Alpha2-adrenoceptor antagonism is neither sufficient nor necessary for the distinctive action of atypical neuroleptics on intracranial self-stimulation in the rat.
Response rates in variable-interval intracranial self-stimulation (ICSS) in rats can provide a continuous record of drug-induced changes in brain function. Use of this procedure has been found to distinguish between typical and atypical neuroleptics, with the latter producing a similarly intense but much briefer depression of responding. This difference has been ascribed to the alpha2-adrenoceptor antagonist properties of atypical neuroleptics, but the evidence is ambiguous. The role of alpha2-adrenoceptors was examined in the present study using ventral tegmental ICSS to track the depressant effects of the typical and atypical neuroleptics, haloperidol (0.075 mg/kg) and olanzapine (0.9 mg/kg), injected alone or in combination with an alpha2-adrenoceptor agonist or antagonist. Neither haloperidol nor olanzapine (despite its atypical features) shows appreciable affinity for the alpha2-adrenoceptor. In the present study, olanzapine was found to depress self-stimulation responding dose-dependently, but with considerable recovery after 4 h. Simultaneous administration of alpha2-adrenoceptor receptor agonists or antagonists (respectively clonidine 0.015 mg/kg or idazoxan 3.0 mg/kg) failed significantly to increase or decrease the action of either haloperidol or olanzapine. These results indicate that alpha2-adrenoceptor antagonism does not necessarily promote recovery from neuroleptic-induced depression, and that 'atypical' features do not necessarily depend on alpha2-adrenoceptor antagonism. Various other explanations remain possible, but the accelerated time course of the atypical agents appears to support more recent explanations, based on their rapid dissociation from the D2 receptor.
Montgomery
A M J
AM
Department of Psychology, London Guildhall University, London, UK. A.M.J.Montgomery@greenwich.ac.uk
Grottick
A J
AJ
Herberg
L J
LJ
D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines; D003000:Clonidine / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D019329:Idazoxan / Q000494:pharmacology; D008297:Male; D009042:Motivation; D000077152:Olanzapine; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D012653:Self Stimulation
D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D014150:Antipsychotic Agents; D018341:Receptors, Adrenergic, alpha-2; D001569:Benzodiazepines; D010890:Pirenzepine; D006220:Haloperidol; D003000:Clonidine; D000077152:Olanzapine; D019329:Idazoxan