title: alpha2-Adrenoceptor-mediated modulation of the release of GABA and noradrenaline in the rat substantia nigra pars reticulata.
abstract: The control of movement by the basal ganglia is influenced by inputs from diverse brain structures. Unfortunately, the mechanisms of modulation are poorly defined. Based on neuroanatomical evidence for alpha2A and alpha2C subtypes of alpha2 adrenergic receptors within this region, we hypothesize that noradrenergic alpha2-receptors can influence transmitter release in the SNr. To test this hypothesis we examined the effect of the alpha 2 adrenergic agonist, clonidine, and antagonist, rauwolscine, on the efflux of [3H]-GABA and [3H]-noradrenaline from brain slices of the rat substantia nigra pars reticulata. At low concentrations (10 nM), rauwolscine caused an 84.2 +/- 18.51% (p < 0.01) increase in KCl-evoked GABA release. At higher concentrations, rauwolscine caused a dose-dependent return to basal levels. Rauwolscine also enhanced basal GABA efflux after KCl washout with a similar biphasic concentration-dependence. Surprisingly, clonidine also enhanced [3H]-GABA release but had no effect on KCl-evoked [3H]-GABA release at concentrations which inhibited [3H]-NA efflux. These effects were potentiated by the GABA re-uptake inhibitor nipecotic acid. Together, our data indicate an important role for noradrenergic modulation in the SNr. The enhancing effect of both the alpha2 adrenoceptor agonist and antagonist on GABA release, while appearing paradoxical, can be rationalised by actions at distinct subsets of alpha2 adrenoceptors, using a simple model where alpha2A adrenoceptors are localized on the terminals of noradrenergic afferents impinging upon alpha2C adrenoceptor-containing GABAergic striato-nigral neurones.
authors.affiliation: Faculty of Life Sciences, University of Manchester, 1.124 Stopford Building, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Amal
authors.initials: A
authors.lastname: Alachkar
authors.forename: Jonathan
authors.initials: J
authors.lastname: Brotchie
authors.forename: Owen T
authors.initials: OT
authors.lastname: Jones
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D009557:Nipecotic Acids / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D009924:Organ Culture Techniques; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D015016:Yohimbine / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D009557:Nipecotic Acids; D018341:Receptors, Adrenergic, alpha-2; C030278:nipecotic acid; D015016:Yohimbine; D005680:gamma-Aminobutyric Acid; D003000:Clonidine; D009638:Norepinephrine