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Antidepressant- and anxiolytic-like effects of the phosphodiesterase-4 inhibitor rolipram on behavior depend on cyclic AMP response element binding protein-mediated neurogenesis in the hippocampus.

Li YF, Huang Y, Amsdell SL, Xiao L, O'Donnell JM, Zhang HT - Neuropsychopharmacology (2009)

Bottom Line: Inhibition of phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP (cAMP), increases phosphorylation of the cAMP response element binding protein (pCREB) and hippocampal neurogenesis, and produces antidepressant-like effects on behavior; however, causal links among these actions have not been established.Finally, 3 weeks after the end of the MAM treatment, when neurogenesis was no longer inhibited, rolipram again increased hippocampal pCREB and its antidepressant- and anxiolytic-like effects were restored.Overall, these results suggest that rolipram produces its effects on behavior in a manner that at least partially depends on its neurogenic action in the hippocampus, targeting mitotic progenitor cells rather than newborn or mature neurons; cAMP/CREB signaling in hippocampal newborn neurons is critical for neurogenesis and contributes to the behavioral effects of rolipram.

View Article: PubMed Central - PubMed

Affiliation: Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, Morgantown, WV 26506-9137, USA.

ABSTRACT
Inhibition of phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP (cAMP), increases phosphorylation of the cAMP response element binding protein (pCREB) and hippocampal neurogenesis, and produces antidepressant-like effects on behavior; however, causal links among these actions have not been established. In this study, chronic administration of rolipram (0.31-1.25 mg/kg, 16-23 days) produced antidepressant- and anxiolytic-like effects on behavior in mice. It also increased cAMP and pCREB levels in the hippocampus and prefrontal cortex, but increased Sox2, a marker for mitotic progenitor cells, only in the hippocampus. Chronic rolipram treatment also increased hippocampal neurogenesis, as evidenced by increased bromodeoxyuridine (BrdU)-positive cells in the hippocampal dentate gyrus. Methylazoxymethanol (MAM), which is toxic to proliferating cells, reversed rolipram-induced increases in BrdU-positive cells and pCREB in the hippocampus and partially blocked its behavioral effects. Approximately 84% of BrdU-positive cells became newborn neurons, 93% of which co-expressed pCREB; these proportions were not altered by rolipram or MAM, either alone or in combination. Finally, 3 weeks after the end of the MAM treatment, when neurogenesis was no longer inhibited, rolipram again increased hippocampal pCREB and its antidepressant- and anxiolytic-like effects were restored. Overall, these results suggest that rolipram produces its effects on behavior in a manner that at least partially depends on its neurogenic action in the hippocampus, targeting mitotic progenitor cells rather than newborn or mature neurons; cAMP/CREB signaling in hippocampal newborn neurons is critical for neurogenesis and contributes to the behavioral effects of rolipram.

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Effects of termination of MAM treatment on rolipram-induced anxiolytic- and antidepressant-like behavior in mice. (a) Rolipram-induced increases in the percentages of entries into and time spent in open arms in the elevated plus-maze were not altered after termination of MAM treatment. (b) Rolipram-induced decreases in immobility in the FST and TST were not changed after termination of MAM. Rolipram (1.25 mg/kg) was given (i.p.) for 33 d before the tests were carried out 1 h after the daily drug injection on days 33 (a), 34 (FST), or 35 (TST). MAM (5 mg/kg) was co-administered (s.c.) with rolipram or vehicle for the first 14 d. Values shown are means ± S.E.M of 8−9 mice per group. * p < 0.05, ** p < 0.01 vs Veh + Sal; # p < 0.05, ## p < 0.01 vs MAM + Veh.
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Figure 8: Effects of termination of MAM treatment on rolipram-induced anxiolytic- and antidepressant-like behavior in mice. (a) Rolipram-induced increases in the percentages of entries into and time spent in open arms in the elevated plus-maze were not altered after termination of MAM treatment. (b) Rolipram-induced decreases in immobility in the FST and TST were not changed after termination of MAM. Rolipram (1.25 mg/kg) was given (i.p.) for 33 d before the tests were carried out 1 h after the daily drug injection on days 33 (a), 34 (FST), or 35 (TST). MAM (5 mg/kg) was co-administered (s.c.) with rolipram or vehicle for the first 14 d. Values shown are means ± S.E.M of 8−9 mice per group. * p < 0.05, ** p < 0.01 vs Veh + Sal; # p < 0.05, ## p < 0.01 vs MAM + Veh.

Mentions: With the recovery from MAM-induced inhibition of neurogenesis and pCREB expression, rolipram's anxiolytic- and antidepressant-like effects on behavior were no longer attenuated by MAM, including the effects in the elevated plus-maze (entries%: F3,30 = 4.97; p < 0.01 and time%: F3,30 = 8.33; p = 0.001; Figure 8a), FST (F3,30 = 4.22; p = 0.01), and TST (F3,30 = 4.29; p = 0.01; Figure 8b). Total arm activity was not changed in the elevated plus-maze test (Table 3).


Antidepressant- and anxiolytic-like effects of the phosphodiesterase-4 inhibitor rolipram on behavior depend on cyclic AMP response element binding protein-mediated neurogenesis in the hippocampus.

Li YF, Huang Y, Amsdell SL, Xiao L, O'Donnell JM, Zhang HT - Neuropsychopharmacology (2009)

Effects of termination of MAM treatment on rolipram-induced anxiolytic- and antidepressant-like behavior in mice. (a) Rolipram-induced increases in the percentages of entries into and time spent in open arms in the elevated plus-maze were not altered after termination of MAM treatment. (b) Rolipram-induced decreases in immobility in the FST and TST were not changed after termination of MAM. Rolipram (1.25 mg/kg) was given (i.p.) for 33 d before the tests were carried out 1 h after the daily drug injection on days 33 (a), 34 (FST), or 35 (TST). MAM (5 mg/kg) was co-administered (s.c.) with rolipram or vehicle for the first 14 d. Values shown are means ± S.E.M of 8−9 mice per group. * p < 0.05, ** p < 0.01 vs Veh + Sal; # p < 0.05, ## p < 0.01 vs MAM + Veh.
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Related In: Results  -  Collection

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Figure 8: Effects of termination of MAM treatment on rolipram-induced anxiolytic- and antidepressant-like behavior in mice. (a) Rolipram-induced increases in the percentages of entries into and time spent in open arms in the elevated plus-maze were not altered after termination of MAM treatment. (b) Rolipram-induced decreases in immobility in the FST and TST were not changed after termination of MAM. Rolipram (1.25 mg/kg) was given (i.p.) for 33 d before the tests were carried out 1 h after the daily drug injection on days 33 (a), 34 (FST), or 35 (TST). MAM (5 mg/kg) was co-administered (s.c.) with rolipram or vehicle for the first 14 d. Values shown are means ± S.E.M of 8−9 mice per group. * p < 0.05, ** p < 0.01 vs Veh + Sal; # p < 0.05, ## p < 0.01 vs MAM + Veh.
Mentions: With the recovery from MAM-induced inhibition of neurogenesis and pCREB expression, rolipram's anxiolytic- and antidepressant-like effects on behavior were no longer attenuated by MAM, including the effects in the elevated plus-maze (entries%: F3,30 = 4.97; p < 0.01 and time%: F3,30 = 8.33; p = 0.001; Figure 8a), FST (F3,30 = 4.22; p = 0.01), and TST (F3,30 = 4.29; p = 0.01; Figure 8b). Total arm activity was not changed in the elevated plus-maze test (Table 3).

Bottom Line: Inhibition of phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP (cAMP), increases phosphorylation of the cAMP response element binding protein (pCREB) and hippocampal neurogenesis, and produces antidepressant-like effects on behavior; however, causal links among these actions have not been established.Finally, 3 weeks after the end of the MAM treatment, when neurogenesis was no longer inhibited, rolipram again increased hippocampal pCREB and its antidepressant- and anxiolytic-like effects were restored.Overall, these results suggest that rolipram produces its effects on behavior in a manner that at least partially depends on its neurogenic action in the hippocampus, targeting mitotic progenitor cells rather than newborn or mature neurons; cAMP/CREB signaling in hippocampal newborn neurons is critical for neurogenesis and contributes to the behavioral effects of rolipram.

View Article: PubMed Central - PubMed

Affiliation: Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, Morgantown, WV 26506-9137, USA.

ABSTRACT
Inhibition of phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP (cAMP), increases phosphorylation of the cAMP response element binding protein (pCREB) and hippocampal neurogenesis, and produces antidepressant-like effects on behavior; however, causal links among these actions have not been established. In this study, chronic administration of rolipram (0.31-1.25 mg/kg, 16-23 days) produced antidepressant- and anxiolytic-like effects on behavior in mice. It also increased cAMP and pCREB levels in the hippocampus and prefrontal cortex, but increased Sox2, a marker for mitotic progenitor cells, only in the hippocampus. Chronic rolipram treatment also increased hippocampal neurogenesis, as evidenced by increased bromodeoxyuridine (BrdU)-positive cells in the hippocampal dentate gyrus. Methylazoxymethanol (MAM), which is toxic to proliferating cells, reversed rolipram-induced increases in BrdU-positive cells and pCREB in the hippocampus and partially blocked its behavioral effects. Approximately 84% of BrdU-positive cells became newborn neurons, 93% of which co-expressed pCREB; these proportions were not altered by rolipram or MAM, either alone or in combination. Finally, 3 weeks after the end of the MAM treatment, when neurogenesis was no longer inhibited, rolipram again increased hippocampal pCREB and its antidepressant- and anxiolytic-like effects were restored. Overall, these results suggest that rolipram produces its effects on behavior in a manner that at least partially depends on its neurogenic action in the hippocampus, targeting mitotic progenitor cells rather than newborn or mature neurons; cAMP/CREB signaling in hippocampal newborn neurons is critical for neurogenesis and contributes to the behavioral effects of rolipram.

Show MeSH
Related in: MedlinePlus