Agnieszka Potasiewicz

The 5-hydroxytryptamine (serotonin) receptor 6 agonist EMD 386088 ameliorates ketamine-induced deficits in attentional set shifting and novel object recognition, but not in the prepulse inhibition in rats

Preclinical data suggest that the 5-hydroxytryptamine (serotonin) 6 (5-HT6) receptor may be a potential target for the development of new therapies for treating cognitive dysfunctions in schizophrenia and other central nervous system disorders. Recent evidence indicates that not only blockade but also activation of 5-HT6 receptors exerts procognitive effects. Nevertheless, little is known about the potential efficacy of 5-HT6 receptor agonists in models of schizophrenia-like cognitive deficits. The aim of the present study was to evaluate the effects of the 5-HT6 receptor agonist, EMD 386088, on the ketamine-induced deficits in the attentional set-shifting task (ASST), novel object recognition (NOR) task and prepulse inhibition (PPI) task in rats. Acute administration of EMD 386088 (2.5 and 5 mg/kg, intraperitoneally) to Sprague-Dawley rats reversed the deficit in the ASST induced by repeated ketamine administration. Moreover, the ketamine-induced deficit in the NOR task was ameliorated by EMD 386088 at a dose of 5 mg/kg. However, in contrast to the antipsychotic drug clozapine, the 5-HT6 agonist did not affect PPI disrupted by ketamine. The present study demonstrated the beneficial effects of the 5-HT6 agonist in ameliorating some of the ketamine-induced deficits relevant to schizophrenia. It thus seems likely that the 5-HT6 receptor activation may represent a useful pharmacological approach to the treatment of cognitive disturbances observed in this disorder.

Pro‐cognitive activity in rats of 3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor

α7 nicotinic acetylcholine receptors (α7 nAChRs) may represent useful targets for cognitive improvement. The aim of this study is to compare the pro‐cognitive activity of selective α7‐nAChR ligands, including the partial agonists, DMXBA and A‐582941, as well as the positive allosteric modulator, 3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide (PAM‐2).

3-Furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the α7 nicotinic receptor, reverses schizophrenia-like cognitive and social deficits in rats

&NA; The cognitive impairments and negative symptoms experienced by schizophrenia patients still await effective treatment. Alpha7 nicotinic acetylcholine receptors (&agr;7 nAChRs) have gain considerable attention in this regard. It has been recently proposed that positive allosteric modulators (PAMs) of &agr;7 nAChRs may represent an alternative strategy to that based on orthosteric agonists. The aim of the present study is to evaluate the efficacy of PAM‐2 (3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide) against cognitive deficits and negative‐like symptoms in a rat model of schizophrenia based on administration of ketamine, a NMDAR antagonist. The activity of PAM‐2 was compared to that elicited by DMXBA, an &agr;7 nAChR partial agonist. For this purpose, the attentional set‐shifting task (ASST) and the novel object recognition task (NORT) were used. The efficacies of PAM‐2 and DMXBA against ketamine‐induced social withdrawal were assessed using the social interaction test (SIT). The results demonstrated that PAM‐2 and DMXBA ameliorated ketamine‐induced cognitive impairments on the ASST and NORT as well as produced pro‐social activities in the SIT. Moreover, the co‐administration of inactive doses of PAM‐2 and antipsychotic drugs, clozapine or risperidone, reversed ketamine‐induced deficits. The present findings provide further support for the concept that &agr;7‐PAMs could be used either alone or in combination with antipsychotics for schizophrenia therapy. HighlightsWe evaluated the pro‐cognitive and pro‐social efficacies of the &agr;7‐nAChRs PAM in rats.PAM‐2 reversed ketamine‐induced cognitive impairments and social withdrawal.The effects of PAM‐2 were comparable to those of the &agr;7‐nAChR agonist, DMXBA.Combination of PAM‐2 and antipsychotics reversed impaired object recognition.

The effects of PDE10 inhibition on attentional set-shifting do not depend on the activation of dopamine D1 receptors.

Inhibitors of phosphodiesterase 10A (PDE10A) represent a novel class of potential antipsychotic compounds. These principles increase the level of cAMP and cGMP in the medium spiny neurons of the striatum and resemble the neurochemical consequences of dopamine D2 receptor inhibition and dopamine D1 receptor stimulation. Cognitive dysfunctions, including an impaired ability to shift perceptual attentional set, are core features of schizophrenia. In the present study, we investigated the involvement of D1 receptors in the procognitive action of the PDE10A inhibitor using the attentional set-shifting task in rats. The performance of the rats in the extradimensional shift stage of the attentional set-shifting task was taken as an index of cognitive flexibility. We first assessed the effects of the D1 agonist in otherwise untreated animals and in animals pretreated with the D1 receptor antagonist. We then investigated the procognitive effects of the PDE10A inhibitor, MP-10, in otherwise untreated animals and in animals pretreated with the D1 receptor antagonist. The dopamine D1 receptor antagonist SCH-23390 produced cognitive impairment at the dose of 0.0125 mg/kg, but not at 0.0063 mg/kg. The D1 receptor agonist, SKF-81,297, produced a procognitive effect that was abolished by 0.0063 mg/kg of SCH-23390. The compound MP-10 produced a procognitive effect at the dose of 0.3 mg/kg, but not at 0.1 mg/kg. Rat pretreatment with 0.0063 mg/kg of SCH-23390 did not block the procognitive effect of 0.3 mg/kg of MP-10. The present study demonstrates that the blockade of dopamine D1 receptors is unlikely to affect the procognitive effects of PDE10A inhibition.

Effects of the selective 5-HT7 receptor antagonist SB-269970 on premature responding in the five-choice serial reaction time test in rats

The antagonists of serotonin 5-HT7 receptors have been demonstrated to ameliorate cognitive impairments in pharmacological animal models of schizophrenia that involve blockade of N-methyl-D-aspartate receptors (NMDARs). The administration of NMDAR antagonists evokes a broad range of cognitive deficits, including a loss of impulse control. The involvement of 5-HT7 receptors in the modulation of impulsivity has been recently suggested but has not been studied in great detail. The aim of the present study was to examine the effect of a selective 5-HT7 receptor antagonist SB-269970 on a measure of impulsive action, i.e., premature responding on the five-choice serial reaction time task (5-CSRTT) in rats. The antagonist of 5-HT2A receptor M100,907 was used as a positive control. The efficacies of both compounds were assessed in conditions of increased impulsivity that were produced by the administration of the NMDAR antagonist MK-801 or/and non-drug stimuli, i.e., using variable inter-trial intervals (vITIs). To examine the general ability of SB-269970 to counteract the MK-801-induced impairments, a discrete paired-trial delayed alternation task in a T-maze was employed. MK-801 significantly increased the number of premature responses in 5-CSRTT, and this effect was abolished by the administration of M100,907 (0.5 mg/kg) and SB-269970 (1 mg/kg). In addition, M100,907, but not SB-269970, reduced premature responding in the prolonged ITI trials. Both M100,907 and SB-269970 attenuated MK-801-induced working memory impairment in a T-maze. The present study demonstrated the efficacy of SB-269970 against MK-801-induced premature responding in the 5-CSRTT. This anti-impulsive action may offer additional benefits to the cognitive-enhancing effects of pharmacological blockade of 5-HT7 receptors.

Stimulation of nicotinic acetylcholine alpha7 receptors rescue schizophrenia-like cognitive impairments in rats

Alpha7 nicotinic acetylcholine receptor (α7 nAChR) dysfunction plays an important role in schizophrenia. Positive allosteric modulators of α7 nAChR have emerged as a promising therapeutic approach to manage cognitive deficits that are inadequately treated in schizophrenic patients. The aim of the present study was to evaluate the ability of type I (CCMI) and type II (PNU120596) α7 nAChR positive allosteric modulators to counteract MK-801-induced cognitive and sensorimotor gating deficits. The activity of these compounds was compared with the action of the α7 nAChR agonist A582941. CCMI, PNU120596 and A582941 reversed the sensorimotor gating impairment evoked by MK-801 based on the prepulse inhibition of the startle response. Additionally, no MK-801-evoked working memory deficits were observed with α7 nAChR ligand pretreatment as assessed in a discrete paired-trial delayed alternation task. However, these compounds did not affect the rats’ attentional performances in the five-choice serial reaction time test. The α7 nAChR agents demonstrated a beneficial effect on sensorimotor gating and some aspects of cognition tested in a rat model of schizophrenia. Therefore, these results support the use of α7 nAChR positive allosteric modulators as a potential treatment strategy in schizophrenia.