Table 4.
Overview of effects of PDE4-Is on cognition
| Task (cognitive process, area involved) | Model (species) | Treatment | Results | Reference |
|---|---|---|---|---|
| Water escape task (spatial memory, hippocampus) | Impaired by microsphere embolism-induced cerebral ischemia (rat) | Rolipram (3 mg/kg, i.p.) 10 days, after embolism | Rolipram attenuates acquisition deficit measured at days 7–9 | Nagakura et al. (2002) |
| Impaired by PDE4B KO (mouse) | – | No effect | Siuciak et al. (2008a) | |
| Delayed matching to position water maze (spatial memory, hippocampus) | Unimpaired (rat) | L-454,560 (0, 0.1, 0.3, or 1 mg/kg, p.o.) 30 min before testing | L-454,560 (0.3 and 1 mg/kg) improved performance | Huang et al. (2007) |
| Radial arm water maze (spatial memory, hippocampus) | Impaired by APP-PS1 Alzheimer KO (mouse) | Rolipram (0.03 mg/kg, s.c.) for 3 weeks | Improvement when tested at 2 months after 3-week treatment | Gong et al. (2004) |
| Impaired by PS1/PDAPP KO (mouse) | Rolipram (0.03 mg/kg, s.c.) once a day for 2 weeks before testing | Rolipram improved working memory | Costa et al. (2007) | |
| Barnes circular maze (spatial memory, hippocampus) | Impaired by age, 18 months old (mouse) | Rolipram (0.016 mg/kg, i.p.) 40 min before training | More mice acquire the task and number of errors is reduced | Bach et al. (1999) |
| Radial arm maze (working and reference memory, hippocampus) | Impaired by scopolamine 0.5/1.0 mg/kg, i.p., 30 min before test (rat) | Rolipram (0.01–1 mg/kg, i.p.) 45 min before test | MED: 0.1 (working memory) and >0.1 mg/kg (reference memory) | Zhang and O’Donnell (2000) |
| Impaired by scopolamine, 0.5 mg/kg, i.p., 30 min before test (rat) | Given 30 min before test (±)-rolipram 0.01–1 mg/kg, p.o.; (−)-rolipram 0.005–1 mg/kg, p.o.; (+)-rolipram 0.1–50 mg/kg, p.o. | MED (working memory): (±)-rolipram 0.02–0.2 mg/kg, (–)-rolipram 0.01–0.02 and 0.2/0.5 mg/kg (bi phasic), (+)-rolipram 20/50 mg/kg | Egawa et al. (1997) | |
| Impaired by MK-801, 0.1 mg/kg, i.p., 60 min before test (rat) | Rolipram (0.01–0.1 mg/kg, i.p.) 30 min before test | MED: 0.05 (working memory) and 0.1 mg/kg (reference memory) | Zhang et al. (2000) | |
| Impaired by MK-801, 0.1 mg/kg, i.p., 60 min before testing (rat) | Rolipram (0.1 mg/kg, i.p.), MEM 1018 or MEM 1091 (0.1–2.5 mg/kg, i.p.) 45 min before test | MED: 0.1 mg/kg rolipram working memory, MED: 2.5 mg/kg MEM 1018 working and reference memory MED:2.5 mg/kg MEM 1091 on reference memory | Zhang et al. (2005) | |
| Impaired by MEK inhibitor UO126, 8 μg/rat into hippocampus, given twice: 60 and 30 min before test (rat) | Rolipram (0.05, 0.1, mg/kg, i.p.) 30 min before test | MED: 0.1 mg/kg (reference memory) | Zhang et al. (2004) | |
| Passive avoidance (inhibitory avoidance learning, hippocampus and amygdala) | Impaired by (1) protein synthesis inhibitor anisomycin, 150 mg/kg, s.c., 30 min before training, (2) low baseline (mouse) | Rolipram (3 or 10 mg/kg, i.p., immediately after training or 3 h after training | MED 10 mg/kg, given immediately after training (1+2) | Randt et al. (1982) |
| Impaired by scopolamine, 1 mg/kg, i.p., 30 min before acquisition (mouse) | Rolipram (1–30 mg/kg, i.p.) 30 min before acquisition | MED: 10 mg/kg | Imanishi et al. (1997) | |
| Impaired by scopolamine, 1.5 mg/kg, i.p., immediately after training (mouse) | Rolipram (10 or 30 mg/kg, p.o.) 30 min before training | MED: 30 mg/kg | Ghelardini et al. (2002) | |
| Impaired by scopolamine, 3 mg/kg, i.p., 30 min before retention test (rat) | Given 60 min before retention test. (±)-rolipram 0.01–0.1 mg/kg, p.o.; (−)-rolipram 0.005–0.02 mg/kg, p.o.; (+)-rolipram 0.3–10 mg/kg, p.o. | MED: (±)-rolipram 0.02–0.1 mg/kg, (−)-rolipram 0.01–0.02 mg/kg, (+)-rolipram 2 mg/kg; no effect at 10 mg/kg | Egawa et al. (1997) | |
| Impaired by MK-801 0.1 mg/kg, i.p., 60 min before test (rat) | Rolipram (0.1 mg/kg, i.p.) 30 min before test | MED: ≤0.1 mg/kg | Zhang et al. (2000) | |
| Impaired by MK-801, 0.1 mg/kg, i.p., 60 min before testing (rat) | Rolipram (0.1 mg/kg, i.p.), MEM 1018 or MEM 1091 (0.1–2.5 mg/kg, i.p.) 45 min before test | MED: rolipram 0.1 mg/kg, MEM1018 0.1–2.5 mg/kg, and MEM 1091 0.5–2.5 mg/kg on reversal latency | Zhang et al. (2005) | |
| Impaired by MEK inhibitor UO126, 8 μg/rat into hippocampus, given twice: 60 and 30 min before test (rat) | Rolipram (0.1, mg/kg, i.p.) 30 min before test or 30 μg/rat into hippocampus, 20 min before test | Reversal retention deficit 48 h post training | Zhang et al. (2004) | |
| Impaired by PDE4B KO (mouse) | – | No effect | Siuciak et al. (2008a) | |
| Three-panel runway task (working memory, hippocampus and prefrontal cortex) | Impaired by scopolamine, 0.56 mg/kg, i.p., 15 min before first trial (rat) | Rolipram (0.032 or 0.1 mg/kg, i.p.) 30 min before first trial | MED: 0.1 mg/kg for decrease errors | Imanishi et al. (1997) |
| Impaired by cerebral ischemia by four-vessel occlusion (rat) | Rolipram (0.032 or 0.1 mg/kg, i.p.) 30 min before first trial (immediately after reperfusion) | MED: 0.1 mg/kg for decrease errors | Imanishi et al. (1997) | |
| Impaired by ECS immediately after training (rat) | Rolipram (0.1 or 0.32 mg/kg, i.p.) just before ECS | MED: 0.32 mg/kg for decrease errors | Imanishi et al. (1997) | |
| Inhibitory avoidance learning (hippocampus and amygdala) | Impaired by (1) protein synthesis inhibitor anisomycin, 150 mg/kg, s.c., 30 min before training, (2) low baseline (mouse) | Rolipram (3 or 10 mg/kg, i.p., immediately after training or 3 h after training | MED 10 mg/kg, given immediately after training (1+2) | Randt et al. (1982) |
| Contextual fear conditioning (learning, hippocampus and amygdala) | Unimpaired (mouse) | Rolipram (0.03 mg/kg, s.c.) 30 min before training | Improved retention 24 h after training | Barad et al. (1998) |
| Unimpaired (rat) | Rolipram 0.5 mg/kg/day for 7 days chronic delivery by osmotic minipumps | Improved memory consolidation and slower extinction of conditioned fear | Monti et al. (2006) | |
| Impaired by TG2576 KO Alzheimer mice (mouse) | Rolipram (0.1 mg/kg, i.p.) 30 min prior to training | Improvement in mutants and wild-type | Comery et al. (2005) | |
| Impaired by APP-PS KO Alzheimer mice (mouse) | Rolipram 0.1 μM/kg for 3 weeks | Improvement when tested 2 months following 3-week treatment | Gong et al. (2004) | |
| Impaired by PDE4D KO (mouse) | – | Impairment LTM for context and cued fear | Rutten et al. (2008b) | |
| Object recognition task (object memory, hippocampus and rhinal cortex) | Unimpaired young (rat) | Rolipram (0.01, 0.03 or 0.1 mg/kg, i.p.) given: (1) 30 min before training, (2) directly after training, (3) 3 h after training | Rolipram (0.03 mg/kg 3 h after T1) improved memory consolidation in ORT | Rutten et al. (2006) |
| Unimpaired young (rat) | Rolipram (0.03 mg/kg, i.p.) given: (1) directly after training, (2) 1 h after training, (3) 3 h after training, (4) 6 h after training | Rolipram (0.03 mg/kg 3 h after T1) improved memory consolidation in ORT | Rutten et al. (2007b) | |
| Impaired by scopolamine, 0.1 mg/kg, i.p., 30 min before training (rat) | Rolipram (0.03, 0.1 or 0.3 mg/kg, i.p.) 30 min before training | Rolipram (0.1 mg/kg) reversed the scopolamine-induced STM deficit | Rutten et al. (2006) | |
| Impaired by acute tryptophan depletion, 3 h before training (rat) | Rolipram (0.01, 0.03 or 0.1 mg/kg, i.p.) 30 min before training | Rolipram (0.1 mg/kg) reversed ATD induced STM deficit | Rutten et al. (2007a) | |
| Unimpaired (rat) | Subchronic treatment of rolipram (0.5 mg/kg, p.o.) for 5 days. Testing before, during (day 2–3) and after treatment (T1–T2 24 h) | Subchronic rolipram treatment improved object recognition memory. Timing of final dose did not affect performance | Rutten et al. (2008c) | |
| Impaired by heterozygous CBP mutation (mouse) | Rolipram (0.1 mg/kg, i.p.) or HT0712 (0.001–0.5 mg/kg, i.p.) 20 min before training | MED: 0.1 mg/kg for both drugs. Improved object recognition at 24 h | Bourtchouladze et al. (2003) | |
| Delayed responding (spatial working memory, prefrontal cortex) | Unimpaired young and aged-impaired (rhesus monkey) | Rolipram (0.01–100 μg/kg, i.m.) 1 h before testing | At 0.1 μg/kg, trend for improvement in young subjects. Aged subjects impaired by 10 μg/kg | Ramos et al. (2003) |
| Impaired by age (rhesus monkey) | Rolipram (0, 0.001–0.05 μg/kg, i.m.) 2 h before testing and guanfacine (0, 0.0001–0.01 mg/kg, i.m. (one animal 0.5 mg/kg)) | Rolipram alone no effect. Rolipram reversed beneficial effect of guanfacine on working memory | Ramos et al. (2006) | |
| Object retrieval (executive functioning and response inhibition, prefrontal cortex) | Unimpaired (cynomolgus macaque) | Rolipram (0.003, 0.01, or 0.03 mg/kg, i.m.) 30 min before testing | Rolipram (0.01, 0.33 mg/kg) improved object retrieval performance | Rutten et al. (2008a) |
| Prepulse inhibition (information processing, frontal cortex) | Unimpaired (mouse) | Rolipram (0.1, 0.66, 1 or 10 mg/kg, i.p.) 15 min before testing | Rolipram (0.66, 1, 10 mg/kg) increased PPI and decreased startle response | Kanes et al. (2007) |
| Impaired by d-amphetamine, 10 mg/kg, i.p., 15 min before testing (mouse) | d-amphetamine (10 mg/kg, i.p.) and rolipram (0.66 mg/kg, i.p.) 15 min before testing | Rolipram attenuated the PPI deficit caused by d-amphetamine, but had no effect on startle response | Kanes et al. (2007) | |
| Impaired by PDE4B KO (mouse) | – | Increased startle response and decreased PPI (independent of startle response) | Siuciak et al. (2008a) | |
| Impaired by d-amphetamine, 5 mg/kg (mouse) | RO-20-1724 (0.25, 2.5, or 4 mg/kg, s.c.) or rolipram (mg/kg, s.c.), 5 min before testing | RO-20-1724 did not reverse PPI deficit caused by d-amphetamine | Halene and Siegel (2008) | |
| Startle response (nonassociative learning) | Unimpaired (zebrafish) | Rolipram (3, 10, or 30 μM) | Rolipram (3 μM) enhanced startle response | Best et al. (2008) |
| Acquisition of conditioned avoidance responding (learning, hippocampus) | Impaired by PDE4B KO (mouse) | – | No effect | Siuciak et al. (2007) |
| Auditory event-related potentials (information processing, frontal cortex) | Unimpaired (mouse) | RO-20-1724 (0.1, 0.25, 0.5, 1, 2.5 mg/kg, s.c.), 5 min before testing | First click: RO-20-1724 increased amplitude of P20 (at a dose of 0.25, 0.5, 1 mg/kg) and of N40 at a dose of (0.25, 0.5, 2.5 mg/kg) in CA3 area. No effects on second click | Halene and Siegel (2008) |
| Impaired by d-amphetamine, 0.5 mg/kg (mouse) | RO-20-1724 (0.25 mg/kg, s.c.), 5 min before testing | First click: P20 no effect. N40 RO-20-1734 reversed deficit caused by d-amphetamine in CA3 area. No effects on second click | Halene and Siegel (2008) |
This table is an adapted and updated version of the overview (Table 3) in Blokland et al. (2006)
KO knockout, i.m. intramuscular, i.p. intraperitoneal, p.o. per os, s.c. subcutaneous, MEK MAPK/ERK kinase, T1 trial 1, T2 trial 2, ECS electroconvulsive shocks, ATD acute tryptophan depletion, ORT object recognition task, MED minimum effective dose