Antipsychotic potential of the type 1 cannabinoid receptor positive allosteric modulator GAT211: preclinical in vitro and in vivo studies.
Animals
Antipsychotic Agents
/ pharmacology
Behavior, Animal
/ drug effects
Cell Line
Dizocilpine Maleate
Dose-Response Relationship, Drug
Dronabinol
/ pharmacology
Excitatory Amino Acid Antagonists
Extracellular Signal-Regulated MAP Kinases
/ metabolism
Indoles
/ pharmacology
Male
Motor Activity
/ drug effects
Phosphorylation
Prepulse Inhibition
/ drug effects
Psychoses, Substance-Induced
/ drug therapy
Rats
Rats, Long-Evans
Receptor, Cannabinoid, CB1
/ drug effects
Acoustic startle
Cannabis
MK-801
NMDA receptor
Open field
Prepulse inhibition
Schizophrenia
THC
Journal
Psychopharmacology
ISSN: 1432-2072
Titre abrégé: Psychopharmacology (Berl)
Pays: Germany
ID NLM: 7608025
Informations de publication
Date de publication:
Apr 2021
Apr 2021
Historique:
received:
08
07
2020
accepted:
28
12
2020
pubmed:
15
1
2021
medline:
31
3
2021
entrez:
14
1
2021
Statut:
ppublish
Résumé
Antipsychotics help alleviate the positive symptoms associated with schizophrenia; however, their debilitating side effects have spurred the search for better treatment options. Novel compounds can be screened for antipsychotic potential in neuronal cell cultures and following acute N-methyl-D-aspartate (NMDA) receptor blockade with non-competitive antagonists such as MK-801 in rodent behavioral models. Given the known interactions between NMDA receptors and type 1 cannabinoid receptors (CB1R), compounds that modulate CB1Rs may have therapeutic potential for schizophrenia. This study assessed whether the CB1R positive allosteric modulator GAT211, when compared to ∆ The effects of GAT211 and THC on cellular signaling were compared in Neuro2a cells, and behavioral effects of GAT211 and THC on altered locomotor activity and prepulse inhibition of the acoustic startle response caused by acute MK-801 treatment were assessed in male, Long Evans rats. GAT211 limited dopamine D2 receptor-mediated extracellular regulated kinase (ERK) phosphorylation in Neuro2a cells, whereas THC did not. As expected, acute MK-801 (0.15 mg/kg) produced a significant increase in locomotor activity and impaired PPI. GAT211 treatment alone (0.3-3.0 mg/kg) dose-dependently reduced locomotor activity and the acoustic startle response. GAT211 (3.0 mg/kg) also prevented hyperlocomotion caused by MK-801 but did not significantly affect PPI impairments. Taken together, these findings support continued preclinical research regarding the usefulness of CB1R positive allosteric modulators as antipsychotics.
Identifiants
pubmed: 33442771
doi: 10.1007/s00213-020-05755-x
pii: 10.1007/s00213-020-05755-x
doi:
Substances chimiques
3-(2-nitro-1-phenylethyl)-2-phenyl-1H-indole
0
Antipsychotic Agents
0
Excitatory Amino Acid Antagonists
0
Indoles
0
Receptor, Cannabinoid, CB1
0
Dizocilpine Maleate
6LR8C1B66Q
Dronabinol
7J8897W37S
Extracellular Signal-Regulated MAP Kinases
EC 2.7.11.24
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1087-1098Références
Ahmari SE, Risbrough VB, Geyer MA, Simpson HB (2012) Impaired sensorimotor gating in unmedicated adults with obsessive-compulsive disorder. Neuropsychopharmacology 37:1216–1223. https://doi.org/10.1038/npp.2011.308
doi: 10.1038/npp.2011.308
pubmed: 22218093
pmcid: 22218093
Al-Amin HA, Schwarzkopf SB (1996) Effects of the PCP analog dizocilpine on sensory gating: potential relevance to clinical subtypes of schizophrenia. Biol Psychiatry 40:744–754. https://doi.org/10.1016/0006-3223(95)00485-8
doi: 10.1016/0006-3223(95)00485-8
pubmed: 8894067
Bagher AM, Laprairie RB, Kelly MEM, Denovan-Wright EM (2013) Co-expression of the human cannabinoid receptor coding region splice variants (hCB1) affects the function of hCB1 receptor complexes. Eur J Pharmacol 721:341–354. https://doi.org/10.1016/j.ejphar.2013.09.002
doi: 10.1016/j.ejphar.2013.09.002
pubmed: 24091169
Bagher AM, Laprairie RB, Toguri JT et al (2017) Bidirectional allosteric interactions between cannabinoid receptor 1 (CB1) and dopamine receptor 2 long (D2L) heterotetramers. Eur J Pharmacol 813:66–83. https://doi.org/10.1016/j.ejphar.2017.07.034
doi: 10.1016/j.ejphar.2017.07.034
pubmed: 28734930
Ballendine SA, Greba Q, Dawicki W et al (2015) Behavioral alterations in rat offspring following maternal immune activation and ELR-CXC chemokine receptor antagonism during pregnancy: implications for neurodevelopmental psychiatric disorders. Prog Neuro-Psychopharmacol Biol Psychiatry 57:155–165. https://doi.org/10.1016/j.pnpbp.2014.11.002
doi: 10.1016/j.pnpbp.2014.11.002
Bast T, Zhang W, Feldon J, White IM (2000) Effects of MK801 and neuroleptics on prepulse inhibition: re-examination in two strains of rats. Pharmacol Biochem Behav 67:647–658. https://doi.org/10.1016/S0091-3057(00)00409-3
doi: 10.1016/S0091-3057(00)00409-3
pubmed: 11164097
Bolognini D, Ross RA (2015) Medical cannabis vs. synthetic cannabinoids: what does the future hold? Clin Pharmacol Ther 97:568–570. https://doi.org/10.1002/cpt
doi: 10.1002/cpt
pubmed: 25761845
Brosda J, Hayn L, Klein C et al (2011) Pharmacological and parametrical investigation of prepulse inhibition of startle and prepulse elicited reactions in Wistar rats. Pharmacol Biochem Behav 99:22–28. https://doi.org/10.1016/j.pbb.2011.03.017
doi: 10.1016/j.pbb.2011.03.017
pubmed: 21447356
Bubeníková-Valešová V, Horáček J, Vrajová M, Höschl C (2008) Models of schizophrenia in humans and animals based on inhibition of NMDA receptors. Neurosci Biobehav Rev 32:1014–1023
Cadinu D, Grayson B, Podda G et al (2018) NMDA receptor antagonist rodent models for cognition in schizophrenia and identification of novel drug treatments, an update. Neuropharmacology 142:41–62
doi: 10.1016/j.neuropharm.2017.11.045
Carlsson M, Carlsson A (1989) The NMDA antagonist MK-801 causes marked locomotor stimulation in monoamine-depleted mice. J Neural Transm 75:221–226. https://doi.org/10.1007/BF01258633
doi: 10.1007/BF01258633
pubmed: 2538557
Chartoff EH, Heusner CL (2005 Jul) Palmiter RD (2005) Dopamine is not required for the hyperlocomotor response to NMDA receptor antagonists. Neuropsychopharmacology. 30(7):1324–1333. https://doi.org/10.1038/sj.npp.1300678
doi: 10.1038/sj.npp.1300678
pubmed: 15688082
Datta U, Kelley LK, Middleton JW, Gilpin NW (2020) Positive allosteric modulation of the cannabinoid type-1 receptor (CB1R) in periaqueductal gray (PAG) antagonizes anti-nociceptive and cellular effects of a mu-opioid receptor agonist in morphine-withdrawn rats. Psychopharmacology 237:3729–3739. https://doi.org/10.1007/s00213-020-05650-5
doi: 10.1007/s00213-020-05650-5
pubmed: 32857187
Fakhoury M (2017) Role of the endocannabinoid system in the pathophysiology of schizophrenia. Mol Neurobiol 54:768–778
doi: 10.1007/s12035-016-9697-5
Fendt M, Li L, Yeomans JS (2001) Brain stem circuits mediating prepulse inhibition of the startle reflex. Psychopharmacology 156:216–224
doi: 10.1007/s002130100794
Galve-Roperh I, Palazuelos J, Aguado T, Guzmán M (2009) The endocannabinoid system and the regulation of neural development: potential implications in psychiatric disorders. Eur Arch Psychiatry Clin Neurosci 259:371–382. https://doi.org/10.1007/s00406-009-0028-y
doi: 10.1007/s00406-009-0028-y
pubmed: 19588184
Garai S, Kulkarni PM, Schaffer PC et al (2020) Application of fluorine- and nitrogen-walk approaches: defining the structural and functional diversity of 2-phenylindole class of cannabinoid 1 receptor positive allosteric modulators. J Med Chem 63:542–568. https://doi.org/10.1021/acs.jmedchem.9b01142
doi: 10.1021/acs.jmedchem.9b01142
pubmed: 31756109
pmcid: 7077750
Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology 156:117–154
doi: 10.1007/s002130100811
Goff DC, Falkai P, Fleischhacker WW et al (2017) The long-term effects of antipsychotic medication on clinical course in schizophrenia. Am J Psychiatry 174:840–849. https://doi.org/10.1176/appi.ajp.2017.16091016
doi: 10.1176/appi.ajp.2017.16091016
pubmed: 28472900
Harkany T, Guzmán M, Galve-Roperh I et al (2007) The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol Sci
Homayoun H, Moghaddam B (2007) NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 27:11496–11500. https://doi.org/10.1523/JNEUROSCI.2213-07.2007
doi: 10.1523/JNEUROSCI.2213-07.2007
pubmed: 17959792
pmcid: 2954603
Hönack D, Löscher W (1993) Sex differences in NMDA receptor mediated responses in rats. Brain Res 620:167–170. https://doi.org/10.1016/0006-8993(93)90287-W
doi: 10.1016/0006-8993(93)90287-W
pubmed: 8402193
Howland JG, Cazakoff BN, Zhang Y (2012) Altered object-in-place recognition memory, prepulse inhibition, and locomotor activity in the offspring of rats exposed to a viral mimetic during pregnancy. Neuroscience 201:184–198. https://doi.org/10.1016/j.neuroscience.2011.11.011
doi: 10.1016/j.neuroscience.2011.11.011
pubmed: 22119062
Hudson R, Renard J, Norris C et al (2019) Cannabidiol counteracts the psychotropic side-effects of Δ-9-tetrahydrocannabinol in the ventral hippocampus through bidirectional control of ERK1-2 phosphorylation. J Neurosci 39:8762–8777. https://doi.org/10.1523/JNEUROSCI.0708-19.2019
doi: 10.1523/JNEUROSCI.0708-19.2019
pubmed: 31570536
pmcid: 6820200
Ignatowska-Jankowska BM, Baillie GL et al (2015) A cannabinoid CB1 receptor-positive allosteric modulator reduces neuropathic pain in the mouse with no psychoactive effects. Neuropsychopharmacology 40:2948–2959. https://doi.org/10.1038/npp.2015.148
doi: 10.1038/npp.2015.148
pubmed: 26052038
pmcid: 4864630
James JR, Oliveira MI, Carmo AM et al (2006) A rigorous experimental framework for detecting protein oligomerization using bioluminescence resonance energy transfer. Nat Methods 3:1001–1006. https://doi.org/10.1038/nmeth978
doi: 10.1038/nmeth978
pubmed: 17086179
Kapur S, Mamo D (2003) Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuro-Psychopharmacol Biol Psychiatry 27:1081–1090. https://doi.org/10.1016/j.pnpbp.2003.09.004
doi: 10.1016/j.pnpbp.2003.09.004
Laprairie RB, Bagher AM, Kelly MEM et al (2014) Type 1 cannabinoid receptor ligands display functional selectivity in a cell culture model of striatal medium spiny projection neurons. J Biol Chem 289:24845–24862. https://doi.org/10.1074/jbc.M114.557025
doi: 10.1074/jbc.M114.557025
pubmed: 25037227
pmcid: 4155654
Laprairie RB, Kulkarni PM, Deschamps JR et al (2017) Enantiospecific allosteric modulation of cannabinoid 1 receptor. ACS Chem Neurosci 8:1188–1203. https://doi.org/10.1021/acschemneuro.6b00310
doi: 10.1021/acschemneuro.6b00310
pubmed: 28103441
Laprairie RB, Bagher AM, Rourke JL et al (2019) Positive allosteric modulation of the type 1 cannabinoid receptor reduces the signs and symptoms of Huntington's disease in the R6/2 mouse model. Neuropharmacology 151:1–12. https://doi.org/10.1016/j.neuropharm.2019.03.033
doi: 10.1016/j.neuropharm.2019.03.033
pubmed: 30940536
pmcid: 6544167
Leweke FM, Mueller JK, Lange B, Rohleder C (2016) Therapeutic potential of cannabinoids in psychosis. Biol Psychiatry 79:604–612
doi: 10.1016/j.biopsych.2015.11.018
Li P, Snyder GL, Vanover KE (2016) Dopamine targeting drugs for the treatment of schizophrenia: past, present and future. Curr Top Med Chem 16:3385–3403. https://doi.org/10.2174/1568026616666160608084834
doi: 10.2174/1568026616666160608084834
pubmed: 27291902
pmcid: 5112764
Lins BR, Marks WN, Phillips AG, Howland JG (2017) Dissociable effects of the d- and l-enantiomers of govadine on the disruption of prepulse inhibition by MK-801 and apomorphine in male Long-Evans rats. Psychopharmacology 234:1079–1091. https://doi.org/10.1007/s00213-017-4540-x
doi: 10.1007/s00213-017-4540-x
pubmed: 28180960
Lu HC, Mackie K (2016) An introduction to the endogenous cannabinoid system. Biol Psychiatry 79:516–525
doi: 10.1016/j.biopsych.2015.07.028
Mackie K (2005) Distribution of cannabinoid receptors in the central and peripheral nervous system. In: Cannabinoids. Springer-Verlag, pp 299–325
Mansbach RS, Braff DL, Geyer MA (1989) Prepulse inhibition of the acoustic startle response is disrupted by N-ethyl-3,4-methylenedioxyamphetamine (MDEA) in the rat. Eur J Pharmacol 167:49–55. https://doi.org/10.1016/0014-2999(89)90746-2
doi: 10.1016/0014-2999(89)90746-2
pubmed: 2776841
Mathé JM, Nomikos GG, Hildebrand BE, Hertel P (1996) Svensson TH (1994) Prazosin inhibits MK-80 induced hyperlocomotion and dopamine release in the nucleus accumbens. Eur J Pharmacol 309(1):1–11. https://doi.org/10.1016/0014-2999(96)00315-9
doi: 10.1016/0014-2999(96)00315-9
pubmed: 8864686
Mechoulam R, Parker LA (2013) The endocannabinoid system and the brain. Annu Rev Psychol. https://doi.org/10.1146/annurev-psych-113011-143739
Mielnik CA, Lam VM, Ross RA (2020) CB1 allosteric modulators and their therapeutic potential in CNS disorders. Prog Neuro-Psychopharmacol Biol Psychiatry in press. https://doi.org/10.1016/j.pnpbp.2020.110163
Moghaddam B, Javitt D (2012) From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37:4–15
doi: 10.1038/npp.2011.181
Moghaddam B, Krystal JH (2012) Capturing the angel in “angel dust”: twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans. Schizophr Bull 38:942–949. https://doi.org/10.1093/schbul/sbs075
doi: 10.1093/schbul/sbs075
pubmed: 22899397
pmcid: 3446228
Moreno-Küstner B, Martín C, Pastor L (2018) Prevalence of psychotic disorders and its association with methodological issues. A systematic review and meta-analyses. PLoS One 13:e0195687. https://doi.org/10.1371/journal.pone.0195687
doi: 10.1371/journal.pone.0195687
pubmed: 29649252
pmcid: 5896987
Nicholl D, Akhras KS, Diels J, Schadrack J (2010) Burden of schizophrenia in recently diagnosed patients: healthcare utilisation and cost perspective. Curr Med Res Opin 26:943–955. https://doi.org/10.1185/03007991003658956
doi: 10.1185/03007991003658956
pubmed: 20163295
Peres FF, Levin R, Almeida V et al (2016) Cannabidiol, among other cannabinoid drugs, modulates prepulse inhibition of startle in the SHR animal model: implications for schizophrenia pharmacotherapy. Front Pharmacol 7:303
pubmed: 27667973
pmcid: 5016523
Pickel VM, Bourie F, Chan J et al (2020) Chronic adolescent exposure to ∆9-tetrahydrocannabinol decreases NMDA current and extrasynaptic plasmalemmal density of NMDA GluN1 subunits in the prelimbic cortex of adult male mice. Neuropsychopharmacology 45:374–383. https://doi.org/10.1038/s41386-019-0466-9
doi: 10.1038/s41386-019-0466-9
pubmed: 31323660
Ross RA (2007) Allosterism and cannabinoid CB1 receptors: the shape of things to come. Trends Pharmacol Sci 28:567–572. https://doi.org/10.1016/j.tips.2007.10.006
doi: 10.1016/j.tips.2007.10.006
pubmed: 18029031
Seibenhener ML, Wooten MC (2015) Use of the open field maze to measure locomotor and anxiety-like behavior in mice. J Vis Exp:e52434. https://doi.org/10.3791/52434
Sendt KV, Tracy DK, Bhattacharyya S (2015) A systematic review of factors influencing adherence to antipsychotic medication in schizophrenia-spectrum disorders. Psychiatry Res 225:14–30
doi: 10.1016/j.psychres.2014.11.002
Silveira MM, Adams WK, Morena M, Hill MN, Winstanley CA (2017a) Delta(9)-tetrahydrocannabinol decreases willingness to exert cognitive effort in male rats. J Psychiatry Neurosci 42:131–138
doi: 10.1503/jpn.150363
Silveira MM, Arnold JC, Laviolette SR et al (2017b) Seeing through the smoke: human and animal studies of cannabis use and endocannabinoid signalling in corticolimbic networks. Neurosci Biobehav Rev 76:380–395
doi: 10.1016/j.neubiorev.2016.09.007
Simeone JC, Ward AJ, Rotella P et al (2015) An evaluation of variation in published estimates of schizophrenia prevalence from 1990─2013: a systematic literature review. BMC Psychiatry 15:193. https://doi.org/10.1186/s12888-015-0578-7
doi: 10.1186/s12888-015-0578-7
pubmed: 26263900
pmcid: 4533792
Slivicki RA, Xu Z, Kulkarni PM, Pertwee RG, Mackie K, Thakur GA, Hohmann AG (2018) Positive allosteric modulation of cannabinoid receptor type 1 suppresses pathological pain without producing tolerance or dependence. Biol Psychiatry 84:722–733. https://doi.org/10.1016/j.biopsych.2017.06.032
doi: 10.1016/j.biopsych.2017.06.032
pubmed: 28823711
Swerdlow NR, Light GA (2018) Sensorimotor gating deficits in schizophrenia: advancing our understanding of the phenotype, its neural circuitry and genetic substrates. Schizophr Res 198:1–5
doi: 10.1016/j.schres.2018.02.042
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
doi: 10.1007/s002130100799
Tsou K, Brown S, Sañudo-Peña MC et al (1998) Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 83:393–411. https://doi.org/10.1016/S0306-4522(97)00436-3
doi: 10.1016/S0306-4522(97)00436-3
pubmed: 9460749
Varty GB, Bakshi VP, Geyer MA (1999) M100907, a serotonin 5-HT(2A) receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in Sprague-Dawley and Wistar rats. Neuropsychopharmacology 20:311–321. https://doi.org/10.1016/S0893-133X(98)00072-4
doi: 10.1016/S0893-133X(98)00072-4
pubmed: 10088132
Wiley JL, Harvey SA, Balster RL, Nicholson KL (2003) Affinity and specificity of N-methyl-D-aspartate channel blockers affect their ability to disrupt prepulse inhibition of acoustic startle in rats. Psychopharmacology 165:378–385. https://doi.org/10.1007/s00213-002-1297-6
doi: 10.1007/s00213-002-1297-6
pubmed: 12459931
Wootten D, Christopoulos A, Sexton PM (2013) Emerging paradigms in GPCR allostery: implications for drug discovery. Nat Rev Drug Discov 12:630–644
doi: 10.1038/nrd4052