Biomedical subjects

Ayhan Sik

Publications and source records attributed to Ayhan Sik.

7 recordsLinked to original sources

PubMed2006

Time-dependent involvement of cAMP and cGMP in consolidation of object memory: studies using selective phosphodiesterase type 2, 4 and 5 inhibitors.

The present study investigated the time-dependent memory enhancing properties of three selective phosphodiesterase inhibitors (PDE-I) vardenafil (PDE5-I), rolipram (PDE4-I) and BAY 60-7550 (PDE2-I) in the object recognition task. In particular, the time-dependent involvement of cAMP and cGMP in memory consolidation was assessed by altering the time points of drug administration. Vardenafil (1 mg/kg, p.o.), rolipram (0.03 mg/kg, i.p.), and BAY 60-7550 (3 mg/kg, p.o.) were tested in rats with a 24 h delay between the learning and the test trial. The PDE-Is were administered at different time points, i.e. directly after, 1 h, 3 h and 6 h after the first trial. Using a 24 h interval, vardenafil only showed an effect on object memory when injected directly after trial 1, rolipram only showed an improvement when injected 3 h after trial 1 and BAY 60-7550 improved memory when injected either directly after or 3 h after trial 1. No treatment effects were found when the compounds were administered 1 h or 6 h after the first trial. Our results extend our previous data that different types of PDE-Is affect different stages of memory consolidation. Moreover, the present study provides further support that selective PDE-Is can influence memory consolidation in a time-dependent manner, assumingly by elevating central cAMP and cGMP levels.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2006

Effects of the novel 5-HT(6) receptor antagonist RO4368554 in rat models for cognition and sensorimotor gating.

Serotonin(6) (5-HT(6)) receptors are almost exclusively located in the central nervous system. High expression in the hippocampus, nucleus accumbens and striatum is consistent with a potential role in cognition and psychosis. The availability of potent, selective and brain-penetrating 5-HT(6) antagonists such as RO4368554 allows further characterization of the role of the 5-HT(6) receptor in these processes. Herein, we tested RO4368554 in several cognition tasks, as well as sensorimotor gating tests. Using scopolamine-impaired and unimpaired adult male rats, RO4368554 was given in novel object discrimination, social recognition, social discrimination, Morris water maze, passive avoidance and autoshaping procedures. RO4368554 reversed the effects of scopolamine in novel object discrimination (active doses in mg/kg, i.p., 3, 10), social recognition (3, 10), social discrimination (1, 3, 10) and passive avoidance (10, 30 i.p. and 100 p.o.) tasks. In unimpaired rats, RO4368554 enhanced object discrimination (3, 10; 4-h forgetting interval) and autoshaping learning (3), but was inactive in a water maze task (doses tested: 1-10 mg/kg, i.p.). In tests sensitive to antipsychotics, RO4368554 did not reverse sensorimotor gating deficits induced by the psychostimulants dizocilpine and amphetamine (doses tested: 1-30 mg/kg, i.p.) or neonatal lesion of the ventral hippocampus (1-10 mg/kg, i.p.). In conclusion, RO4368554 enhanced learning and memory processes in unimpaired and scopolamine-impaired rats, supporting the notion that the cognitive enhancing effects of 5-HT(6) receptor antagonists involve modulation of cholinergic neurotransmission.

Acoustic Stimulation↗

PubMed2005

The selective 5-HT6 receptor antagonist Ro4368554 restores memory performance in cholinergic and serotonergic models of memory deficiency in the rat.

Antagonists at serotonin type 6 (5-HT(6)) receptors show activity in models of learning and memory. Although the underlying mechanism(s) are not well understood, these effects may involve an increase in acetylcholine (ACh) levels. The present study sought to characterize the cognitive-enhancing effects of the 5-HT(6) antagonist Ro4368554 (3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)1H-indole) in a rat object recognition task employing a cholinergic (scopolamine pretreatment) and a serotonergic- (tryptophan (TRP) depletion) deficient model, and compared its pattern of action with that of the acetylcholinesterase inhibitor metrifonate. Initial testing in a time-dependent forgetting task employing a 24-h delay between training and testing showed that metrifonate improved object recognition (at 10 and 30 mg/kg, p.o.), whereas Ro4368554 was inactive. Both, Ro4368554 (3 and 10 mg/kg, intraperitoneally (i.p.)) and metrifonate (10 mg/kg, p.o., respectively) reversed memory deficits induced by scopolamine and TRP depletion (10 mg/kg, i.p., and 3 mg/kg, p.o., respectively). In conclusion, although Ro4368554 did not improve a time-related retention deficit, it reversed a cholinergic and a serotonergic memory deficit, suggesting that both mechanisms may be involved in the facilitation of object memory by Ro4368554 and, possibly, other 5-HT(6) receptor antagonists.

Animals↗

PubMed2004

Delayed non-matching to position performance in aged hybrid Fischer 344 x brown Norway rats: a longitudinal study.

In this study, the effects of aging on the performance in a delayed non-matching to position (DNMTP) task were investigated longitudinally in hybrid Fischer 344 x Brown Norway rats. The rats were first trained to perform the task. Subsequently, their performance was assessed monthly from 28 to 34 months of age. The measures of responding on the DNMTP schedule did not decrease in the course of the study. After the last DNMTP test, choline acetyltransferase (ChAT) activity and glial fibrillary acidic protein (GFAP) content were measured in frontal cortex and hippocampus. We found that higher levels of GFAP in the frontal cortex, but not hippocampus, were associated with a poorer performance in the DNMTP task. Our findings support the notion that repeated testing prevents the age-related decline in cognitive functions that has been reported in cross-sectional studies. Pathology of the frontal cortex seems to predict a faster rate of forgetting in aging rats.

Age Factors↗

PubMed2004

Dissociable effects of acetylcholinesterase inhibitors and phosphodiesterase type 5 inhibitors on object recognition memory: acquisition versus consolidation.

RATIONALE: Phosphodiesterase enzyme type 5 (PDE5) inhibitors and acetylcholinesterase (AChE) inhibitors have cognition-enhancing properties. However, it is not known whether these drug classes affect the same memory processes. OBJECTIVE: We investigated the memory-enhancing effects of the PDE5 inhibitor sildenafil and AChE inhibitors metrifonate and donepezil in the object recognition task to find out whether acquisition or consolidation processes were affected by these drugs. METHODS: The object recognition task measures whether rats remembered an object they have explored in a previous learning trial. All drugs were given orally 30 min before or immediately after learning to study acquisition and consolidation, respectively. RESULTS: Sildenafil given immediately after the first trial improved the memory performance after 24 h and resulted in an inverted U-shaped dose-effect curve with the peak dose at 3 mg/kg. When given before the first trial, sildenafil also improved the memory performance. However, the dose needed for the best performance under this condition was 10 mg/kg, suggesting that the dose-effect curve shifted to the right. This can be explained by the metabolic clearance of the high dose of sildenafil. Donepezil had no memory improving effect when given after the first trial. However, when given before the first trial, a gradually increasing dose-effect curve was found which had its maximum effect at the highest dose tested (1 mg/kg). Likewise, only when metrifonate (30 mg/kg) was given before the first trial did rats show an improved memory performance. CONCLUSION: Our data strongly suggest that PDE5 inhibitors improve processes of consolidation of object information, whereas AChE inhibitors improve processes of acquisition of object information.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2004

Phosphodiesterase type 5 inhibition improves early memory consolidation of object information.

The nitric oxide (NO)-cyclic GMP (cGMP) signaling pathway is assumed to play an important role in processes underlying learning and memory. We used phosphodiesterase type 5 (PDE5) inhibitors to study the role of cGMP in object- and spatial memory. Our results and those reported in other studies indicate that elevated hippocampal cGMP levels are required to improve the memory performance of rodents in object recognition and passive avoidance learning, but not in spatial learning. The timing of treatment modulates the effects on memory and strongly supports a role for cGMP in early stages of memory formation. Alternative explanations for the improved memory performance of PDE5 inhibitors are also discussed. Immunocytochemical studies showed that in vitro slice incubations with PDE5 inhibitors increase NO-stimulated cGMP levels mainly in hippocampal varicose fibers. Reviewing the available data on the localization of the different components of the NO-cGMP signaling pathway, indicates a complex interaction between NO and cGMP, which may be independent of each other. It is discussed that further studies are needed, immunocytochemical and behavioral, to better understand the cGMP-mediated molecular mechanisms underlying memory formation.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2003

Performance of different mouse strains in an object recognition task.

In the present study, we tested the memory performance of different mouse strains (129/Sv, BALB/c, C57BL and Swiss) in an object recognition task. In this one-trial learning task, mice showed a good object memory performance when a 1-h delay was interposed between the first and second trial. However, when a 24-h delay was used, the mice did not discriminate between the novel and the familiar object in the second trial, indicating that the mice did not remember the object, which was presented in the first trial. Using a 4-h delay, the discrimination performance was at an intermediate level, suggesting a delay-dependent forgetting in this task. Although strain differences were found in the absolute level of exploration activity, no strain differences were found on the relative discrimination index (d2). The present data show that object memory can be assessed in mice and, in contrast to other memory tasks, appears to be less strain-dependent. The reliability of the discrimination measures is discussed.

Analysis of Variance↗