Serotoninergic nerves are known to modulate sensitization of dopamine receptors (DA-R) in a rodent model of Parkinson’s disease (PD). However, serotoninergic nerves are not known to have a prominent role on DA exocytosis in intact rats. The current study was undertaken to explore the possible influence of serotoninergic nerves on DA exocytosis in Parkinsonian rats. Rat pups were treated at 3 days after birth with the neurotoxin 6-hydroxydopamine (6-OHDA; 134 μg icv, half into each lateral ventricle; desipramine, 1 h pretreatment), in order to produce marked long-lasting destruction of neostriatal dopaminergic innervation, as evidenced by the 90–95% depletion of DA (p < 0.001) [HPLC/ED] into adulthood. Controls received vehicle/desipramine in place of 6-OHDA. Other groups received the serotoninergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 25 μg base, icv, half in each lateral ventricle; desipramine, 1 h; 75 mg/kg pargyline HCl, 30 min) at 3 days post-birth; or both 6-OHDA+5,7-DHT treatments. In adulthood, an in vivo microdialysis study was undertaken to ascertain that p-chloroamphetamine (PCA, 1 mM in the microdialysate)-evoked DA release in the neostriatum was reduced approximately 50% in the 6-OHDA group, while PCA-evoked DA release in the 6-OHDA+5,7-DHT group was substantially increased, to a level equivalent to that of the vehicle control. The baseline neostriatal microdialysate level of 3,4-dihydroxyphenylacetic acid (DOPAC) was also higher in the 6-OHDA+5,7-DHT group vs 6-OHDA group; also, during the 2nd hour of PCA infusion. PCA-enhanced DA exocytosis occurred in the absence of changes in hydroxyl radical (HO·) in the microdialysate (i.e., assay of 2,3- and 2,5-dihydroxybenzoic acid, 2,3-DHBA; 2,5-DHBA). The overall findings demonstrate that an adulthood serotoninergic nerve lesion enhanced PCA-evoked DA exocytosis in a rodent model of severe PD, while susceptibility to oxidative stress was unchanged. The implication is that serotoninergic nerves may normally suppress the release of DA and/or act as an uptake site and storage sink for accumulated DA in parkinsonian-like neostriatum. Potentially, serotoninergic agonists or antagonists, targeting subtype-selective serotonin receptors, may be viable therapeutic adjuncts in PD.
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- DA R:
- DA RSS:
Dopamine receptor supersensitivity
Ethylenediamine tetra-acetic acid
High-performance liquid chromatography/electrochemical detection
Neonatally administered 5,7-DHT
Neonatally administered 6-OHDA
Auclair A, Blanc G, Glowinski J, Tassin JP (2004) Role of serotonin 2A receptors in the D-amphetamine-induced release of dopamine: comparison with previous data on alpha1beta-adrenergic receptors. J Neurochem 91:318–326
Baumann MH, Clark RD, Rothman RB (2008) Locomotor stimulation produced by 3,4-methylenedioxymethamphetamine (MDMA) is correlated with dialysate levels of serotonin and dopamine in rat brain. Pharmacol Biochem Behav 90:208–217
Baumann MH, Clark RD, Woolverton WL, Wee S, Blough BE, Rothman RB (2011) In vivo effects of amphetamine analogs reveal evidence for serotonergic inhibition of mesolimbic dopamine transmission in the rat. J Pharmacol Exp Ther 337:218–225
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 336:354–358
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 behavioural responses to intracerebral microinjection of D1 and D2-dopamine agonists into nucleus accumbens and striatum without changing dopamine antagonist binding. J Pharmacol Exp Ther 240:167–176
Breese GR, Criswell HE, Duncan GE, Mueller RA (1990) A dopamine deficiency model of Lesch-Nyhan disease – the neonatal-6-OHDA-lesioned rat. Brain Res Bull 25:477–484 Review
Breese GR, Criswell HE, Johnson KB, O'Callaghan JP, Duncan GE, Jensen KF, Simson PE, Mueller RA (1994) Neonatal destruction of dopaminergic neurons. Neurotoxicology 15:149–159 Review
Breese GR, Knapp DJ, Criswell HE, Moy SS, Papadeas ST, Blake BL (2005) The neonate-6-hydroxydopamine-lesioned rat: a model for clinical neuroscience and neurobiological principles. Brain Res Brain Res Rev 48:57–73 Review
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
Brus R, Nowak P, Szkilnik R, Mikołajun U, Kostrzewa RM (2004) Serotoninergics attenuate hyperlocomotor activity in rats. Potential new therapeutic strategy for hyperactivity. Neurotox Res 6:317–325
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
De Deurwaerdère P, Di Giovanni G (2017) Serotonergic modulation of the activity of mesencephalic dopaminergic systems: therapeutic implications. Prog Neurobiol 151:175–236
De Deurwaerdère P, Spampinato U (1999) Role of serotonin(2A) and serotonin(2B/2C) receptor subtypes in the control of accumbal and striatal dopamine release elicited in vivo by dorsal raphe nucleus electrical stimulation. J Neurochem 73:1033–1042
De Deurwaerdère P, Navailles S, Berg KA, Clarke WP, Spampinato U (2004) Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens. J Neurosci 24:3235–3241
Descarries L, Soghomonian JJ, 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
Doucet G, Descarries L, Garcia S (1986) Quantification of the dopamine innervation in adult rat neostriatum. Neuroscience 19:427–445
Egerton A, Ahmad R, Hirani E, Grasby PM (2008) Modulation of striatal dopamine release by 5-HT2A and 5-HT2C receptor antagonists: [11C]raclopride PET studies in the rat. Psychopharmacology 200:487–496
Gobert A, Millan MJ (1999) Serotonin (5-HT)2A receptor activation enhances dialysate levels of dopamine and noradrenaline, but not 5-HT, in the frontal cortex of freely-moving rats. Neuropharmacology 38:315–317
Gobert A, Rivet JM, Lejeune F, Newman-Tancredi A, Adhumeau-Auclair A, Nicolas JP, Cistarelli L, Melon C, Millan MJ (2000) Serotonin(2C) receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: a combined dialysis and electrophysiological analysis in the rat. Synapse 36:205–221
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, Perry KW, Fuller RW (1993) Dose-related effects of a neonatal 6-OHDA lesion on SKF 38393- and m-chlorophenylpiperazine-induced oral activity responses of rats. Dev Brain Res 76:233–238
Gong L, Kostrzewa RM, Li C (1994) Neonatal 6-OHDA 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
Huang N-Y, Kostrzewa RM, Li C, Perry KW, Fuller RW (1997) Persistent spontaneous oral dyskinesias 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
Ichikawa J, Meltzer HY (1995) DOI, a 5-HT2A/2C receptor agonist, potentiates amphetamine-induced dopamine release in rat striatum. Brain Res 698:204–208
Jonsson G, Pycock C, Fuxe K, Sachs C (1974) Changes in the development of central noradrenaline neurones following neonatal administration of 6-hydroxydopamine. J Neurochem 22:419–426
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, Jacobowitz D (1974) Pharmacological actions of 6-hydroxydopamine. Pharmacol Rev 26:199–288 Review
Kostrzewa RM, Gong L, Brus R (1992) Serotonin (5-HT) systems mediate dopamine (DA) receptor supersensitivity. Acta Neurobiol Exp 53:31–41
Kostrzewa RM, Brus R, Perry KW, Fuller RW (1993) Age-dependence of a 6-hydroxydopamine lesion on SKF 38393- and m-chlorophenylpiperazine-induced oral activity responses of rats. Dev Brain Res 76:87–93
Kostrzewa RM, Brus R, Kalbfleish JW, Perry KW, Fuller RW (1994) Proposed animal model of attention deficit hyperactivity disorder. Brain Res Bull 34:161–167
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, Kostrzewa JP, Brus R (2000) Dopaminergic denervation enhances susceptibility to hydroxyl radicals in rat neostriatum. Amino Acids 19:183–199
Kostrzewa RM, Kostrzewa JP, Brus R (2003) Dopamine receptor supersensitivity: an outcome and index of neurotoxicity. Neurotox Res 5:111–118
Kostrzewa RM, Nowak P, Kostrzewa JP, Kostrzewa RA, Brus R (2005) Peculiarities of L-DOPA treatment of Parkinson's disease. Amino Acids 28:157–164
Kostrzewa RM, Kostrzewa JP, Brus R, Kostrzewa RA, Nowak P (2006) Proposed animal model of severe Parkinson’s disease: neonatal 6-hydroxydopamine lesion of dopaminergic innervation of striatum. J Neural Transm Suppl 70:277–279
Kostrzewa RM, Huang N-Y, Kostrzewa JP, Nowak P, Brus R (2007) Modeling tardive dyskinesia: predictive 5-HT2C receptor antagonist treatment. Neurotox Res 11:41–50
Kostrzewa RM, Kostrzewa JP, Brown R, Nowak P, Brus R (2008) Dopamine receptor supersensitivity: development, mechanisms, presentation, and clinical applicability. Neurotox Res 14:121–128
Kuroki T, Meltzer HY, Ichikawa J (2003) 5-HT 2A receptor stimulation by DOI, a 5-HT2A/2C receptor agonist, potentiates amphetamine-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens. Brain Res 972:216–221
Lucas G, Spampinato U (2000) Role of striatal serotonin2A and serotonin2C receptor subtypes in the control of in vivo dopamine outflow in the rat striatum. J Neurochem 74:693–701
Luthman J, Bolioli B, Tsutsumi T, Verhofstad A, Jonsson G (1987) Sprouting of striatal serotonin nerve terminals following selective lesions of nigrostriatal dopamine neurons in neonatal rat. Brain Res Bull 19:269–274
Molina-Holgado E, Dewar KM, Descarries L, Reader TA (1994) Altered dopamine and serotonin metabolism in the dopamine-denervated and serotonin-hyperinnervated neostriatum of adult rat after neonatal 6-hydroxydopamine. J Pharmacol Exp Ther 270:713–721
Mrini A, Soucy JP, 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
Murnane KS, Andersen ML, Rice KC, Howell LL (2013) Selective serotonin 2A receptor antagonism attenuates the effects of amphetamine on arousal and dopamine overflow in non-human primates. J Sleep Res 22:581–588
Nowak P, Szczerbak G, Biedka I, Drosik M, Kostrzewa RM, Brus R (2006) Effect of ketanserin and amphetamine on nigrostriatal neurotransmission and reactive oxygen species in Parkinsonian rats. In vivo microdialysis study. J Physiol Pharmacol 57:583–597
Nowak P, Bortel A, Dąbrowska J, Oświęcimska J, Drosik M, Kwieciński A, Opara J, Kostrzewa RM, Brus R (2007) Amphetamine and mCPP effects on dopamine and serotonin striatal in vivo microdialysates in an animal model of hyperactivity. Neurotox Res 11:131–144
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic Press, Sydney
Porras G, Di Matteo V, De Deurwaerdère P, Esposito E, Spampinato U (2002) Central serotonin4 receptors selectively regulate the impulse-dependent exocytosis of dopamine in the rat striatum: in vivo studies with morphine, amphetamine and cocaine. Neuropharmacology 43:1099–1109
Schmidt CJ, Fadayel GM, Sullivan CK, Taylor VL (1992) 5-HT2 receptors exert a state-dependent regulation of dopaminergic function: studies with MDL 100,907 and the amphetamine analogue, 3,4-methylenedioxymethamphetamine. Eur J Pharmacol 223:65–74
Sharp T, Zetterström T, Ljungberg T, Ungerstedt U (1987) A direct comparison of amphetamine-induced behaviours and regional brain dopamine release in the rat using intracerebral dialysis. Brain Res 401:322–330
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
Stamford JA, Kruk ZL, Millar J (1990) Striatal dopamine terminals release serotonin after 5-HTP pretreatment: in vivo voltammetric data. Brain Res 515(1–2):173–180
Towle AG, Criswell HE, Maynard EH, Lauder JM, Joh TH, 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
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Schematic representation of in vivo microdialysis procedure. The microdialysis probe was surgically implanted in rat neostriatum one day prior to study. All subsequent experimental procedures were conducted in freely moving rats without anesthesia. On the day of study, and after acclimation, p-chloroamphetamine (PCA, 1 mM) was added to the microdialysate which contained 5 nM salicylic acid for enabling indirect analysis of HO●. Effluent was collected and analyzed by HPLC/ED for DA, DOPAC, 5-HT, 5-HIAA, and HO● (PDF 187 kb).
Effect of PCA on DOPAC concentration of neostriatal microdialysates of (a) Saline control rats, (b) neonatally 6-OHDA-lesioned rats, (c) neonatally 5,7-DHT-lesioned rats, and (d) neonatally 6-OHDA + 5,7-DHT-lesioned rats. PCA was administered when the zero-time sample collection was taken for HPLC/ED analysis. Each group is the mean of 4 or 5 samples. + p<0.05, ++ p<0.003 vs. Saline group; * p<0.05, ** p<0.003 vs. 6-OHDA + 5,7-DHT-lesioned group; δ p<0.05, δδ p<0.003 vs. 5,7-DHT-lesioned group (PDF 187 kb).
Effect of PCA on 2,3-dihydroxybenzoic acid (2,3-DHBA) concentration of neostriatal microdialysates of (a) Saline control rats, (b) neonatally 6-OHDA-lesioned rats, (c) neonatally 5,7-DHT-lesioned rats, and (d) neonatally 6-OHDA + 5,7-DHT-lesioned rats. Remainder of legend as in Supplementary FIG. 2 (PDF 187 kb).
Summated effects of PCA on 2,3-DHBA concentration of neostriatal microdialysates of (a) Saline control rats, (b) neonatally 6-OHDA-lesioned rats, (c) neonatally 5,7-DHT-lesioned rats, and (d) neonatally 6-OHDA + 5,7-DHT-lesioned rats. Remainder of legend as in Supplementary FIG. 2 (PDF 187 kb).
Effect of PCA on 2,5-dihydroxybenzoic acid (2,5-DHBA) concentration of neostriatal microdialysates of (a) Saline control rats, (b) neonatally 6-OHDA-lesioned rats, (c) neonatally 5,7-DHT-lesioned rats, and (d) neonatally 6-OHDA + 5,7-DHT-lesioned rats. Remainder of legend as in Supplementary FIG. 2. * p<0.05 vs. 6-OHDA group; δ p<0.05 vs. 6-OHDA + 5,7-DHT group; + p<0.05 vs. Saline group (PDF 187 kb).
Summated effects of PCA on 2,5-DHBA concentration of neostriatal microdialysates of (a) Saline control rats, (b) neonatally 6-OHDA-lesioned rats, (c) neonatally 5,7-DHT-lesioned rats, and (d) neonatally 6-OHDA + 5,7-DHT-lesioned rats. Remainder of legend as in Supplementary FIG. 2. * p<0.05 vs. 6-OHDA + 5,7-DHT group; δ p<0.05 vs. 6-OHDA group; + p<0.05 vs. Saline group (PDF 187 kb).
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Kostrzewa, J.P., Kostrzewa, R.M. p-Chloroamphetamine-Enhanced Neostriatal Dopamine Exocytosis in Rats Neonatally Co-lesioned with 6-OHDA and 5,7-DHT: Relevance to Parkinson’s Disease. Neurotox Res (2020). https://doi.org/10.1007/s12640-019-00145-4
- Parkinson disease
- In vivo microdialysis