Abstract
Tardive dyskinesia (TD), first appearing in humans after introduction of the phenothiazine class of antipsychotics in the 1950s, is now recognized as an abnormality resulting predominately by long-term block of dopamine (DA) D2 receptors (R). TD is thus reproduced in primates and rodents by chronic administration of D2-R antagonists. Through a series of studies predominately since the 1980s, it has been shown in rodent modeling of TD that when haloperidol or other D2-R antagonist is added to drinking water, rats develop spontaneous oral dyskinesias, vacuous chewing movements (VCMs), after ~3 months, and this TD is associated with an increase in the number of striatal D2-R. This TD persists for the duration of haloperidol administration and another ~2 months after haloperidol withdrawal. By neonatally lesioning dopaminergic nerves in brain in neonatal rats with 6-hydroxydopamine (6-OHDA), it has been found that TD develops sooner, at ~2 months, and also is accompanied by a much higher number of VCMs in these haloperidol-treated lesioned rats, and the TD persists lifelong after haloperidol withdrawal, but is not associated with an increased D2-R number in the haloperidol-withdrawn phase. TD apparently is related in part to supersensitization of both D1-R and serotoninergic 5-HT2-R, which is also a typical outcome of neonatal 6-OHDA (n6-OHDA) lesioning. Testing during the haloperidol-withdrawn phase in n6-OHDA rats displaying TD reveals that receptor agonists and antagonists of a host of neuronal phenotypic classes have virtually no effect on spontaneous VCM number, except for 5-HT2-R antagonists which acutely abate the incidence of VCMs in part. Extrapolating to human TD, it appears that (1) 5-HT2-R supersensitization is the crucial alteration accounting for persistence of TD, (2) dopaminergic—perhaps age-related partial denervation—is a risk factor for the development of TD, and (3) 5-HT2-R antagonists have the therapeutic potential to alleviate TD, particularly if/when an antipsychotic D2-R blocker is withdrawn.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Arnt J, Hyttel J, Perregard J (1987) Dopamine D-1 receptor agonists combined with the selective D-2 agonist, quinpirole, facilitate the expression of oral stereotyped behaviour in rats. Eur J Pharmacol 133:137–145
Baldessarini RJ, Cohen BM, Teicher MH (1988) Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses. Arch Gen Psychiatry, 45(1):79–91. Review. PMID: 2892478
Berger TW, Kaul S, Stricker EM, Zigmond MJ (1985) Hyperinnervation of the striatum by dorsal raphe afferents after dopamine-depleting brain lesions in neonatal rats. Brain Res 366:354–358
Breese GR, Baumeister AA, McCown TJ, Emerick SG, Frye GD, Crotty K, Mueller RA (1984) Behavioural differences between neonatal and adult 6-hydroxydopamine-treated rats to dopamine agonists: relevance to neurological symptoms in clinical syndromes with reduced brain dopamine. J Pharmacol Exp Ther 231:343–354
Breese GR, Baumeister A, Napier TC, Frye GD, Mueller RA (1985a) Evidence that D1 dopamine receptors contribute to the supersensitive behavioral responses induced by L-dihydroxyphenylalanine in rats treated neonatally with 6-hydroxydopamine. J Pharmacol Exp Ther 235:287–295
Breese GR, Napier TC, Mueller RA (1985b) Dopamine agonist-induced locomotor activity in rats treated with 6-hydroxydopamine at differing ages: functional supersensitivity of D1 dopamine receptors in neonatally lesioned rats. J Pharmacol Exp Ther 234:447–455
Breese GR, Duncan GE, Napier TC, Bondy SC, Iorio LC, Mueller RA (1987) 6-Hydroxydopamine treatments enhance behavioral responses to intracerebral microinjection of D1- and D2-dopamine agonists into the nucleus accumbens and striatum without changing dopamine antagonist binding. J Pharmacol Exp Ther 240:167–176
Brus R, Kostrzewa RM, Perry KW, Fuller RW (1994) Supersensitization of the oral response to SKF 38393 in neonatal 6-hydroxydopamine-lesioned rats is eliminated by neonatal 5,7-dihydroxytryptamine treatment. J Pharmacol Exp Ther 268:231–237
Casey DE (1987) Tardive dyskinesia, In: Meltzer HY (ed) Psychopharmacology: the third generation of progress. Raven Press, New York, pp 1411–1419
Criswell H, Mueller RA, Breese GR (1989) Priming of D1-dopamine receptor responses: long-lasting behavioral supersensitivity to a D1-dopamine agonist following repeated administration to neonatal 6-OHDA-lesioned rats. J Neurosci 9:125–133
Descarries L, Soghomonian J-J, Garcia S, Doucet G, Bruno JP (1992) Ultrastructural analysis of the serotonin hyperinnervation in adult rat neostriatum following neonatal dopamine denervation with 6-hydroxydopamine. Brain Res 569:1–13
Descarries L, Soucy J-P, Lafaille F, Mrini A, Tanguay R (1995) Evaluation of three transporter ligands as quantitative markers of serotonin innervation density in rat brain. Synapse 211:131–139
Dewar KM, Soghomonian J-J, Bruno JP, Descarries L, Reader TA (1990) Elevation of dopamine D2 but not D1 dopamine receptors in adult rat neostriatum after neonatal 6-hydroxydopamine denervation. Brain Res 536:287–296
Doucet G, Descarries L, Garcia S (1986) Quantification of the dopamine innervation in adult rat neostriatum. Neuroscience 19:427–445
Duncan GE, Criswell HE, McCown TJ, Paul IA, Mueller RA, Breese GR (1987) Behavioral and neurochemical responses to haloperidol and SCH-23390 in rats treated neonatally or as adults with 6-hydroxydopamine. J Pharmacol Exp Ther 243:1027–1034
El Mansari M, Radja F, Ferron A, Reader TA, Molina-Holgado E, Descarries L (1994) Hypersensitivity to serotonin and its agonists in serotonin-hyperinnervated neostriatum after neonatal dopamine denervation. Eur J Pharmacol 261:171–178
Ellison GD, See RE (1989) Rats administered chronic neuroleptics develop oral movements which are similar in form to those in humans with tardive dyskinesia. Psychopharmacology 98:564–566
Gong L, Kostrzewa RM (1992) Supersensitized oral responses to a serotonin agonist in neonatal 6-OHDA-treated rats. Pharmacol Biochem Behav 41:621–623
Gong L, Kostrzewa RM, Fuller RW, Perry KW (1992) Supersensitization of the oral response to SKF 38393 in neonatal 6-OHDA-lesioned rats is mediated through a serotonin system. J Pharmacol Exp Ther 261:1000–1007
Gong L, Kostrzewa RM, Brus R, Fuller RW, Perry KW (1993) Ontogenetic SKF 38393 treatments sensitize dopamine D1 receptors in neonatal 6-OHDA-lesioned rats. Dev Brain Res 76:59–65
Gong L, Kostrzewa RM, Li C (1994) Neonatal 6-hydroxydopamine and adult SKF 38393 treatments alter dopamine D1 receptor mRNA levels: absence of other neurochemical associations with the enhanced behavioral responses of lesioned rats. J Neurochem 63:1282–1290
Gunne LM, Growdon J, Glaeser B (1982) Oral dyskinesia in rats following brain lesions and neuroleptic drug administration. Psychopharmacology 77(2):134–139
Huang N-Y, Kostrzewa RM, Li C, Perry KW, Fuller RW (1997) Increased spontaneous oral dyskinesias persist in haloperidol-withdrawn rats neonatally lesioned with 6-hydroxydopamine: absence of an association with the Bmax for [3H]raclopride binding to neostriatal homogenates. J Pharmacol Exp Ther 280:268–276
Jeste DV, Caligiuri MP (1993) Tardive dyskinesia. Schizophr Bull 19:303–315
Koshikawa N, Aoki S, Tomiyama M, Maruyama Y, Kobayashi M (1987) Sulpiride injection into the dorsal striatum increases methamphetamine-induced gnawing in rats. Wur J Pharmacol 133:119–125
Kostrzewa RM (1995) Dopamine receptor supersensitivity. Neurosci Biobehav Rev 19:1–17
Kostrzewa RM, Gong L (1991) Supersensitized D1 receptors mediate enhanced oral activity after neonatal 6-OHDA. Pharmacol Biochem Behav 39:677–682
Kostrzewa RM, Hamdi A (1991) Potentiation of spiperone-induced oral activity in rats after neonatal 6-hydroxydopamine. Pharmacol Biochem Behav 38:215–218
Kostrzewa RM, Reader TA, Descarries L (1998) Serotonin neural adaptations to ontogenetic loss of dopamine neurons in rat brain. J Neurochem 70:889–898
Kostrzewa RM, Huang NY, Kostrzewa JP, Nowak P, Brus R (2007) Modeling tardive dyskinesia: predictive 5-HT2C receptor antagonist treatment. Neurotox Res 11(1):41–50
Levin ED, See RE, South D (1989) Effects of dopamine D1 and D2 receptor antagonists on oral activity in rats. Pharmacol Biochem Behav 34:43–48
Luthman J, Botioli B, Tustsumi T, Verhofstad A, Jonsson G (1987) Sprouting of striatal serotonin nerve terminals following selective lesions of nigro-striatal dopamine neurons in neonatal rat. Brain Res Bull 19:269–274
Molloy AG, Waddington JL (1988) Behavioural responses to the selective D1-dopamine receptor agonist R-SK&F 38393 and the selective D2-agonist RU 24213 in young compared with aged rat. Br J Pharmacol 95:335–342
Morgenstern H, Glazer WM (1993) Identifying risk factors for tardive dyskinesia among long-term outpatients maintained with neuroleptic medications. Results of the Yale Tardive Dyskinesia Study. Arch Gen Psychiatry 50(9):723–733
Mrini A, Soucy J-P, Lafaille F, Lemoine P, Descarries L (1995) Quantification of the serotonin hyperinnervation in adult rat neostriatum after neonatal 6-hydroxydopamine lesion of nigral dopamine neurons. Brain Res 669:303–308
Murray AM, Waddington JL (1989) The induction of grooming and vacuous chewing by a series of selective D-1 dopamine receptor agonists: two directions of D-1:D-2 interaction. Eur J Pharmacol 160:377–387
Plech A, Brus R, Kalbfleisch JH, Kostrzewa RM (1995) Enhanced oral activity responses to intrastriatal SKF 38393 and m-CPP are attenuated by intrastriatal mianserin in neonatal 6-OHDA-lesioned rats. Psychopharmacology 119:466–473
Radja F, El Mansari M, Soghomonian J-J, Dewar KM, Ferron A, Reader TA, Descarries L (1993a) Changes in D1 and D2 receptors in adult rat neostriatum after neonatal dopamine denervation: quantitative data from ligand binding, in situ hybridization and iontophoresis. Neuroscience 57:635–648
Radja F, Descarries L, Dewar KM, Reader TA (1993b) Serotonin 5-HT1 and 5-HT2 receptors in adult rat brain after neonatal destruction of nigrostriatal dopamine neurons: a quantitative autoradiographic study. Brain Res 606:273–285
Rana AQ, Chaudry ZM, Blanchet PJ (2013) New and emerging treatments for symptomatic tardive dyskinesia. Drug Des Devel Ther 7:1329–1340. Review. PMID: 24235816
Rosengarten H, Schweitzer JW, Friedhoff AJ (1983a) Induction of oral dyskinesias in naïve rats by D1 stimulation. Life Sci 33:2479–2482
Rosengarten H, Schweitzer JW, Egawa J, Friedhoff AJ (1983b) Diminished D2 dopamine receptor function and the emergence of repetitive jaw movements. Adv Exp Med Biol 235:159–169
Rosengarten H, Schweitzer JW, Egawa J, Friedhoff AJ (1986) Diminished D2 dopamine receptor function and the emergence of repetitive jaw movements. Adv Exp Med Biol 235:159–167
Rupniak NMJ, Jenner P, Marsden CD (1985) Pharmacological characterization of spontaneous or drug-associated purposeless chewing movements in rats. Psychopharmacology (Berlin) 85:71–79
Snyder AM, Zigmond MJ, Lund RD (1986) Sprouting of serotonergic afferents into striatum after dopamine depleting lesions in infant rats: a retrograde transport and immunocytochemical study. J Comp Neurol 245:274–281
Stachowiak MK, Bruno JP, Snyder AM, Stricker EM, Zigmond MJ (1984) Apparent sprouting of striatal serotonergic terminals after dopamine-depleting brain lesions in neonatal rats. Brain Res 291:164–167
Towle AC, Criswell HE, Maynard EH, Lauder JM, Joh RH, Mueller RA, Breese GR (1989) Serotonergic innervation of the rat caudate following a neonatal 6-hydroxydopamine lesion: an anatomical, biochemical and pharmacological study. Pharmacol Biochem Behav 34:367–374
van Harten PN, Tenback DE (2011) Tardive dyskinesia: clinical presentation and treatment. Int Rev Neurobiol 98:187–210. Review. PMID: 21907088
Waddington JL (1990) Spontaneous orofacial movements induced in rodents by very long-term neuroleptic drug administration: Phenomenology, pathophysiology and putative relationship to tardive dyskinesia. Psychopharmacology (Berlin) 101:431–447
Waddington JL, Cross AJ, Gamble SJ, Bourne RC (1983) Spontaneous orofacial dyskinesia and dopaminergic function in rats after 6 months of neuroleptic treatment. Science 220:530–532
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Kostrzewa, R.M., Brus, R. (2015). Lifelong Rodent Model of Tardive Dyskinesia—Persistence After Antipsychotic Drug Withdrawal. In: Kostrzewa, R.M., Archer, T. (eds) Neurotoxin Modeling of Brain Disorders—Life-long Outcomes in Behavioral Teratology. Current Topics in Behavioral Neurosciences, vol 29. Springer, Cham. https://doi.org/10.1007/7854_2015_395
Download citation
DOI: https://doi.org/10.1007/7854_2015_395
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-34134-7
Online ISBN: 978-3-319-34136-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)