Elsevier

Neuroscience

Volume 94, Issue 2, September 1999, Pages 505-514
Neuroscience

Prior D1 dopamine receptor stimulation is required to primeD2-mediated striatal Fos expression in 6-hydroxydopamine-lesioned rats

https://doi.org/10.1016/S0306-4522(99)00338-3Get rights and content

Abstract

Repeated dopamine agonist administration to rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway potentiates behavioral and neuronal activation in response to subsequent dopamine agonist treatment. This response sensitization has been termed “priming” or “reverse-tolerance”. Our prior work has shown that three pretreatment injections of the mixed D1/D2 agonist apomorphine (0.5 mg/kg) into 6-hydroxydopamine-lesioned rats permits a previously inactive dose of the D2 agonist quinpirole (0.25 mg/kg) to induce robust contralateral rotation and striatal Fos expression in striatoentopeduncular “direct” pathway neurons. These striatal neurons typically express D1 but not D2 receptors. Because apomorphine acts as an agonist at both D1 and D2 receptors, the present study sought to determine whether D1, D2, or concomitant D1/D2 receptor stimulation was required to prime D2-mediated contralateral rotation and striatal Fos expression. Twenty-one days following unilateral stereotaxic injection of 6-hydroxydopamine into the medial forebrain bundle, rats received three pretreatment injections, at three- to six-day intervals, with either: the mixed D1/D2 agonist apomorphine, the D1 agonist SKF38393, the D2 agonist quinpirole, or a combination of SKF38393+quinpirole. Ten days following the third pretreatment injection, 6-hydroxydopamine-lesioned rats were challenged with the D2 agonist quinpirole (0.25 mg/kg). Pretreatment with SKF38393 (10 mg/kg), quinpirole (1 mg/kg) or SKF38393 (1 mg/kg)+quinpirole (0.25 mg/kg) permitted an otherwise inactive dose of quinpirole (0.25 mg/kg) to induce robust contralateral rotation which was similar in magnitude to that observed following apomorphine priming. However, only pretreatment with SKF38393 (10 mg/kg) or SKF38393 (1 mg/kg)+quinpirole (0.25 mg/kg) permitted the same dose of quinpirole (0.25 mg/kg) to induce striatal Fos expression. These results demonstrate that while prior stimulation of D1, D2 or D1/D2 receptors can effectively prime D2-mediated contralateral rotation, prior stimulation of D1 receptors is required to prime D2-mediated striatal Fos expression.

This study demonstrates that priming of 6-hydroxydopamine-lesioned rats with a D1 agonist permits a subsequent challenge with a D2 agonist to produce robust rotational behavior that is accompanied by induction of immediate-early gene expression in neurons that comprise the “direct” striatal output pathway. These responses are equivalent to the changes observed in apomorphine-primed 6-hydroxydopamine-lesioned rats challenged with D2 agonist. In contrast, D2 agonist priming was not associated with D2-mediated induction of striatal immediate-early gene expression even though priming of D2-mediated rotational behavior was not different from that observed following priming with apomorphine or D1 agonist. Therefore, while priming-induced alterations in D2-mediated immediate early gene expression in the “direct” striatal output pathway may contribute to the enhanced motor behavior observed, such changes in striatal gene expression do not appear to be required for this potentiated motor response in dopamine-depleted rats.

Section snippets

Drug treatments and behavioral recordings

Male Sprague–Dawley rats (Charles River Laboratories, Wilmington, MA) weighing 250–300 g were anesthetized with ketamine (50 mg/kg): xylazine (10 mg/kg) (1:1) and pretreated with desmethylimipramine (25 mg/kg, i.p.) to prevent damage to noradrenergic neurons. Four microliters of a saline solution containing 6-OHDA-HBr (3 mg/ml) and ascorbic acid (2 mg/ml) was infused into the left medial forebrain bundle at a rate of 1 μl/min (stereotaxic coordinates from bregma: −3.7 mm AP, +1.6 mm ML, and −8.8 mm DV)

Dopamine depletion following 6-hydroxydopamine lesion

Unilateral injection of 6-OHDA into the medial forebrain bundle lead to a profound reduction of striatal dopamine levels (t12=19.3, P<0.0001). These 6-OHDA rats exhibited >99% dopamine depletion in the ipsilateral striatum which was associated with robust 180° contralateral rotations following the first (364±47), second (405±91), and third (409±130) apomorphine (0.5 mg/kg) pretreatment injections. Previously, we have shown that these apomorphine-primed 6-OHDA rats also show a marked reduction of

Priming of quinpirole-mediated contralateral rotation and striatal Fos

In agreement with other reports, administration of quinpirole (0.25 mg/kg) did not induce contralateral rotation or striatal Fos expression in water-pretreated (unprimed) 6-OHDA rats.42., 48. However, three pretreatment injections with the D1/D2 agonist apomorphine (0.5 mg/kg) permitted the same dose of quinpirole to induce robust contralateral rotation in 6-OHDA rats, consistent with previous observations.3., 43., 48., 54. In addition, three apomorphine pretreatment injections permitted an

Conclusions

The present findings demonstrate that prior administration of D1, D2 or D1/D2 agonists to 6-OHDA-lesioned rats potentiates D2-mediated rotational behavior consistent with the priming response. However, prior treatment with a D1 agonist is required to prime D2-mediated striatal Fos expression in D1-expressing23., 29. striatoentopeduncular neurons48 that comprises the “direct” striatal output pathway.1 These data suggest that prior D1 receptor stimulation alters the responsiveness of the “direct”

Acknowledgements

We greatly appreciate the technical assistance of Saundra Patrick with the HPLC analyses and the statistical expertise of Drs Rebecca Burwell and William Heindel. This work was supported by funds from the American Parkinson Disease Association and Brown University.

References (62)

  • T.M. Engber et al.

    Dopaminergic modulation of striatal neuropeptides: differential effects of D1 and D2 receptor stimulation on somatostatin, neuropeptide Y, neurotensin, dynorphin, and enkephalin

    Brain Res.

    (1992)
  • T.M. Engber et al.

    Continuous and intermittent levodopa differentially affect rotation induced by D1 and D2 dopamine agonists

    Eur. J. Pharmac.

    (1989)
  • S. Gancher et al.

    Sensitization to apomorphine-induced rotational behavior in 6-OHDA-lesioned rats: effects of NMDA antagonists on drug response

    Brain Res.

    (1995)
  • K.A. Keefe et al.

    D1-D2 dopamine receptor synergy in striatum: effects of intrastriatal infusions of dopamine agonists and antagonists on immediate early gene expression

    Neuroscience

    (1995)
  • R.M. Kostrzewa et al.

    Production of prolonged supersensitization of dopamine D2 receptors

    Eur. J. Pharmac.

    (1990)
  • C. LeMoine et al.

    D2 dopamine receptor gene expression by cholinergic neurons in the rat striatum

    Neurosci. Lett.

    (1990)
  • M. Mashurano et al.

    Stereotyped behavior in response to the selective D2 dopamine receptor agonist RU 24213 is enhanced by pretreatment with the selective D1 agonist SKF 38393

    Neuropharmacology

    (1986)
  • M. Morelli et al.

    Agonist-induced homologous and heterologous sensitization to D1 and D2 dependent contraversive turning

    Eur. J. Pharmac.

    (1987)
  • M. Morelli et al.

    Blockade of muscarinic receptors potentiates D1 dependent turning behavior and c-fos expression in 6-hydroxydopamine-lesioned rats but does not influence D2 mediated responses

    Neuroscience

    (1993)
  • M. Morelli et al.

    Behavioral expression of D1 receptor supersensitivity depends on previous stimulation of D2 receptors

    Life Sci.

    (1987)
  • M. Morelli et al.

    Time and dose dependence of the `priming' of the expression of dopamine receptor supersensitivity

    Eur. J. Pharmac.

    (1989)
  • J.I. Morgan et al.

    Stimulus-transcription coupling in neurons: role of cellular immediate-early genes

    Trends Neurosci.

    (1989)
  • S.S. Moy et al.

    Altered activity patterns following neonatal 6-hydroxydopamine lesions to dopaminergic neurons: effect of SKF-38393

    Brain Res.

    (1994)
  • S.L. Patrick et al.

    Concomitant sensitization of amphetamine-induced behavioral stimulation and in vivo dopamine release from rat caudate nucleus

    Brain Res.

    (1991)
  • M.L. Paul et al.

    Priming of a D1 dopamine receptor behavioral response is dissociated from striatal immediate-early gene activity

    Neuroscience

    (1995)
  • A. Pinna et al.

    Priming of 6-hydroxydopamine-lesioned rats with L-DOPA or quinpirole results in an increase in dopamine D1 receptor-dependent cyclic AMP production in striatal tissues

    Eur. J. Pharmac.

    (1997)
  • A.E. Pollack et al.

    Time dependence and role of NMDA glutamate receptors in the priming of D2-mediated rotational behavior and striatal Fos expression in 6-hydroxydopamine lesioned rats

    Brain Res.

    (1999)
  • A.E. Pollack et al.

    Apomorphine priming alters the response of striatal outflow pathways to D2 agonist stimulation in 6-hydroxydopamine lesioned rats

    Neuroscience

    (1997)
  • G.S. Robertson et al.

    Striatonigral projection neurons contain D1 receptor-activated c-fos

    Brain Res.

    (1990)
  • G.S. Robertson et al.

    D1 and D2 dopamine receptors differentially regulate c-fos expression in striatonigral and striatopallidal neurons

    Neuroscience

    (1992)
  • P. Rogue et al.

    Dopamine D2 receptor antagonists induce immediate early genes in the rat striatum

    Brain Res. Bull.

    (1992)
  • Cited by (20)

    • 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 :

      Thus, it may be that Quin (1 mg/kg)-primed 6-OHDA rats would have developed limb and grooming AIMs if they were treated over a longer time course, an effect that may have been hastened in our three-injection priming paradigm by using a higher dose of Quin (2.5 mg/kg). We have previously reported that while Quin (0.25 mg/kg) challenge did not induce rotational behavior in water-primed 6-OHDA rats, priming with Apo (0.5 mg/kg), SKF (10 mg/kg) or Quin (1 mg/kg) led to robust contralateral rotational behavior following Quin challenge (Pollack et al., 1997; Pollack and Thomas, 2010; Pollack and Yates, 1999). Similarly, in this study Quin challenge was unable to produce AIMs in water-primed 6-OHDA rats, whereas animals primed with Apo, SKF or Quin (1 or 2.5 mg/kg) exhibited combinations of axial, limb, locomotor or grooming AIMs.

    • Local modulation of striatal glutamate efflux by serotonin 1A receptor stimulation in dyskinetic, hemiparkinsonian rats

      2011, Experimental Neurology
      Citation Excerpt :

      Finally, a post-test with l-DOPA alone was performed at the end of the study to ensure stable AIMs throughout testing (Fig. 1). Three weeks after 6-OHDA (n = 10) or sham (n = 7) lesions of the MFB and unilateral striatal microdialysis cannulations, rats in the second experiment received injections of the D1R agonist SKF81297 (0.8 mg/kg, sc; Sigma), dissolved in 20% dimethyl sulfoxide (DMSO) in 0.9% NaCl, on 3 separate occasions 2–3 days apart in order to sensitize D1R (Pollack & Yates, 1999; Dupre et al., 2007). The dose of SKF81297 and priming regimen have been used in our lab to produce stable AIMs expression that is similar to the AIMs induced by our current dose of l-DOPA (Dupre et al., 2007; Dupre et al., 2008a).

    • The differential effects of 5-HT<inf>1A</inf> receptor stimulation on dopamine receptor-mediated abnormal involuntary movements and rotations in the primed hemiparkinsonian rat

      2007, Brain Research
      Citation Excerpt :

      A time course including surgery, drug administration and behavioral testing is shown in Fig. 1. Three weeks after 6-OHDA lesions, rats received injections of the D1R agonist R(+)-SKF-81297 hydrobromide (SKF81297; 0.8 mg/kg, i.p.; Sigma) on 3 separate occasions 2 to 3 days apart in order to sensitize both D1 and D2 receptors (Pollack and Yates, 1999). Contralateral rotations and AIMs (see description below) were observed immediately after injections.

    View all citing articles on Scopus
    View full text