Reversal of a cholinergic-induced deficit in a rodent model of recognition memory by the selective 5-HT6 receptor antagonist, Ro�04-6790

Woolley, Marie L.; Marsden, C.A.; Sleight, Andrew J.; Fone, Kevin C. F.

doi:10.1007/s00213-003-1552-5

Cited by 117 publications

(73 citation statements)

References 59 publications

(73 reference statements)

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“…Previous behavioral studies indicated such an enhanced cholinergic neurotransmission after administration with a 5-HT 6 antagonist (Bentley et al, 1999). The present finding that Ro4368554 reversed a scopolamine-induced deficit in novel object recognition corroborates other studies showing scopolamine reversal in cognition tasks (Foley et al, 2004;Meneses, 2001;Woolley et al, 2003). These data strongly support the notion that the cognition-enhancing effects of 5-HT 6 antagonists involve a cholinergic mechanism.…”

Section: Neurochemical Mechanisms Involved In the Effects Of 5-ht 6 Asupporting

confidence: 91%

“…Ro046790 enhanced nonspatial working memory in an object recognition task (ORT) (Woolley et al, 2003), increased consolidation in an autoshaping task, and reversed scopolamine-induced deficits in both an autoshaping and a passive avoidance task (Bos et al, 2001;Meneses, 2001). However, some of these effects in the autoshaping and Morris water maze task could not be replicated (Lindner et al, 2003;Russell and Dias, 2002).…”

Section: Introductionmentioning

confidence: 99%

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The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

Lieben

Blokland

Şık

et al. 2005

Neuropsychopharmacol

135

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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.

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Section: Neurochemical Mechanisms Involved In the Effects Of 5-ht 6 Asupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

Lieben

Blokland

Şık

et al. 2005

Neuropsychopharmacol

135

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“…This is despite good preclinical data describing that 5-HT 6 receptor antagonists improve cognitive processes in animals (Riemer et al, 2003;Rogers and Hagan, 2001;Woolley et al, 2001a;Woolley et al, 2001b) and may be attributed to the global nature of the MMSE.…”

Section: Discussionmentioning

confidence: 99%

Differential Involvement of 5-HT1B/1D and 5-HT6 Receptors in Cognitive and Non-cognitive Symptoms in Alzheimer's Disease

García-Alloza

Hirst

Chen

et al. 2003

Neuropsychopharmacol

134

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Growing evidence suggests that a compromised serotonergic system plays an important role in the pathophysiology of Alzheimer's disease (AD). We assessed the expression of 5-HT 1B/1D and 5-HT 6 receptors and cholinacetyltransferase (ChAT) activity in post-mortem frontal and temporal cortex from AD patients who had been prospectively assessed for cognitive function using the Mini-Mental State Examination (MMSE) and behavioral changes using the Present Behavioral Examination (PBE). 5-HT 1B/1D and 5-HT 6 receptor densities were significantly reduced in both cortical areas. 5-HT 1B/1D receptor density was correlated to MMSE decline in the frontal cortex, supporting its implication in memory impairment. The best predictor for lowered 5-HT 6 receptor density in the temporal cortex was the PBE measure of overactivity. The 5-HT 6 /ChAT ratio was related to aggression both in the frontal and temporal cortex. Therefore, antagonists acting at 5-HT 6 receptors could be useful in the treatment of non-cognitive symptoms associated to AD.

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“…Mice were tested at the ages of 4 and 10 weeks (10 -16 mice per group). The object recognition task was performed essentially as described previously (Ennaceur et al, 1997;Woolley et al, 2003). Briefly, the mice were habituated for 30 min to a plastic box with vertical opaque walls (73 ϫ 33 ϫ 25 cm) on the first day.…”

Section: Methodsmentioning

confidence: 99%

Full Reversal of Alzheimer's Disease-Like Phenotype in a Mouse Model with Conditional Overexpression of Glycogen Synthase Kinase-3

Engel¹,

Hernández²,

Ávila³

et al. 2006

J. Neurosci.

230

182

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Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase that is particularly abundant in the CNS. Dysregulation of GSK-3 activity is believed to play a key role in the pathogenesis of CNS chronic disorders such as Alzheimer's disease (AD), bipolar disorder, and Huntington's disease, and of metabolic disorders such as type II diabetes. Accordingly, GSK-3 inhibitors have been postulated as therapeutic tools for these diseases. Interestingly, pathophysiological and pharmacological regulation of GSK-3 is affected by an amplification mechanism that applies both to inhibition and activation. The possibility therefore exists that sustained inhibition or activation might persist after cessation of the initial trigger. Regarding AD, GSK-3 has been shown to accumulate in pretangle neurons. Furthermore, GSK-3 phosphorylates tau in most serine and threonine residues hyperphosphorylated in PHF (paired helical filament)-tau and GSK-3 activity contributes both to ␤-amyloid production and to ␤-amyloid-mediated neuronal death. In good agreement, mice with conditional overexpression of GSK-3 in forebrain neurons (Tet/GSK-3␤ mice) recapitulate aspects of AD neuropathology such as tau hyperphosphorylation, apoptotic neuronal death, and reactive astrocytosis as well as spatial learning deficit. Here, we exploit the conditional system used to generate Tet/GSK-3␤ mice to explore whether the biochemical, histopathological, and behavioral consequences of increased GSK-3 activity are susceptible to revert after restoration of normal GSK-3 levels. Here, we show that transgene shutdown in symptomatic mice leads to normal GSK-3 activity, normal phospho-tau levels, diminished neuronal death, and suppression of the cognitive deficit, thus further supporting the potential of GSK-3 inhibitors for AD therapeutics.

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Reversal of a cholinergic-induced deficit in a rodent model of recognition memory by the selective 5-HT6 receptor antagonist, Ro�04-6790

Cited by 117 publications

References 59 publications

The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

Differential Involvement of 5-HT1B/1D and 5-HT6 Receptors in Cognitive and Non-cognitive Symptoms in Alzheimer's Disease

Full Reversal of Alzheimer's Disease-Like Phenotype in a Mouse Model with Conditional Overexpression of Glycogen Synthase Kinase-3

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