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Lesions of the nigrostriatal dopamine projection increase the inhibitory effects of D1 and D2 dopamine agonists on caudate-putamen neurons and relieve D2 receptors from the necessity of D1 receptor stimulation.
J Neurosci. 1990 Jul; 10(7):2318-29.JN

Abstract

Extracellular single unit recording and microiontophoretic techniques were used to determine the sensitivities and interactions of D1 and D2 dopamine (DA) receptors in the caudate putamen (CPu) of rats that were denervated of DA by intraventricular injections of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA). Seven to 10 d after the 6-OHDA injection, DA levels in the ipsilateral CPu were reduced to 11.8% of control. Current-response curves revealed that the inhibitory responses of CPu neurons to microiontophoretic administration of both the selective D1 receptor agonist SKF-38393 and the selective D2 receptor agonist quinpirole were significantly increased in 6-OHDA-pretreated rats, suggesting up-regulation of both receptor subtypes. Although our previous studies have established that D1 receptor activation is normally required for (enables) the inhibitory effects of selective D2 agonists in the CPu, this requirement was no longer evident in 6-OHDA-denervated rats. Whereas acute DA depletion [produced by the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT)] attenuated the inhibitory effects of quinpirole on CPu neurons, long-term DA denervation (produced by 6-OHDA) enhanced the inhibitory effects of the D2 agonist. The enhanced effects of quinpirole in 6-OHDA-lesioned rats were not due to residual DA stimulating supersensitive D1 receptors (i.e., enabling) since further DA depletion (99.7%), produced by acute administration of AMPT in 6-OHDA-lesioned rats, failed to diminish the inhibitory efficacy of quinpirole. In addition to relieving D2 receptors from the need for D1 receptor-mediated enabling, 6-OHDA lesions also abolished the normal synergistic relationship between the receptor subtypes since low (subinhibitory) currents of SKF-38393 (4 nA) failed to potentiate the inhibitory effects of quinpirole on CPu neurons in lesioned rats. Similar findings (i.e., supersensitivity and loss of synergistic effects) were obtained from rats that had received repeated pretreatment with reserpine (2.5 mg/kg) for 4 d, indicating that these effects of 6-OHDA lesions were due to the depletion of synaptic DA rather than to the structural loss of DA terminals. Therefore, both the quantitative (potentiation) and the qualitative (enabling) synergistic effects between D1 and D2 receptors in the rat CPu were abolished when these receptors were functionally supersensitive. The present study provides electrophysiological support for previous behavioral studies indicating that the requirement of D1 receptor stimulation for D2 receptor-mediated functional effects (enabling) is not maintained in rats chronically depleted of DA by either 6-OHDA lesions or repeated reserpine.

Authors+Show Affiliations

Neuropsychopharmacology Laboratory, Wayne State University School of Medicine, Lafayette Clinic, Detroit, Michigan 48207.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

1973947

Citation

Hu, X T., et al. "Lesions of the Nigrostriatal Dopamine Projection Increase the Inhibitory Effects of D1 and D2 Dopamine Agonists On Caudate-putamen Neurons and Relieve D2 Receptors From the Necessity of D1 Receptor Stimulation." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 10, no. 7, 1990, pp. 2318-29.
Hu XT, Wachtel SR, Galloway MP, et al. Lesions of the nigrostriatal dopamine projection increase the inhibitory effects of D1 and D2 dopamine agonists on caudate-putamen neurons and relieve D2 receptors from the necessity of D1 receptor stimulation. J Neurosci. 1990;10(7):2318-29.
Hu, X. T., Wachtel, S. R., Galloway, M. P., & White, F. J. (1990). Lesions of the nigrostriatal dopamine projection increase the inhibitory effects of D1 and D2 dopamine agonists on caudate-putamen neurons and relieve D2 receptors from the necessity of D1 receptor stimulation. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 10(7), 2318-29.
Hu XT, et al. Lesions of the Nigrostriatal Dopamine Projection Increase the Inhibitory Effects of D1 and D2 Dopamine Agonists On Caudate-putamen Neurons and Relieve D2 Receptors From the Necessity of D1 Receptor Stimulation. J Neurosci. 1990;10(7):2318-29. PubMed PMID: 1973947.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lesions of the nigrostriatal dopamine projection increase the inhibitory effects of D1 and D2 dopamine agonists on caudate-putamen neurons and relieve D2 receptors from the necessity of D1 receptor stimulation. AU - Hu,X T, AU - Wachtel,S R, AU - Galloway,M P, AU - White,F J, PY - 1990/7/1/pubmed PY - 1990/7/1/medline PY - 1990/7/1/entrez SP - 2318 EP - 29 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 10 IS - 7 N2 - Extracellular single unit recording and microiontophoretic techniques were used to determine the sensitivities and interactions of D1 and D2 dopamine (DA) receptors in the caudate putamen (CPu) of rats that were denervated of DA by intraventricular injections of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA). Seven to 10 d after the 6-OHDA injection, DA levels in the ipsilateral CPu were reduced to 11.8% of control. Current-response curves revealed that the inhibitory responses of CPu neurons to microiontophoretic administration of both the selective D1 receptor agonist SKF-38393 and the selective D2 receptor agonist quinpirole were significantly increased in 6-OHDA-pretreated rats, suggesting up-regulation of both receptor subtypes. Although our previous studies have established that D1 receptor activation is normally required for (enables) the inhibitory effects of selective D2 agonists in the CPu, this requirement was no longer evident in 6-OHDA-denervated rats. Whereas acute DA depletion [produced by the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT)] attenuated the inhibitory effects of quinpirole on CPu neurons, long-term DA denervation (produced by 6-OHDA) enhanced the inhibitory effects of the D2 agonist. The enhanced effects of quinpirole in 6-OHDA-lesioned rats were not due to residual DA stimulating supersensitive D1 receptors (i.e., enabling) since further DA depletion (99.7%), produced by acute administration of AMPT in 6-OHDA-lesioned rats, failed to diminish the inhibitory efficacy of quinpirole. In addition to relieving D2 receptors from the need for D1 receptor-mediated enabling, 6-OHDA lesions also abolished the normal synergistic relationship between the receptor subtypes since low (subinhibitory) currents of SKF-38393 (4 nA) failed to potentiate the inhibitory effects of quinpirole on CPu neurons in lesioned rats. Similar findings (i.e., supersensitivity and loss of synergistic effects) were obtained from rats that had received repeated pretreatment with reserpine (2.5 mg/kg) for 4 d, indicating that these effects of 6-OHDA lesions were due to the depletion of synaptic DA rather than to the structural loss of DA terminals. Therefore, both the quantitative (potentiation) and the qualitative (enabling) synergistic effects between D1 and D2 receptors in the rat CPu were abolished when these receptors were functionally supersensitive. The present study provides electrophysiological support for previous behavioral studies indicating that the requirement of D1 receptor stimulation for D2 receptor-mediated functional effects (enabling) is not maintained in rats chronically depleted of DA by either 6-OHDA lesions or repeated reserpine. SN - 0270-6474 UR - https://www.unboundmedicine.com/medline/citation/1973947/Lesions_of_the_nigrostriatal_dopamine_projection_increase_the_inhibitory_effects_of_D1_and_D2_dopamine_agonists_on_caudate_putamen_neurons_and_relieve_D2_receptors_from_the_necessity_of_D1_receptor_stimulation_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=1973947 DB - PRIME DP - Unbound Medicine ER -