Combined intrastriatal dopamine d1 and serotonin 5-ht2 receptor stimulation reveals a mechanism for hyperlocomotion in 6-hydroxydopamine-lesioned rats

doi:10.1016/S0306-4522(03)00516-5

Neuroscience

Volume 121, Issue 3, 15 October 2003, Pages 649-657

https://doi.org/10.1016/S0306-4522(03)00516-5 Get rights and content

Abstract

Loss of dopaminergic innervation to the striatum increases the sensitivity of dopamine (DA) D1 and serotonin (5-HT) 5-HT2 receptor signaling. Previous work from our laboratory has shown that systemic co-administration of D1 and 5-HT2 receptor agonists leads to the synergistic overexpression of striatal preprotachykinin mRNA levels in the DA-depleted, but not intact animals. In the present study, we examined this mechanism as related to locomotor behavior. Adult male Sprague–Dawley rats were subject to bilateral i.c.v. 6-hydroxydopamine (6-OHDA; 200 μg in 10 μl/side) or vehicle (0.9% saline and 0.1% ascorbic acid). After 3 weeks, rats were tested for locomotor responses to bilateral intrastriatal infusions of vehicle (0.9% NaCl), the D1 agonist SKF82958 [(±)6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetra-hydro-(1H)-3-benzazepine hydrobromide; 0.1, 1.0 or 10.0 μg/side], the 5-HT2 agonist DOI [(±)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane; 0.1, 1.0 or 10.0 μg/side] or subthreshold doses of DOI and SKF82958 (0.1 μg+0.1 μg in 0.8 μl/side). Rats with DA loss demonstrated supersensitive locomotor responses to SKF82958, but not DOI. Combined administration of subthreshold SKF82958 and DOI doses (0.1 μg+0.1 μg) synergistically increased locomotor behavior only in 6-OHDA-lesioned rats. These effects were blocked by either the D1 antagonist SCH23390 3-methyl-1-phenyl-2,3,4,5-tetrahydro-7-chloro-8-hydroxy-(1H)-3-benzazepine or the 5-HT2 antagonist ritanserin (each 1.0 μg in 0.8 μl/side).

The results of this study suggest that the behavioral synergy induced by local co-stimulation of D1 and 5-HT2 receptors within the 6-OHDA-lesioned striatum may lead to hyperkinesias that can occur with continued pharmacological treatment of Parkinson's disease.

Section snippets

Animals

Adult male Sprague–Dawley rats were used (225–250 g; Charles River Laboratory, Wilmington, MA, USA). All animals were housed in plastic cages (22 cm high, 45 cm deep and 23 cm wide) within a temperature controlled colony room (22–23 °C) illuminated on a 12-h light/dark cycle (lights on 06:00 h). Standard laboratory chow (Rodent Diet 5001; LabDiet, Brentwood, MO, USA) and water were available throughout the experiment. Throughout the study rat numbers were minimized and appropriate anesthesia

Attrition and histology

Over the course of the experiment two rats lost cannulae and two rats were found to have significant gliosis in the area surrounding the cannulae tracts. Data from these latter rats were not included in the final analyses. Fig. 1A shows a representative section of striatum with shaded ovals denoting the target area for drug injection. Schematic representations of coronal brain sections identifying placements for all rats included in the study are shown in Fig. 1B. All rats that completed the

Discussion

This study demonstrates that intrastriatal co-administration of the D1 agonist SKF82958 and the 5-HT2 agonist DOI synergistically enhances locomotor responses in adult 6-OHDA-lesioned rats. Sub-threshold doses of SKF and DOI co-infused directly into dorsal striatum were shown to increase total distance traveled, movement bouts and stereotypy counts in 6-OHDA-lesioned rats alone. Further, these effects were attenuated by administration of either the D1 antagonist SCH23390 or the 5-HT2 antagonist

Acknowledgements

The authors thank Mr. Dev Kamdar for technical assistance on this project. This work was supported by NIH grant NS39013 (PDW). A partial report of these findings was presented at the 2002 Society for Neuroscience meeting in Orlando, FL.

References (40)

R.L. Albin et al.
The functional anatomy of basal ganglia disorders
Trends Neurosci
(1989)
G.J. Basura et al.
Serotonin 2A receptor mRNA levels in the neonatal dopamine-depleted rat striatum remain upregulated following suppression of serotonin hyperinnervation
Brain Res Dev Brain Res
(1999)
G.J. Basura et al.
Stimulated serotonin release from hyperinnervated terminals subsequent to neonatal dopamine depletion regulates striatal tachykinin, but not enkephalin gene expression
Mol Brain Res
(2000)
G.J. Basura et al.
Serotonin 2A receptor regulation of striatal neuropeptide gene expression is selective for tachykinin, but not enkephalin neurons following dopamine depletion
Mol Brain Res
(2001)
B.M. Campbell et al.
Neonatal dopamine depletion reveals a synergistic mechanism of mRNA regulation that is mediated by dopamine(D1) and serotonin(2) receptors and is targeted to tachykinin neurons of the dorsomedial striatum
Neuroscience
(2001)
L. Descarries et al.
Ultrastructural analysis of the serotonin hyperinnervation in adult rat neostriatum following neonatal dopamine denervation with 6-hydroxydopamine
Brain Res
(1992)
M. el Mansari et al.
Hypersensitivity to serotonin and its agonists in serotonin-hyperinnervated neostriatum after neonatal dopamine denervation
Eur J Pharmacol
(1994)
L. Gong et al.
Supersensitized oral responses to a serotonin agonist in neonatal 6-OHDA-treated rats
Pharmacol Biochem Behav
(1992)
P.J. Gresch et al.
Synergistic interaction between serotonin-2 receptor and dopamine D1 receptor stimulation on striatal preprotachykinin mRNA expression in the 6-hydroxydopamine lesioned rat
Brain Res Mol Brain Res
(1999)
P.H. Hutson et al.
Activation of mesolimbic dopamine function by phencyclidine is enhanced by 5-HT2C/2B receptor antagonistsneurochemical and behavioral studies
Neuropsychopharmacology
(2000)

J.H. Kehne et al.

Effects of the selective 5-HT2A receptor antagonist MDL 100, 907 on MDMA-induced locomotor stimulation in rats

Neuropsychopharmacology

(1996)

G. Lucas et al.

Endogenous serotonin enhances the release of dopamine in the striatum only when nigro-striatal dopaminergic transmission is activated

Neuropharmacology

(2000)

H.Y. Meltzer

The role of serotonin in antipsychotic drug action

Neuropsychopharmacology

(1999)

S. Numan et al.

Increased expression of 5HT2 receptor mRNA in rat striatum following 6-OHDA lesions of the adult nigrostriatal pathway

Brain Res Mol Brain Res

(1995)

M.F. O'Neill et al.

5-HT2 receptor antagonism reduces hyperactivity induced by amphetamine, cocaine, and MK-801 but not D1 agonist C-APB

Pharmacol Biochem Behav

(1999)

T.A. Reader et al.

Effects of denervation and hyperinnervation on dopamine and serotonin systems in rat neostriatumimplications for human Parkinson's disease

Neurochem Int

(1999)

P.D. Walker et al.

Serotonin regulation of neostriatal tachykinins following neonatal 6-hydroxydopamine lesions

Brain Res

(1991)

S.K. Yeghiayan et al.

Serotonergic stimulation of the ventrolateral striatum induces orofacial stereotypy

Pharmacol Biochem Behav

(1995)

K.A. Berg et al.

Signal transduction differences between 5-hydroxytrptamine type 2A and type 2C receptor systems

Mol Pharmacol

(1994)

G.R. Breese et al.

Dopamine agonist-induced locomotor activity in rats treated with 6-hydroxydopamine at differing agesfunctional supersensitivity of D-1 dopamine receptors in neonatally lesioned rats

J Pharmacol Exp Ther

(1985)

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Combined intrastriatal dopamine d1 and serotonin 5-ht2 receptor stimulation reveals a mechanism for hyperlocomotion in 6-hydroxydopamine-lesioned rats

Abstract

Section snippets

Animals

Attrition and histology

Discussion

Acknowledgements

Trends Neurosci

Brain Res Dev Brain Res

Mol Brain Res

Mol Brain Res

Neuroscience

Brain Res

Eur J Pharmacol

Pharmacol Biochem Behav

Brain Res Mol Brain Res

Neuropsychopharmacology

Neuropsychopharmacology

Neuropharmacology

Neuropsychopharmacology

Brain Res Mol Brain Res

Pharmacol Biochem Behav

Neurochem Int

Brain Res

Pharmacol Biochem Behav

Signal transduction differences between 5-hydroxytrptamine type 2A and type 2C receptor systems

Mol Pharmacol

Dopamine agonist-induced locomotor activity in rats treated with 6-hydroxydopamine at differing agesfunctional supersensitivity of D-1 dopamine receptors in neonatally lesioned rats

J Pharmacol Exp Ther