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 α₁-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 α₁-adrenoceptor agonists and antagonists markedly inhibited this response. Head-twitches induced by 5-MeODMT were potently inhibited by low doses of the α₂-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 β-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 α₂-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.