Effects of the Selective 5-HT7 Receptor Antagonist SB-269970 and Amisulpride on Ketamine-Induced Schizophrenia-like Deficits in Rats

Abstract

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.

Brexpiprazole II: Antipsychotic-Like and Procognitive Effects of a Novel Serotonin-Dopamine Activity Modulator

“…It has been reported that haloperidol is ineffective whereas risperidone, olanzapine, and clozapine show nonsignificant trends toward improved ED-shift performance, and other antipsychotics, sertindole, and quetiapine show full reversal (Rodefer et al, 2008;Goetghebeur and Dias, 2009;Nikiforuk and Popik, 2012). In addition, studies of selective 5-HT receptor subtype antagonists indicate that the 5-HT 2A antagonist M100907 has borderline effects similar to risperidone whereas a 5-HT 6 antagonist [SB-271046, 5-chloro-N-[4-methoxy-3-(1-piperazinyl) phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide hydrochloride] and 5-HT 7 antagonist [SB-269970, (R)-3-{2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidin-1-ylsulfonyl}phenol] replicate the profile of sertindole (Rodefer et al, 2008;Nikiforuk et al, 2013). Therefore, the effect of brexpiprazole in this model would be associated with its potent 5-HT 2A and modest 5-HT 6 receptor antagonist activity (Maeda et al, 2014).…”

Serotonin 7 Receptor Variants Are Not Associated with Response to Second-Generation Antipsychotics in Japanese Schizophrenia Patients

“…Recently, 5-HT7R has been found to play important roles in circadian rhythm [10,11], sleep [12,13], body temperature regulation [14], and neurological development of the hippocampus and prefrontal cortex [15,16,17]. In addition, in the field of psychiatry, its roles in antidepressant and anxiolytic actions [18,19,20], memory, and learning have been demonstrated in animal models [21,22,23,24,25,26]. Several lines of evidence suggest that 5-HT7R plays a relevant role in schizophrenia pathogenesis and treatment response.…”

“…Indeed, a decrease in the expression of the HTR7 gene in the prefrontal cortex has been reported in postmortem brain tissue of patients with schizophrenia [27], and a relationship with sites located near to the HTR7 gene has been reported in genome-wide linkage studies of schizophrenia [28,29]. Based on ethnopharmacological animal studies, it has been hypothesized that 5-HT7R antagonism may be related to the etiology of schizophrenia and may be effective for improving cognitive function [22,23,24,25,26]. Indeed, several second-generation antipsychotic (SGA) drugs, such as amisulpride, clozapine, lurasidone, risperidone, quetiapine, aripiprazole, and perospirone, are known to have a high affinity for 5-HT7R [30,31,32,33].…”

“…Indeed, several second-generation antipsychotic (SGA) drugs, such as amisulpride, clozapine, lurasidone, risperidone, quetiapine, aripiprazole, and perospirone, are known to have a high affinity for 5-HT7R [30,31,32,33]. In addition, during treatment with amisulpride or lurasidone, an association between 5-HT7R antagonism and improvements in cognitive function has been demonstrated [24,26,34]. This evidence suggests that 5-HT7R antagonism may be a mechanism for the improvement of schizophrenia symptoms.…”

Drug design of 5-substituted-2-aminotetralins targeting the serotonin 5-HT7 receptor

“…34 These results show that 5-HT 7 blockade may be beneficial when in amnesic states or in improving memory consolidation. In regard to amnesic conditions SB-269970 also was able to improve on baseline recognition memory in a novel object recognition test 35 Blockade also improved cognitive inflexibility, a measurement of executive function, 36 which is often impaired in ASD. This also importantly shows that 5-HT 7 blockade can have positive effects on cognition without using drugs that attenuate baseline cognitive performance.…”