ALPHA(2)-AUTORECEPTORS AND ALPHA(2)-HETERORECEPTORS MODULATING TYROSINE AND TRYPTOPHAN-HYDROXYLASE ACTIVITY IN THE RAT-BRAIN IN-VIVO - AN INVESTIGATION INTO THE ALPHA(2)-ADRENOCEPTOR SUBTYPES

The subtype determination of auto- and hetero-alpha(2)-adrenoceptors m odulating the synthesis of noradrenaline (NA) and serotonin (5-HT), re spectively, was assessed using the accumulation of 3,4-dihydroxyphenyl alanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inh ibition as a measure of the rate of tyrosine and tryptophan hydroxylat ion in the rat brain in vivo. In the cerebral cortex and hippocampus, Org 3770 (non-selective alpha(2)-adrenoceptor antagonist, 0.5-10 mg/kg , i.p.) increased (43%-58%) and clonidine (non-selective alpha(2)-adre noceptor agonist, 1 mg/kg) decreased (37%-49%) the synthesis of dopa. Also the antagonist ARC 239 (alpha(2B/C) selective, 5-40 mg/kg) increa sed the synthesis of dopa in cortex (39%-46%) and hippocampus (17%-85% ). In contrast, the antagonist BRL 44408 (alpha(2D) selective, 1-10 mg /kg) did not increase the synthesis of dopa in cortex, and increased i t modestly in hippocampus only. The agonist guanoxabenz (alpha(2B/C) s elective, 0.03-3 mg/kg) decreased the synthesis of dopa in both brain regions (20%-65%), whereas the agonist oxymetazoline (alpha(2D) select ive, 0.1-3 mg/kg) failed to do so. These results indicated that the al pha(2)-autoreceptors that modulate the synthesis of dopa/NA are probab ly associated with the alpha(2B/C)-subtypes. In cortex and hippocampus , clonidine decreased (35%-53%) the synthesis of 5-HTP but Org 3770 fa iled to induce the opposite effect (except the 2 mg/kg dose in cortex) . BRL 44408 markedly increased the synthesis of 5-HTP in cortex (113%- 148%) but not in hippocampus. Similarly, also ARC 239 increased the fo rmation of 5-HTP in cortex (36%-48%) but not in hippocampus, where it was decreased (30%-55%). Oxymetazolinedecreased the synthesis of 5-HTP in hippocampus (28%-30%) but failed to do so in cortex. Guanoxabenz i n the low dose range (0.03-0.3 mg/kg) did not decrease the synthesis o f 5-HTP in any brain region. These results indicated that the alpha(2) -heteroreceptors that modulate the synthesis of 5-HTP/5-HT may well be different from the proposed alpha(2B/C)-autoreceptors modulating the synthesis of dopa/NA. These alpha(2)-heteroreceptors appear to be asso ciated with the alpha(2D)-subtype.