Involvement of different subregions of the dorsal raphe nucleus in the anti-panic action mechanism of antidepressant drugs

A wealth of evidence indicates that the dorsal raphe nucleus (DR) is a heterogeneous structure, composed of anatomically and functionally distinct populations of serotonergic neurons, which have been differently implicated in the pathophysiology of anxiety, such as panic disorder. Antidepressant drugs are the first choice in treatment of anxiety disorders, and the delay for the therapeutic effect have consistently been associated with changes in serotonergic neurotransmission within the DR. However, it is unknown whether these alterations can be heterogeneous among the different subregions of the DR, and this is the focus of investigation of the present study. First, it was investigated the profile of neuronal activation of different subregions of the DR - by using the evaluation of Fos protein expression of rats exposed to the escape task in the elevated T-maze test, after acute or chronic administration of fluoxetine or imipramine. In the same animals, it was also investigated the number of positive triptophan hidroxylasis cells. For comparative reasons, it was evaluated the behavioral and immunohistochemical effects of imipramine treatment on inhibitory avoidance acquisition in the elevated T-maze, a response associated with anxiety. The results of the immunohistochemical analysis indicated that animals exposed to escape behavior exhibited higher expression of Fos protein in non-serotonergic neurons in the DR lateral wings. This effect was not observed in fluoxetine or imipramine chronically treated animals. Moreover, chronic treatment with fluoxetine, but not imipramine, was able to increase the activation of serotonergic neurons on this subregion. On the other hand, the inhibitory avoidance task promoted an increase in the activation of serotonergic neurons in the sub-regions DRC, DRD, and DRV. This profile was not observed after acute or chronic treatment with imipramine. Additionally, only the long-term treatment with imipramine showed a decrease in the activation of non-serotonergic neurons in different subregions of the DR. Based on the results obtained with fluoxetine experiment, we evaluated the role of the 5-HT1A autoreceptors located in the lateral wings. For this, we used the whole-cell patch clamp technique in a transgenic mouse line, which exhibit fluorescence in serotonergic neurons. The results indicate that the animals treated chronically with fluoxetine presented an increase in the basal excitability, with lower responsivity to the 5-HT1A agonist - 8-OH-DPAT. Altogether, the results suggest that the anti-panic effect caused by chronic fluoxetine treatment is associated with a reduction in the activation of non-serotonergic neurons, and an increase in the recruitment of non-serotonergic neurons in lateral wings. This last observation seems to be related to a 5-HT1A autoreceptor desensitization in the lateral wings. Regarding imipramine, this panicolytic effect caused by chronic administration of this drug seems to be related to a decreased activation of the non-serotonergic neurons in the lateral wings. Finally, the anxiolytic effect, of imipramine may be associated to a decrease in the recruitment of non-serotonergic neurons in different DR subregions, allied with a decreased activation of serotonergic neurons in the DRC, DRD and DRV. (AU)