performed experiments: H.Z.V., J.M.S., A.M.J., M.d.l.F.R., and J.J. Supervised the research and obtained funding: J.G.-M. Provided advice on behavioral assays and editorial suggestions on early drafts of the report: A.F.-T., J.T.W., and P.M.B. All authors discussed the results and commented on the manuscript prior to submission for publication consideration.
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Experiments were conducted in accord with NIH guidelines and were approved by the Virginia Commonwealth University Animal Care and Use Committee.
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J.G.-M. has a sponsored research contract with Neuristic, and M.d.l.F.R. has a consulting agreement with Noetic Fund. The remaining authors declare that they have no conflict of interest.
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Vohra, H.Z., Saunders, J.M., Jaster, A.M. et al. Sex-specific effects of psychedelics on prepulse inhibition of startle in 129S6/SvEv mice. Psychopharmacology 239, 1649–1664 (2022). https://doi.org/10.1007/s00213-021-05913-9
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DOI: https://doi.org/10.1007/s00213-021-05913-9