Modulation of the extracellular 5-hydroxytryptamine brain concentrations by the serotonin and noradrenaline reuptake inhibitor, milnacipran. Microdialysis studies in rats.

We examined the effects of the administration of milnacipran, a dual inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline uptake on the 5-HT output in rat brain. Local milnacipran administration increased the 5-HT output in frontal cortex and the midbrain raphe nuclei 7- and 10-fold by a Ca(2+)- and tetrodotoxin-dependent mechanism. However, the subcutaneous administration of milnacipran (1-60 mg/kg s.c.) elevated the 5-HT output much less in these areas (200-230% of baseline at 60 mg/kg). In hypothalamus, 10 mg/kg s.c. raised 5-HT levels to 170%. The 5-HT1A antagonist WAY-100635 caused a small potentiation of the effects of milnacipran. The baseline 5-HT output was unaffected by 2-week treatments with milnacipran (30 and 60 mg/kg.day). The distinct regional profile and the lack of enhancement of its effects by WAY-100635 and prolonged treatment suggest that milnacipran does not exert its antidepressant action through an enhancement of the serotonergic function.

Regional distribution of extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the brain of freely moving rats.

The extracellular concentrations of 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) have been determined in six brain areas of awake rats (frontal cortex, striatum, hypothalamus, hippocampus, inferior colliculus, and raphe nuclei) using intracerebral microdialysis. The extracellular levels of 5-HT showed no significant differences among the brain regions studied. The tissue levels of 5-HT and 5-HIAA as well as the extracellular concentration of 5-HIAA were significantly higher in raphe nuclei. The regional distribution of tissue and extracellular 5-HIAA were very similar, suggesting that extracellular 5-HIAA depends mainly on the output from the intracellular compartment. On the other hand, extracellular 5-HT and tissue 5-HT showed a different distribution pattern. The tissue/extracellular ratio for 5-HT ranged from 739 in frontal cortex to 2,882 in raphe, whereas it only amounted to 1.8-3.6 for 5-HIAA. The relationship between the present results and the density of 5-HT uptake sites in these areas is discussed.

The effect of non-convulsant doses of lindane on temperature and body weight.

The effect of lindane (gamma-HCH) on temperature, food intake and body weight was studied in male and female rats after single or repeated non-convulsant oral doses. A single dose of 30 mg/kg induced a significant decrease of core temperature (0.4 degrees C in males and 0.66 degrees C in females) 5 h after administration when compared to the control value. Lindane-induced hypothermia was strongly potentiated (1.45 degrees C) by cold stress when rats were kept at 4 degrees C. The same dose of lindane produced a significant decrease in body weight gain (-85% in males and -219% in females compared to the control gain), accompanied by a diminution of food intake, 24 h after administration. No decrease in both parameters was observed when alpha- or delta-HCH isomers 30 mg/kg were tested. After daily administration with 10 mg/kg lindane for 7 days, no hypothermic effects were observed. However, a slight but significant decrease in body weight gain was recorded over the treatment period. This effect was also accompanied by a reduced food intake. The observed stereoselective effects of HCH isomers on core temperature and body weight could be a useful model to study the mechanisms of lindane neurotoxicity at low subconvulsant doses.