The influence of central noradrenergic function on 5-HT2-mediated head-twitch responses in mice: possible implications for the actions of antidepressant drugs.
This study has investigated the influence of central noradrenergic function on 5-HT2-mediated head-twitch responses in mice. Central injection of low doses of the alpha 1-adrenoceptor agonists phenylephrine or methoxamine, or peripheral administration of the antagonist prazosin had no effect on the head-twitches induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). High doses of both alpha 1-adrenoceptor agonists and antagonists markedly inhibited this response. Head-twitches induced by 5-MeODMT were potently inhibited by low doses of the alpha 2-adrenoceptor agonist clonidine, and potentiated by the antagonists idazoxan and yohimbine. Clonidine also potently inhibited this response when produced by 5-hydroxytryptophan (5-HTP) and carbidopa. The action of the beta-adrenoceptor agonist clenbuterol on head-twitches was paradoxical, this drug enhancing the responses to precursor loading (5-HTP/carbidopa) but inhibiting those induced by direct agonists (5-MeODMT, quipazine). Lesioning noradrenergic neurons by central injection of 6-hydroxydopamine (6-OHDA) or peripheral administration of DSP-4 resulted in enhanced head-twitch behaviour. 6-Hydroxydopamine lesioning did not alter the inhibition of head-twitch responses by clonidine but prevented their enhancement following withdrawal from repeated desmethylimipramine (DMI) administration. It is therefore suggested that head-twitch behaviour may be under tonic control by a population of alpha 2-adrenoceptors which are not on presynaptic noradrenergic terminals, but are postsynaptic and located "down-stream" of the 5-HT2 receptor. In addition, the enhancement of this behaviour produced by withdrawal from repeated DMI administration probably also resulted from alterations in central noradrenergic function.
D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D002395:Catecholamines / Q000032:analysis; D003891:Desipramine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology*; D009638:Norepinephrine / Q000502:physiology*; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D011985:Receptors, Serotonin / Q000502:physiology*; D009435:Synaptic Transmission
D002395:Catecholamines; D011942:Receptors, Adrenergic, alpha; D011985:Receptors, Serotonin; D003891:Desipramine; D009638:Norepinephrine