5-HT6 receptor antagonists improve performance in an attentional set shifting task in rats

Hatcher, Paula; Brown, Valerie J.; Tait, David S.; Bate, Simon T.; Overend, Philip; Hagan, Jim J.; Jones, Declan N.C.

doi:10.1007/s00213-005-2261-z

Cited by 108 publications

(72 citation statements)

References 38 publications

(48 reference statements)

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“…In both vehicle and PCP-treated rats the first reversal (R1) required more trials to reach criterion compared to earlier stages of the task. This is supported by data showing a significant increase in trials to criterion in control rats [26]; however, other studies have shown more modest increases [8,16,18].…”

Section: Discussionmentioning

confidence: 57%

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A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats

McLean

Beck

Woolley

et al. 2008

Behavioural Brain Research

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Rationale: The NMDA receptor antagonist, phencyclidine (PCP), has been shown to induce symptoms characteristic of schizophrenia. A loss in executive function and the ability to shift attention between stimulus dimensions is impaired in schizophrenia; this can be assessed in rodents by the perceptual attentional set-shifting task. Objective: The aim of this study was to investigate whether the deficits induced by sub-chronic PCP in attentional set-shifting could be reversed by sub-chronic administration of clozapine, risperidone or haloperidol. Methods: Adult female hooded-Lister rats received subchronic PCP (2 mg/kg) or vehicle (1 ml/kg) i.p. twice daily for seven days, followed by a seven-day washout period. PCP-treated rats then received clozapine, risperidone, haloperidol or vehicle once daily for seven days and were then tested in the perceptual set-shifting task. Results: PCP significantly (p<0.01) increased the number of trials to reach criterion in the EDS phase when compared to vehicle and this deficit was significantly (p<0.01) attenuated by sub-chronic clozapine (2.5 mg/kg) and risperidone (0.2 mg/kg), but not by sub-chronic haloperidol treatment (0.05 mg/kg). Conclusions:These data show that sub-chronic PCP produced a robust deficit within the EDS phase in the attentional set-shifting task, in female rats. Atypical antipsychotics, clozapine and risperidone, but not the classical agent, haloperidol, significantly improved the PCPinduced cognitive deficit.

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Section: Discussionmentioning

confidence: 57%

“…Clozapine has affinity at a wide range of receptors including 5-HT 6 receptors. A selective 5-HT 6 receptor antagonist has been shown to improve set-shifting ability [26], this may be via facilitation of cortical and hippocampal glutamatergic activity [12].…”

Section: Discussionmentioning

confidence: 99%

A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats

McLean

Beck

Woolley

et al. 2008

Behavioural Brain Research

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“…Activity at 5-HT 6 receptors has been postulated to be important in cognitive dysfunction (Mitchell and Neumaier, 2005) and psychopathology (East et al, 2002), and in the present study, the 5-HT 6 antagonist reversed the PCP-induced impairment as did sertindole, while the 5-HT 2A receptor antagonist treatment did not improve EDS performance significantly, very similar to effects observed with clozapine, olanzapine, and risperidone. Although a previous study reported that receptor antagonist treatment improved performance in control rats (Hatcher et al, 2005), a more recent study found that selective 5-HT 6 receptor antagonism reversed PCP deficits without influencing performance in control rats (Wunsch et al, 2006). These latter findings are consistent with those of the current study.…”

Section: Discussionmentioning

confidence: 98%

“…Drugs were administered immediately before behavioral testing, with the exception of sertindole (2 h, due to a delayed peak effect), to evaluate the effects of drug on all discrimination problems in the set-shifting procedure. We selected dose ranges for compounds that did not produce behavioral disruption and that have been shown to induce DA D 2 receptor occupancies corresponding to therapeutically effective levels (Olsen et al, 2006) or to be effective in relevant mechanistic in vivo models (Zhang and Bymaster, 1999;Sanchez and Arnt, 2000;Hatcher et al, 2005;Wunsch et al, 2006). The compounds examined differ on activity at DA D 2 , 5-HT 2A , and 5-HT 6 receptors.…”

Section: Drug Administrationmentioning

confidence: 99%

Reversal of Subchronic PCP-Induced Deficits in Attentional Set Shifting in Rats by Sertindole and a 5-HT6 Receptor Antagonist: Comparison Among Antipsychotics

Rodefer

Nguyen

Karlsson

et al. 2007

Neuropsychopharmacol

114

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Currently accepted treatments for schizophrenia can effectively control positive symptoms but have limited impact on cognitive deficits in schizophrenia. The purpose of these experiments was to address this unmet need by characterizing the effects of classical and secondgeneration antipsychotics on cognitive impairments associated with schizophrenia. An additional aim was to characterize the part(s) of the pharmacological profile of drugs that were important to reverse deficits. Cognitive deficits were assessed using a frontally mediated attentional set-shifting task in rats that is analogous to tasks used in humans and nonhuman primates that assess executive function. Mirroring findings in patients with schizophrenia, the classical antipsychotic haloperidol was ineffective in treating set-shifting deficits induced by subchronic treatment with phencyclidine (PCP). Similarly, second-generation antipsychotics, risperidone, clozapine, and olanzapine were ineffective. In contrast, selected doses of sertindole and the 5-HT 6 receptor antagonist SB 271046 attenuated PCPinduced set-shifting deficits. Finally, the 5-HT 2A receptor antagonist M100907 was without effect. Further examination revealed that repeated treatment (21 days) with sertindole, but not olanzapine, also was effective in reversing the executive function deficit. These data suggest that the combination of 5-HT 6 antagonistic activity and the absence of antimuscarinic activity may represent key characteristics of the pharmacological profile for improved antipsychotic drugs for schizophrenia.

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“…5-HT 6 R antagonists also enhanced acquisition and reversed a scopolamine-evoked deficit in rat operant autoshaping and passive avoidance tasks (Bos et al, 2001;Meneses, 2001;Riemer et al, 2003). Pretreatment with a 5-HT 6 R antagonist also improved rat performance of an attentional set-shifting task, a rodent analog of the Wisconsin card sorting test, a commonly used assay of cognitive-guided sorting (Hatcher et al, 2005). However, other investigators have been unable to demonstrate 5-HT 6 R-induced enhancements of cognitive function (Russell and Dias, 2002;Lindner et al, 2003).…”

Section: -Ht 6 R-influenced Behaviorsmentioning

confidence: 99%

A Null Mutation of the Serotonin 6 Receptor Alters Acute Responses to Ethanol

Bonasera

Chu

Brennan

et al. 2006

Neuropsychopharmacol

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The anatomical distribution and pharmacology of serotonin 6 receptors (5-HT 6 Rs) implicate them as contributors to the serotonergic regulation of complex behavior. To complement the limited range of pharmacological tools available to examine 5-HT 6 R function, we have generated a mouse line bearing a constitutive null mutation of the 5-HT 6 R gene. No perturbations of baseline behavior were noted in a wide array of assays pertinent to multiple neurobehavioral processes. However, 5-HT 6 R mutant mice demonstrated reduced responses to the ataxic and sedative effects of ethanol. No differences in ethanol metabolism were evident between wild-type and 5-HT 6 R mutant mice. These findings implicate 5-HT 6 Rs in the serotonergic modulation of responses to ethanol.

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5-HT6 receptor antagonists improve performance in an attentional set shifting task in rats

Abstract: 5-HT(6) receptor antagonists improved performance in the attentional set shifting task and may have therapeutic potential in the treatment of disorders where cognitive deficits are a feature, including schizophrenia.

Cited by 108 publications

References 38 publications

A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats

A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats

Reversal of Subchronic PCP-Induced Deficits in Attentional Set Shifting in Rats by Sertindole and a 5-HT6 Receptor Antagonist: Comparison Among Antipsychotics

A Null Mutation of the Serotonin 6 Receptor Alters Acute Responses to Ethanol

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