Activation of alpha 2-adrenoreceptors enhances haloperidol-induced suppression of operant behavior.
Inhibition of catecholamine synthesis by alpha-methyl paratyrosine (alpha-MT) was previously shown to potentiate the behavioral suppression caused by dopamine-receptor antagonists. This effect of alpha-MT is in all probability due to inhibition of the compensatory increase in dopamine turnover induced by the dopamine receptor antagonists. In the present study we investigated the effect of the alpha 2-adrenoreceptor agonist clonidine on the haloperidol-induced suppression of food-reinforced lever-pressing behavior (fixed ratio 40:1) in rats. Small behaviorally inactive doses of clonidine were found, in analogy with alpha-MT, to enhance the haloperidol-induced suppression of the lever-pressing behavior. The haloperidol-induced increase in dopamine synthesis (measured as the accumulation of DOPA after inhibition of aromatic amino acid decarboxylate) was antagonized by clonidine in the striatum as well as in the dopamine rich limbic regions. Prazosin, a selective alpha 1-adrenoreceptor antagonist had no effect on the clonidine induced behavioral changes. Idazoxane, a selective alpha 2-adrenoreceptor antagonist, counteracted both the behavioral and biochemical effects of clonidine, indicating that these effects of clonidine are mediated via its action on alpha 2-adrenoreceptors. The present findings provide support for the notion that alpha 2-adrenoreceptors may participate in the regulation of nigro-striatal as well as meso-limbic dopaminergic activity. It is suggested that alpha 2-adrenoreceptor agents, especially in combination with classical antipsychotics, might be of therapeutic value in the treatment of disorders associated with abnormal dopaminergic activity.
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004146:Dioxanes / Q000494:pharmacology; D004347:Drug Interactions; D006220:Haloperidol / Q000494:pharmacology*; D019329:Idazoxan; D008297:Male; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000502:physiology
D004146:Dioxanes; D011942:Receptors, Adrenergic, alpha; D004295:Dihydroxyphenylalanine; D006220:Haloperidol; D003000:Clonidine; D011224:Prazosin; D019329:Idazoxan