The effect in rats of chronic treatment with two specific 5-HT reuptake inhibitors (SSRI) with antidepressant properties, citalopram (10 mg/kg, i.p. twice a day for 14 days, one day washout) and fluoxetine (15 mg/kg, p.o. twice a day for 21 days, 7 days washout), was evaluated on some mechanisms involved in central 5-HT neurotransmission. No adaptive modifications of brain 5-HT uptake (sites) were found by measuring functional [3H]5-HT uptake and [3H]citalopram binding in cortical and hippocampal synaptosomes, and by [3H]citalopram binding autoradiography in the raphe nuclei (5-HT cell bodies) and the ventral tegmental area (5-HT axonal pathway). Chronic treatments had no effect on presynaptic 5-HT1B autoreceptors, functionally evaluated by measuring 5-HT1B-mediated inhibition of depolarization-induced [3H]5-HT release from cortical and hippocampal synaptosomes. Chronic citalopram or fluoxetine did not significantly affect the binding of [3H]BRL-43694 to 5-HT3 receptors in the rat brain cortex. Citalopram had no effect on [125I]SB-207710 binding to 5-HT4 receptors, measured by autoradiography in the substantia nigra. Negative results, such as those reported in the present study, could be due to a number of variables including the animal species, the treatment schedule or the brain areas considered, thus explaining the differences from some previous reports of significant effects of SSRI. However, our negative data are in agreement with many other published studies, suggesting that adaptive modifications of brain 5-HT transporters, terminal 5-HT1B receptors, 5-HT3 and 5-HT4 receptors may not be a general effect induced by all SSRI.

The density and functional activity of the N-methyl-D-aspartate (NMDA)-sensitive glutamate receptor was examined in various brain areas of 3-, 18- and 24-month-old rats. The total numbers of binding sites for the NMDA receptor antagonists [3H]CGP 39653 and [3H]MK 801 binding sites were decreased in the hippocampus, cerebral cortex and striatum of 18- and 24-month-old rats, relative to 3-month-old animals. In the hippocampus of 18-month-old rats, the reduced number of NMDA receptors was associated with an increased sensitivity of [3H]MK 801 binding to the stimulatory action of glycine and glutamate. Thus, 10 microM glycine and 10 microM glutamate increased [3H]MK 801 binding in the hippocampus of 18-month-old rats by 75 and 160%, respectively; in 3-month-old animals, the same concentration of these amino acids increased binding by 37 and 95%, respectively. The sensitivity of [3H]MK 801 binding to glycine and glutamate was not increased in the cerebral cortex and striatum of aged rats. Moreover, an increased efficacy of glycine and glutamate in stimulating the binding of [3H]MK 801 in the hippocampus was no longer apparent in the 24-month-old rats. The increased sensitivity of [3H]MK 801 binding to glycine and glutamate in the hippocampus of 18-month-old rats may reflect an increase in NMDA receptor activity to compensate for the decrease in receptor number.

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We previously reported that neurosteroids, including dehydroepiandrosterone sulfate (DHEAS), inhibit the production of TNF in vitro and in vivo. In this paper we evaluated the effect of DHEAS on TNF production by cultured rat astrocytes and murine glial cell clones, and compared it with the effect on monocytic THP-1 cells. We found that DHEAS at a concentration of 10^–4–10^–7Minhibits TNF production induced by lipopolysaccharide (LPS, 1µg/ ml) in these cells. Since the inhibitory effect of HEAS is not mediated by the glucocorticoid (GC) receptor and DHEAS is an allosteric antagonist of the GABA_Areceptor, we investigated the possible role of GABA_Areceptors in this effect. The results showed that the inhibitory effect of DHEAS (10^–6M) on TNF production by THP-1 cells was completely reversed by addition of 10^–6MGABA. However, a GABA_Areceptor antagonist (bicuculline) did not mimic the action of DHEAS. In conclusion, DHEAS can inhibit TNF production in astrocytic and microglial cells suggesting it could be an endogenous regulator of TNF production in the brain.

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