Pharmacological effects of milnacipran, a new antidepressant, given repeatedly on the α 1 -adrenergic and serotonergic 5-HT 2A systems

Abstract

Milanacipran (MIL) is a representative of a new class of antidepressants (SNRIs) which inhibit selectively the reuptake of serotonin and noradrenaline but, in contrast to tricyclics, show no affinity for neurotransmitter receptors. The present study was aimed at determining whether repeated MIL treatment induced adaptive changes in the alpha1-adrenergic and serotonergic 5-HT2A systems, similar to those reported by us earlier for tricyclic antidepressants. The experiments were carried out on male mice and rats. MIL was administered at a dose of 10 or 30 mg/kg p.o. once or repeatedly (twice daily for 14 days). The obtained results showed that MIL administered repeatedly potentiated the clonidine-induced aggressiveness and the methoxamine-induced exploratory hyperactivity, the effects mediated by alpha1-adrenoceptors. MIL did not change the number or affinity (Bmax and K(D)) of alpha1-adrenergic receptors in the cerebral cortex for [3H]prazonsin, however, the ability of the alpha1-adrenoceptor agonist phenylephrine to compete for these sites was significantly enhanced. MIL given repeatedly (but not acutely) inhibited both the head twitch reaction induced by L-5-HTP or (+/-)DOI, the effects mediated by serotonergic 5-HT2A receptors. MIL also decreased the binding (Bmax) or [3H]-ketanserin to 5-HT2A receptors in the cerebral cortex. The above results indicate that repeated MIL administration increases the responsiveness of alpha1-adrenergic system (behavioural and biochemical changes) and decreases the responsiveness of the serotonergic 5-HT2A receptors (especially behavioural changes) as tricyclics do. It may be concluded that the lack of MIL affinity for neurotransmitter receptors is of no importance to the development of adaptive changes in the studied systems, observed after repeated treatment with antidepressants.

Chronic effects of antidepressants on serotonin release in rat raphe slice cultures: high potency of milnacipran in the augmentation of serotonin release

“…Another possible explanation is that an indirect pathway, such as a changing affinity for an agonist, may be involved in the effect of milnacipran, rather than direct effects on the α 1 -adrenoceptor. In support of this hypothesis, there is a report suggesting that milnacipran enhances the ability of α 1 -adrenoceptor agonists to compete for the [ 3 H]prazosin binding site without changing the number of binding sites or the affinity for [ 3 H]prazosin in the rat brain cortex (Maj et al, 2000). However, further studies into this issue will be needed.…”

Emerging Evidence for a Central Epinephrine-Innervated α1-Adrenergic System that Regulates Behavioral Activation and is Impaired in Depression

“…Many authors have reported that chronic treatment with tricyclic antidepressants or ECS increases either the density (Maj et al, 1985;Nowak et al, 1988;Vetulani et al, 1984), agonist affinity (Maj et al, 2000;Menkes et al, 1983a), electrophysiological response (Menkes et al, 1980), or behavioral response of brain a 1 -receptors (Maj et al, 1998(Maj et al, , 2000Menkes et al, 1983b;Mogilnicka et al, 1987;Plaznik et al, 1984). As noted above, an antidepressant, citalopram, was also shown to reverse the stressinduced desensitization of the a 1 -potentiation of cAMP responses.…”

Head‐twitch response in rodents induced by the hallucinogen 2,5‐dimethoxy‐4‐iodoamphetamine: a comprehensive history, a re‐evaluation of mechanisms, and its utility as a model

“…SNRIs) decrease the DOI-elicited HTR. [122,123] Similarly, repeated exposure to MDMA, which acts partially through interactions with the serotonin, dopamine, and norepinephrine transporters, may alter sensitivity to DOI. Although one early paper suggested no lasting effect of MDMA administration, [124] a more recent report found that repeated MDMA treatment resulted in an enhanced sensitivity to DOI at a higher (3.0 mg/kg) but not a lower dose (0.5 mg/kg).…”