Effect of long-term administration of the antidepressant drug milnacipran on serotonergic and noradrenergic neurotransmission in the rat hippocampus.
The effect of a long-term administration of the antidepressant milnacipran on the function of the serotonergic (5-HT) and noradrenergic (NE) systems was studied using single cell recording of CA3 hippocampal pyramidal cells in chloral hydrate-anesthetized male Sprague-Dawley rats, and in vitro [3H]5-HT release measurement from hippocampal slices. The sensitivity of neither the extrasynaptic nor that of the postsynaptic 5-HT1A receptors of the pyramidal neurons was altered, as indicated by their unchanged responsiveness to the microiontophoretic application of 5-HT, and by the unchanged effect of the electrical stimulation at low frequency of the ascending 5-HT bundle, respectively. Increasing the frequency of stimulation (from 1 to 5 Hz) decreased its efficacy in control rats; the milnacipran treatment abolished this phenomenon. This cannot be attributed to a desensitisation of the terminal 5-HT1B autoreceptor, since the suppressive effect of 5-HT agonist 5-carboxyamidotryptamine on [3H]5-HT release was enhanced in milnacipran-treated rats. As for the NE system, the unchanged suppressing effect of microiontophoretic applications of NE and that of the 5 Hz stimulation in the locus coeruleus (LC) on the firing activity of pyramidal neurons indicates that the milnacipran treatment not altered the sensitivity of extrasynaptic alpha2- and postsynaptic alpha1-adrenergic receptors on pyramidal cells, as well as that of the presynaptic alpha2-autoreceptor on NE terminals. The decreased inhibitory effect of NE on the [3H]5-HT release in milnacipran-treated rats revealed that this treatment results in a desensitisation of the presynaptic alpha2-heteroreceptor located on serotonergic terminals. Taken together with the decreased suppressive effect of a low frequency of stimulation of the NE tract, the present results suggest that long-term milnacipran treatment enhances the efficacy of the 5-HT and reduces that of the NE neurotransmission.
Weiss
Michel
M
Neurobiological Psychiatry Unit, Mc Gill University, 1033 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1. drpmweiss@aol.com
Blier
Pierre
P
de Montigny
Claude
C
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003521:Cyclopropanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007478:Iontophoresis; D008297:Male; D000078764:Milnacipran; D009638:Norepinephrine / Q000502:physiology*; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000187:drug effects; D017661:Receptors, Presynaptic / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects; D012701:Serotonin / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects*
D000928:Antidepressive Agents; D003521:Cyclopropanes; D011941:Receptors, Adrenergic; D017661:Receptors, Presynaptic; D011985:Receptors, Serotonin; D012701:Serotonin; D000078764:Milnacipran; D009638:Norepinephrine