Effects of rolipram on the elevated plus-maze test in rats: a preliminary study

Abstract

The objective of the present study was to assess the behavioural effects of rolipram, a specific cAMP phosphodiesterase (PDE4) inhibitor, in the elevated plus-maze (EPM) test in rats. Results showed that rolipram at the highest dose tested (0.1 mg/kg) increased the percentage of both time spent and entries into open arms, although a decrease of locomotor activity in the EPM test was also observed. In contrast, diazepam (3.0 mg/kg) exhibited the typical profile of an anxiolytic in the EPM test, increasing the percentage of time spent and entries into open arms as well as locomotor activity. A posterior statistical analysis, however, established that the effects of both rolipram and diazepam on parameters denoting anxiolytic-like activity were statistically independent from those reflecting locomotor activity reduction. Furthermore, the effects of both rolipram and diazepam were shown to be distinct from those exhibited by tricyclic antidepressant imipramine which did not show any anxiolytic-like effects in the EPM test, although a reduction of locomotor activity was also detected. Although these preliminary results suggest that rolipram may have some anxiolytic-like properties on the EPM test in rats, such an interpretation should be taken cautiously due to the observed effects on locomotor activity, which could complicate the interpretation of results from rolipram and other PDE4 inhibitors in the current test and in other anxiety animal models.

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

“…They also may induce anxiogenic-like effects and sedation (Heaslip and Evans, 1995;Imaizumi et al, 1994;Silvestre et al, 1999b), although an anxiolytic-like effect also has been reported (Silvestre et al, 1999a). While studies have shown that PDE4D plays an important role in the mediation of antidepressant-like effect (Zhang et al, 2002) and may be involved in memory , the role of PDE4B has not been investigated due to the lack of highly selective inhibitors of individual PDE4 subtypes and the complexity of the PDE4 family in terms of its numerous variants and compartmentation (Conti et al, 2003;Houslay et al, 2005;Terrin et al, 2006).…”

“…The reports to date are inconsistent. One study showed that the PDE4 inhibitor rolipram produced an anxiolytic-like effect in rats (Silvestre et al, 1999a), whereas Data shown represent the mean7SEM of 6-7 mice per group. The latency was the time before the animal descended to the grid floor where they had previously received a mild, inescapable footshock.…”

“…Administration of PDE4 inhibitors such as rolipram produces antidepressant-like effects (Zhang et al, 2002(Zhang et al, , 2006, reverses memory deficits induced pharmacologically, physically, or genetically (Bourtchouladze et al, 2003;Imanishi et al, 1997;Zhang et al, 2000Zhang et al, , 2004, alters anxiogenic-like behavior (Imaizumi et al, 1994;Silvestre et al, 1999a), and induces analgesia in rodents (Kumar et al, 2000). Inhibition of PDE4 also increases adult neurogenesis (Nakagawa et al, 2002), which is believed to be involved in antidepressant activity (Dranovsky and Hen, 2006;Malberg and Duman, 2003;Santarelli et al, 2003).…”

The cyclic AMP phenotype of fragile X and autism

“…During an elevated plus-maze test, the selective PDE4 inhibitor rolipram produces anxiolytic-like behavior in rats independent of simultaneous locomotor behavior (Silvestre, Fernandez et al 1999). Thought to originate as intracellular cAMP, extracellular cAMP levels detected by microdialysis in rats increase in right medial prefrontal areas in response to a restraint stressor or peritoneal saline injection stressor (Stone and John 1992).…”

The Role of Protein Kinase A in Anxiety Behaviors

“…Studies with rodents support the role of PDE4 in CNS processes including depression [89], learning and memory [90], and anxiety [91]. Studies using PDE4 inhibitors (rolipram and etazolate) demonstrate an antidepressant-like effect [92,93,94,95,96], a reversal of memory deficits [97,98,99] and a reduction in anxiogenic behavior [100,101,102,103]. Amplification of the cAMP pathway with type IV-specific PDE inhibitor rolipram [90,97,104,105] increased the long-term but not the short-term memory of contextual fear conditioning and object recognition (table 1).…”