Brain Region-Specific Effects of Short-Term Treatment with Duloxetine, Venlafaxine, Milnacipran and Sertraline on Monoamine Metabolism in Rats

Abstract

We examined brain region-specific changes in monoamines and metabolites, and their ratios, after short-term administration of antidepressants to rats. Serotonin noradrenaline reuptake inhibitors (SNRIs; duloxetine, venlafaxine, milnacipran) and a serotonin-selective reuptake inhibitor (SSRI; sertraline) elevated serotonin (5-HT) levels in the midbrain (MB). Duloxetine and venlafaxine increased 5-HT levels in the brainstem and 5-HT terminal areas, whereas milnacipran and sertraline increased levels in the brainstem only. Significant reductions in 5-HT turnover were observed in various forebrain regions, including the hippocampus and hypothalamus, after treatment with all of the tested drugs except for milnacipran. In addition, there was reduced 5-HT turnover in the dorsolateral frontal cortex (dlFC), the medial prefrontal cortex (mPFC), and both the dlFC and the mPFC after treatment with duloxetine, sertraline, and venlafaxine, respectively. Venlafaxine significantly increased dopamine (DA) levels in the nucleus accumbens (NAc) and the substantia nigra and decreased DA turnover in the NAc. Similar changes were observed after treatment with duloxetine and sertraline in the NAc, whereas milnacipran increased DA levels in the mPFC. Limited increases in noradrenaline levels were detected after treatment with duloxetine, venlafaxine, or sertraline, but not after treatment with milnacipran. These results show that SNRIs and SSRIs induced region-specific monoaminergic changes after short-term treatment.

Tipepidine increases dopamine level in the nucleus accumbens without methamphetamine-like behavioral sensitization

“…Endorsing these findings, various types of antidepressants developed to date, which have little effect on treatment-resistant depression, do not increase dopamine levels in the NAc [10][11][12][13]. On the other hand, our pharmacological studies suggested that the central dopaminergic system may be partly involved in the tipepidine effects described above [1][2][3].…”

Neural Activation by Milnacipran and Memory Extinction

“…In the present study, repeated administration of milnacipran reduced Fos counts in the infralimbic region. The same treatment with milnacipran increased dopamine levels in the prefrontal cortex [8]. There may be some relationships between dopamine and extinction in the infralimbic region.…”

“…The rationale for choosing the dose of milnacipran stems from previous animal studies that milnacipran 20 mg/kg exerted antidepressant-like effects [10]. The duration of drug regimen was based on a recent study [8]. A control group was injected with saline alone.…”

“…Neurochemically, acute and subchronic milnacipran treatment increased basal extracellular norepinephrine concentrations in the prefrontal cortex [6,7]. Furthermore, repeated administration of milnacipran increased dopamine levels in the prefrontal cortex [8].…”

Untitled

“…Duloxetine is a potent serotonin and norepinephrine reuptake inhibitor 24 . The dual action makes it an interesting drug in the treatment of depression 9,19,20 .…”