Acute and long-term regulation of brain alpha 2-adrenoceptors after manipulation of noradrenergic transmission in the rat.
The specific binding of [3H]clonidine (KD and Bmax) to rat brain membranes was used as a biochemical index to directly evaluate alpha 2-adrenoceptor changes after manipulation of synaptic noradrenaline (NA) pools or stimulation or blockade of the receptor. Acute (2 h) and prolonged (7 days) inhibition of NA synthesis with alpha-methyl-p-tyrosine (150 mg/kg) or acute (2 h) and chronic (14 days) treatment with reserpine (0.1-0.5 mg/kg) reduced the NA content by 15-90%, which also resulted in marked reductions (35-55%) of the KD values for [3H]clonidine in all brain regions studied. In contrast to alpha-methyl-p-tyrosine, chronic reserpine treatment did not alter the Bmax values for [3H]clonidine or [3H]UK 14304 in any brain region. In the hypothalamus and cerebral cortex, acute (2 h) and chronic (7-14 days) treatment with the monoamine oxidase (MAO) inhibitors clorgyline (1 mg/kg) or tranylcypromine (5 mg/kg) increased the content of NA by 6-100%, which led to marked reductions (20-50%) of Bmax without altering the KD values for [3H]clonidine. Similarly, prolonged (21 days) inhibition of NA neuronal uptake with cocaine or protriptyline (10 mg/kg) also resulted in decreases in Bmax (20-25%) with no alterations in KD in the hypothalamus. In various brain regions, chronic (14 days) but not short-term (1 day) treatment with clonidine (0.1 mg/kg) or yohimbine (10 mg/kg) resulted in decreases (30-40%) and increases (15-20%), respectively, in Bmax without altering the KD values for [3H]clonidine. The results indicate that drugs which deplete endogenous NA up-regulate alpha 2-adrenoceptors (increased affinity of [3H]clonidine binding sites) while drugs which increase the intraneuronal and/or synaptic NA pools down-regulate the receptors (decreased number of [3H]clonidine binding sites). These adaptive receptor changes appear to be dependent on NA availability.
Giralt
M T
MT
Department of Pharmacology, Faculty of Medicine, University of the Basque Country, Leioa, Spain.
García-Sevilla
J A
JA
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D003000:Clonidine / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*; D015016:Yohimbine / Q000378:metabolism
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D008996:Monoamine Oxidase Inhibitors; D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine; D003000:Clonidine; D009638:Norepinephrine