The NMDA receptor/nitric oxide (NO)/cyclic GMP pathway and its modulation by

The NMDA receptor/nitric oxide (NO)/cyclic GMP pathway and its modulation by 5-hydroxytryptamine (5-HT) was studied in slices of neocortical samples obtained from patients undergoing neurosurgery. (5-HT2A B C) ketanserin (5-HT2A C) or SB 200646A (5-HT2B C); it was completely abolished by 0.1?μM of the selective 5-HT2C receptor antagonist SB 242084. The NMDA-induced cyclic GMP elevation also was potently inhibited by the selective 5-HT2C agonist RO 60-0175 and by the antidepressant trazodone both added at 1?μM in an SB 242084-sensitive manner. Finally the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 1?μM) inhibited the NMDA-evoked cyclic GMP response an effect blocked by the selective 5-HT1A receptor antagonist WAY 100635. In conclusion the NMDA receptor/NO/cyclic GMP pathway in human neocortex slices can be potently inhibited by activation of 5-HT2C or 5-HT1A receptors. microdialysis in PF-3758309 the cerebellum and hippocampus of awake freely moving rats (Vallebuona & Raiteri 1994 Fedele & Raiteri 1999 The glutamate receptor/NO/cyclic GMP pathway has so far not been investigated in experiments of functional neurochemistry with fresh human brain tissue. This would certainly represent an excellent model in which to test agents able to curb excessive glutamatergic transmission. Previously it was found that the release of glutamate from rat cerebellar synaptosomes (Davies & Leighton 1984 Raiteri microdialysis (Abi Saab et al. 1999 One could therefore hypothesize that 5-HT2C receptors located on GABAergic interneurons in the human neocortex mediate release of GABA onto receptors co-localized with NMDA receptors on NO synthase-containing cells leading to inhibition of the NMDA-evoked cGMP elevation. As to the inhibitory 5-HT1A receptors they could be co-localized with NMDA receptors PF-3758309 on the NO synthase-containing cells. Using intracellular recordings in slices of human neocortex it was recently observed that neurons (apparently glutamatergic pyramidal neurons) can be hyperpolarized by serotonin via 5-HT1A receptors (Newberry et al. 1999 A third result of the present investigation is the ability of trazodone to inhibit Rabbit Polyclonal to DBH. PF-3758309 the NMDA receptor/NO/cGMP pathway through the activation of 5-HT2C receptors. Trazodone is an antidepressant drug marketed in several countries (see for a review Haria et al. 1994 Although it is unclear how the drug acts to alleviate symptoms of depression interactions of trazodone with the 5-HT system have been proposed by several authors. The drug can inhibit 5-HT uptake (Garattini et al. 1976 Stefanini et al. 1976 such an activity appears however too weak to explain the clinical efficacy of trazodone particularly if compared with those of antidepressants that are selective serotonin uptake inhibitors (Owens et al. 1997 Trazodone is thought of as a 5-HT receptor antagonist (Bryant & Ereshefsky 1982 Fuller et al. 1984 Jenck et al. 1993 Cusack et al. 1994 Owens et al. 1997 Takeuchi et al. 1997 More precisely trazodone appears to target preferentially receptors of the 5-HT2 type and the few data available in part based on behavioural studies suggest that the drug may be a 5-HT2C (Jenck et al. 1993 and a 5-HT2A (Siegel et al. 1996 Takeuchi et al. 1997 receptor antagonist. Our results with human neocortex slices appear to contrast with this view. In this model trazodone mimics 5-HT and (±)-DOI thus behaving as a 5-HT2 receptor agonist. Moreover the effect of trazodone is completely abolished by the selective 5-HT2C receptor antagonist SB 242084. These results support the view that trazodone at concentrations compatible with those reached during antidepressant treatment can behave as a 5-HT2C receptor agonist in the human cerebral cortex. Interestingly a recent behavioural study PF-3758309 in rats mice and monkeys reports that the selective 5-HT2C agonist RO 60-0175 exhibits a favourable therapeutic potential in depression (Martin et al. 1998 the compound was also reported to be sedative but lacking any anxiolytic or anxiogenic effects in rats (Kennett et al. 2000 In human neocortex slices RO 60-0175 inhibited the cGMP response similarly to trazodone (Figure 5). Our results suggest therefore that 5-HT2C receptor activation could be relevant to the antidepressant activity of trazodone and possibly of.