Chronicl-DOPA treatment in the unilateral 6-OHDA rat: evidence for behavioral sensitization and biochemical tolerance

doi:10.1016/0006-8993(91)91399-L

Brain Research

Volume 568, Issues 1–2, 24 December 1991, Pages 205-214

https://doi.org/10.1016/0006-8993(91)91399-L Get rights and content

Abstract

Two separate experiments were conducted to assess the behavioral and biochemical effects of chronicl-dihydroxyphenylalanine (l-DOPA) treatment in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions. In this animal model, contralateral rotation provides the behavioral indicator response forl-DOPA activation of the dopamine denervated striatum. Following 30 dailyl-DOPA treatments, a subthreshold dose (10 mg/kg) for rotation became suprathreshold and the contralateral rotation induced by a suprathreshold dose (20 mg/kg) became exaggerated. This motoric sensitization tol-DOPA was not reversed by a three-day period ofl-DOPA withdrawal. In contrast with the emergence of behavioral sensitization tol-DOPA, biochemical measurements showed that the increase of dopamine metabolite concentrations (DOPAC and HVA) induced by acutel-DOPA treatment became attenuated with chronic treatment. This finding suggests that chronicl-DOPA treatment produces a partial tolerance in the conversion ofl-DOPA to extracellular dopamine. The emergence ofl-DOPA sensitization-overstimulation effects was hypothesized to reflect the combined effects of dopamine receptor priming and Pavlovian drug conditioning and to contribute to the emergence of dyskinetic effects ofl-DOPA therapy. The partial tolerance observed for dopamine metabolites was hypothesized to represent a decreased conversion ofl-DOPA to dopamine which with long-term treatment could progress to an eventual wearing-off effect ofl-DOPA therapy.

Reference (42)

AbercrombieE.D. et al.
Effects ofl-DOPA on extracellular dopamine in striatum of normal and 6-hydroxydopamine-treated rats
Brain Research
(1990)
BonatzA. et al.
Video image analysis of behavior by microcomputer: categorization of turning and locomotion after 6-OHDA injection into the substantia nigra
J. Neurosci. Methods
(1987)
CareyR.J.
Dopamine receptors mediate drug-induced but not Pavlovian conditioned contralateral rotation in the unilateral 6-OHDA animal model
Brain Research
(1990)
CareyR.J.
Naloxone reversesl-DOPA induced overstimulation effects
Life Sci.
(1991)
CareyR.J.
The relationship of changes in spontaneous motor activity to spontaneous circling in rats with 6-hydroxydopamine lesions of the substantia nigra
Exp. Neurol.
(1986)
DunnettS.B. et al.
Conditioned turning in rats: dopamine involvement in the initiation of movement rather than the movement itself
Neurosci. Lett.
(1983)
HawkinsK.N. et al.
Autoradiographic localization of³H-MePhe³-d-Pro⁴ morphiceptin (³H PLO 17) to mu opioid receptors in the brain
Eur. J. Pharmacol.
(1987)
KaroumF. et al.
d-DOPA andl-DOPA similarly elevate brain dopamine and produce turning behavior in rats
Brain Research
(1988)
MannistoP.T. et al.
New selective COMT inhibitors: useful adjuncts for Parkinson's disease
Trends Pharmacol. Sci.
(1989)
McIntyreI.M. et al.
Carbidopa effect on rat brain monoamine oxidase and pineal melatonin
Biol. Psychiatr.
(1985)

MorelliM. et al.

Time and dose-dependence of the ‘priming’ of the expression of dopamine receptor supersensitivity

Eur. J. Pharmacol.

(1989)

OlneyJ.W. et al.

Excitotoxicity ofl-DOPA and 6-OH-DOPA: implications for Parkinson's and Huntington's disease

Exp. Neurol.

(1990)

SchwartingR. et al.

Short-term effects of ether, equithesin, and droperidol/fentanyl on catecholamine and indoleamine metabolism in the brain in the rat

Neuropharmacology

(1987)

ZetterstromT. et al.

Simultaneous measurement of dopamine release and rotational behaviour in 6-hydroxydopamine denervated rats using intracerebral dialysis

Brain Research

(1986)

AchesonA.L. et al.

Short and long term changes in tyrosine hydroxylase activity in rat brain after subtotal destruction of central noradrenergic neurons

J. Neurosci.

(1981)

BaldessariniR.J.

Dopamine and the pathophysiology of dyskenesias induced by antipsychotic drugs

Annu. Rev. Neurosci.

(1980)

BanT.A.

Pharmacology of schizophrenia

Curr. Psych. Ther.

(1976)

CalneD.B. et al.

Dopamine agonists and Parkinson's disease

Can. J. Neurol. Sci.

(1984)

Carey, R.J., Conditioning ofl-DOPA induced movement, Psychopharmacology, in...

CareyR.J.

l-DOPA accumulates selectively in the dopamine depleted striatum following chronic treatment

Abstr. Soc. Neurosci.

(1990)

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Thirty-two adult albino male rabbits, in two- and four-week-treatment groups, were divided into three subgroups: control group (saline-injected) (n = 4), 3 mg/kg/day (low dose) l-DOPA-injected groups (n = 6) and 12 mg/kg/day (high dose) l-DOPA-injected groups (n = 6). After the intraperitoneal injection treatments, the corpus cavernosum tissues were placed in organ bath chambers. The EFS-mediated responses, and the concentration-response curve to carbachol, sodium nitroprusside (SNP), sildenafil were assessed.
The two-week treatment with high-dose l-DOPA decreased the NO-dependent NANC relaxation responses, while there was no change in the low-dose two- and four-week treatment groups. The NO-independent NANC relaxation responses in the two-week groups decreased, and the responses in the four-week groups were unchanged when compared to the controls. The relaxation responses to carbachol showed no differences among all groups except for the high-dose four-week l-DOPA group. The relaxation responses of SNP and sildenafil were increased in all of the treatment groups when compared to the controls.
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The preferential nNOS inhibitor 7-nitroindazole and the non-selective one N<sup>G</sup>-nitro-l-arginine methyl ester administered alone or jointly with l-DOPA differentially affect motor behavior and monoamine metabolism in sham-operated and 6-OHDA-lesioned rats
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Reciprocal interactions between nitrergic and dopaminergic systems play a key role in the control of motor behavior. In the present study, we performed a comparative analysis of motor behavior (locomotor activity, catalepsy, rotational behavior) and monoamine metabolism in the striatum and substantia nigra of unilaterally sham-operated and 6-OHDA-lesioned rats treated with the preferential neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI) or the non-selective one N^G-nitro-l-arginine methyl ester (l-NAME), alone or in combination with l-DOPA. Each NOS inhibitor given alone (50 mg/kg) induced a distinct catalepsy 30 min after injection but only 7-NI impaired spontaneous locomotion after 10 min. In 6-OHDA-lesioned rats, chronic l-DOPA (25 mg/kg) induced 2.5-h long contralateral rotations. 7-NI (30 and 50 mg/kg) markedly reduced the intensity of l-DOPA-induced contralateral rotations while extending their duration until 4.5 h whereas l-NAME (50 and 100 mg/kg) only tended to attenuate their intensity without affecting the duration. 7-NI but not l-NAME significantly increased endogenous tissue DA levels in the nigrostriatal system of both sham-operated and 6-OHDA-lesioned rats. In l-DOPA-treated group, 7-NI significantly enhanced the l-DOPA-derived tissue DA content in this system and decreased the level of the intracellular DA metabolite DOPAC produced by monoamine oxidase (MAO). In contrast to 7-NI, l-NAME decreased markedly DA content and did not affect DOPAC level in the ipsilateral striatum. It means that the differences in 7-NI and l-NAME-mediated modulation of l-DOPA-induced behavioral and biochemical effects resulted not only from the inhibition of NOS activity but also from differences in their ability to inhibit MAO.
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Chronic l-DOPA treatment attenuates behavioral and biochemical deficits induced by unilateral lactacystin administration into the rat substantia nigra
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The aim of the study was to determine whether the dopamine (DA) precursor l-DOPA attenuates parkinsonian-like symptoms produced by the ubiquitin-proteasome system inhibitor lactacystin. Wistar rats were injected unilaterally with lactacystin (2.5 μg/2 μl) or 6-OHDA (8 μg/2 μl) into the substantia nigra (SN) pars compacta. Four weeks after the lesion, the animals were treated chronically with l-DOPA (25 or 50 mg/kg) for two weeks. During l-DOPA treatment, the lactacystin-treated rats were tested for catalepsy and forelimb asymmetry. Rotational behavior was evaluated after apomorphine (0.25 mg/kg) and l-DOPA in both PD models. After completion of experiments, the animals were killed and the levels of DA and its metabolites in the striatum and SN were assayed. We found that acute l-DOPA administration effectively decreased catalepsy and increased the use of the compromised forelimb in the cylinder test. However, the lactacystin group did not respond to apomorphine or acute l-DOPA administration in the rotational test. Repeated l-DOPA treatment produced contralateral rotations in both PD models, but the number of rotations was much greater in the 6-OHDA-lesioned rats. Both toxins markedly (>90%) reduced the levels of DA and its metabolites in the striatum and SN, while l-DOPA diminished these decreases, especially in the SN. By demonstrating the efficacy of l-DOPA in several behavioral tests, our study confirms the usefulness of the lactacystin lesion as a model of PD. However, marked differences in the rotational response to apomorphine and l-DOPA suggest different mechanisms of neurodegeneration evoked by lactacystin and 6-OHDA.
Abnormal involuntary movement (AIM) expression following D2 dopamine agonist challenge is determined by the nature of prior dopamine receptor stimulation (priming) in 6-hydroxydopamine lesioned rats
2013, Pharmacology Biochemistry and Behavior
Citation Excerpt :
Numerous studies have demonstrated that 6-OHDA rats treated with D1, D2, or D1/D2 dopamine agonists display a behavioral sensitization phenomenon known as “priming” or “reverse tolerance” such that repeated administration of the same dose of dopamine agonist produces contralateral rotational behavior of increasing magnitude (Asin et al., 1995; Carey, 1991; Gancher and Mayer, 1995; Paul et al., 1995; Pinheiro-Carrera et al., 1994; Pollack et al., 1997; Rouillard et al., 1987). As this priming effect is thought to be analogous to the development of dyskinesias in humans with PD (Carey, 1991), there is considerable interest in using 6-OHDA rats as a means to explore how to eliminate/minimize the motor side-effects associated with the pharmacologic treatment of PD. Despite the success of the 6-OHDA rat model, questions have been raised regarding the use of rotational behavior as the sole means of studying dopamine-mediated motor responses and this sensitization phenomenon (Nutt, 1990).
Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions show sensitization (priming) of rotational behavior upon repeated treatment with dopamine agonists. To relate these observations to dyskinesias exhibited by Parkinson's Disease patients, we assessed abnormal involuntary movements (AIMs) in 6-OHDA rats, which were primed with three injections of either the following: water, D1/D2 agonist apomorphine (Apo) (0.5 mg/kg), D1 agonist SKF38393 (SKF) (10 mg/kg) or D2 agonist quinpirole (Quin) (1 or 2.5 mg/kg). The rats were challenged one week later with Quin (0.25 mg/kg). Axial, limb, orolingual, locomotor, and grooming AIMs were scored (0–4) every 5 min. Priming with water did not produce AIMs. Priming with Quin (1 mg/kg) produced axial and locomotor AIMs, while priming with Apo, SKF or Quin (2.5 mg/kg) produced axial, locomotor, limb, and grooming AIMs. The disparity in AIM profiles between Quin (1 mg/kg) and (2.5 mg/kg) was not the result of D1 receptor stimulation since there was little striatal Fos expression following the third priming injection with Quin (1 or 2.5 mg/kg) compared to following SKF, which led to robust striatal Fos expression. Challenge with Quin (0.25 mg/kg) essentially reproduced the categories of AIMs exhibited during priming, with no AIMs in water-primed 6-OHDA rats, mild, non-significant, axial and locomotor AIMs in Quin (1 and 2.5 mg/kg)-primed 6-OHDA rats, and axial, limb, locomotor, and grooming AIMs in Apo- and SKF-primed 6-OHDA rats. These data suggest that the types of AIMs expressed following challenge with Quin depend on the dopamine receptor subtype and dose of dopamine agonist used during priming.
The dopaminergic stabilizer pridopidine decreases expression of l-DOPA-induced locomotor sensitisation in the rat unilateral 6-OHDA model
2013, European Journal of Pharmacology
Citation Excerpt :
Memantine has also shown potential to reduce LID (Varanese et al., 2010). Contralateral rotations in the 6-OHDA lesioned rat are related to anti-parkinsonian (Ungerstedt and Arbuthnott, 1970) and dyskinetic potential of compounds (Carey, 1991). The introduction of the AIM rating scale in rodents (Cenci et al., 1998) placed the association between contralateral rotation and dyskinesia in a more critical light (Lundblad et al., 2002).
Treatment-limiting motor complications occur in patients with Parkinson's disease after chronic levodopa (l-DOPA) treatment, and represent an unmet medical need. We examined the motor and neurochemical effects of the dopaminergic stabilizer pridopidine (NeuroSearch A/S, Ballerup, Denmark) in the unilateral rodent 6-OHDA lesion model, which is often used to evaluate the potential of experimental compounds for such dopamine-related motor complications. In total, 72 rats were hemi-lesioned and allocated to receive twice-daily injections of either vehicle; 6.5 mg/kg l-DOPA; l-DOPA+25 μmol/kg pridopidine; or l-DOPA+25 μmol/kg (−)-OSU6162—a prototype dopaminergic stabilizer used previously in 6-OHDA hemi-lesion models. Animals were treated for 7, 14 or 21 days, and locomotor activity and ex vivo brain tissue neurochemistry analysed. In agreement with previous studies, l-DOPA sensitised the motor response, producing significantly more contralateral rotations than vehicle (P<0.05). Concomitant administration of pridopidine and l-DOPA significantly decreased the number of l-DOPA-induced contralateral rotations on day 7, 14 and 21 (P<0.05 versus l-DOPA alone), while still allowing a beneficial locomotor stimulant effect of l-DOPA. Concomitant pridopidine also reduced l-DOPA-induced rotation asymmetry (P<0.05 versus l-DOPA alone) and had no adverse effects on distance travelled. Brain neurochemistry was generally unaffected in all treatments groups. In conclusion, pridopidine shows potential for reducing motor complications of l-DOPA in Parkinson's disease and further testing is warranted.

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Chronicl-DOPA treatment in the unilateral 6-OHDA rat: evidence for behavioral sensitization and biochemical tolerance

Abstract

Brain Research

J. Neurosci. Methods

Brain Research

Life Sci.

Exp. Neurol.

Neurosci. Lett.

Eur. J. Pharmacol.

Brain Research

Trends Pharmacol. Sci.

Biol. Psychiatr.

Eur. J. Pharmacol.

Exp. Neurol.

Neuropharmacology

Brain Research

Short and long term changes in tyrosine hydroxylase activity in rat brain after subtotal destruction of central noradrenergic neurons

J. Neurosci.

Dopamine and the pathophysiology of dyskenesias induced by antipsychotic drugs

Annu. Rev. Neurosci.

Pharmacology of schizophrenia

Curr. Psych. Ther.

Dopamine agonists and Parkinson's disease

Can. J. Neurol. Sci.

l-DOPA accumulates selectively in the dopamine depleted striatum following chronic treatment

Abstr. Soc. Neurosci.