Effects of the selective 5-HT7 receptor antagonist SB-269970 and amisulpride on ketamine-induced schizophrenia-like deficits in rats.

A wide body of evidence suggests that 5-HT7 receptors are implicated in a variety of central nervous system functions, including control of learning and memory processes. According to recent preclinical data, the selective blockade of these receptors may be a potential target for cognitive improvement in schizophrenia. The first aim of the present study was to evaluate the effects of the selective 5-HT7 receptor antagonist, SB-269970, and the antipsychotic drug with a high affinity for 5-HT7 receptors, amisulpride, on ketamine-induced deficits in attentional set-shifting and novel object recognition tasks in rats. Because the role of 5-HT7 receptor blockade in ameliorating positive and negative symptoms of schizophrenia remains equivocal, the second aim of these experiments was to examine the effectiveness of SB-269970 and amisulpride in reversing ketamine-induced deficits in prepulse inhibition of the startle reflex and in social interaction test in rats. The study revealed that acute administration of SB-269970 (1 mg/kg) or amisulpride (3 mg/kg) ameliorated ketamine-induced cognitive inflexibility and novel object recognition deficit in rats. Both compounds were also effective in attenuating ketamine-evoked disruption of social interactions. In contrast, neither SB-269970 nor amisulpride affected ketamine-disrupted prepulse inhibition or 50 kHz USVs accompanying social behaviour. In conclusion, antagonism of 5-HT7 receptors may represent a useful pharmacological approach in the treatment of cognitive deficits and some negative symptoms of schizophrenia

The effect of amisulpride on the ketamine-induced disruption of PPI.

<p>PPI was evaluated at three prepulse intensities (70, 73 and 76 dB). Data are shown as the mean ± S.E.M. N = 6–10 rats per group.</p

Order of discriminations performed.

<p>An example of the cue combinations used in the attentional set shifting task (ASST) of rats that were shifted from the digging medium to odour as the relevant dimension. Rats performed a series of 7 discriminations: simple discrimination (SD), compound discrimination (CD), reversal 1 (Rev1), intradimensional shift (ID), reversal 2 (Rev 2), extradimensional shift (ED), reversal 3 (Rev 3). The correct exemplar (shown in bold) was paired with either of two exemplars from the irrelevant dimension (i.e., at the CD phase, the clay pellets were paired with either rum or cream odour, etc). In the ID and ED, there were novel pairs of exemplars of each dimension.</p

The effect of SB-269970 on ketamine-induced cognitive impairment in the NOR test.

<p>Data are shown as the mean ± S.E.M. N<i> = </i>8–9 rats per group. <b>A</b> Exploration time of two identical objects in the acquisition trial (T1); <b>B</b> Exploration time of a novel and a familiar object in the retention trial (T2). Symbols: ***p<0.001 significant difference in time spent exploring the novel compared with the familiar object; <b>C</b> Discrimination Index (DI). Symbols: ***p<0.001 significant reduction in DI compared to the vehicle-treated group, ^###p<0.001, significant improvement in DI compared to the ketamine-treated group.</p

The effect of SB-269970 and amisulpride on the ketamine-disrupted social behaviour and ultrasonic vocalisations.

<p>Results represent the mean ± S.E.M. of total time spent in active social interaction (A) and the total number of USVs (B) per pair of rats. N = 5–6 pairs of rats per group. Symbols: ***p<0.001 significant reduction compared to the vehicle-treated group, ^##p<0.01, ^#p<0.05 significant reversal of ketamine-induced deficit.</p

The effect of amisulpride on ketamine-induced cognitive impairment in the NOR test.

<p>Data are shown as the mean ± S.E.M. N = 9–10 rats per group. <b>A</b> Exploration time of two identical objects in the acquisition trial (T1); <b>B</b> Exploration time of a novel and a familiar object in the retention trial (T2). Symbols: ***p<0.001 significant difference in time spent exploring the novel compared with the familiar object; <b>C</b> Discrimination index (DI). Symbols: ***p<0.001, **p<0.01, significant reduction in DI compared to the vehicle-treated group, ^###p<0.001, significant improvement in DI compared to the ketamine-treated group.</p