The selective 5-HT 6 receptor antagonist SLV has putative cognitive- and social interaction enhancing properties in rodent models of cognitive impairment

Characterization of Behavioral, Signaling and Cytokine Alterations in a Rat Neurodevelopmental Model for Schizophrenia, and Their Reversal by the 5-HT6 Receptor Antagonist SB-399885

“…Locomotor hyperactivity in isolation-reared rats has been attributed to sensitization of the mesolimbic dopaminergic pathway [ 54 – 56 ] but the transient nature of this hyperactivity in the current study, together with the locomotor effect of SB-399885 in group-housed rats precludes any firm conclusions on drug-induced normalization of the housing effect. Likewise the lack of an isolation-induced PPI deficit in the current study (which may be related to strain and/or weaning age [ 57 , 58 ]) prevented any evaluation of potential reversal by SB-399885, but other recent studies have just revealed that chronic 5-HT 6 receptor antagonist administration can restore PPI in isolation-reared Wister rats [ 15 ] and may have some adjunctive benefit against the positive symptoms in female patient sub-groups [ 59 ].…”

“…Although 5-HT 6 receptor antagonists prolong memory in normal animals and reverse a variety of pharmacological deficits, their effects in relevant neurodevelopmental models are less well characterized. In addition to supporting known links to PI3K/Akt [ 14 ] and Erk1/2 [ 17 – 19 ] signaling and replicating reversal of isolation-induced recognition memory deficits [ 13 , 15 ] with a structurally unrelated antagonist, this study provides the first evidence for potential modulation of associative memory and cell proliferation within the dentate gyrus in this model, and is also the first to reveal downstream effects of a 5-HT 6 receptor antagonist on members of the JNK signaling pathway. The reverse-phase protein microarray technique provides a more direct functional measure than RNA analysis, and has previously been employed to study allergy [ 46 ], inflammation [ 47 ], cancer [ 48 ] and tumor necrosis factor receptor-associated periodic syndrome (TRAPS) [ 25 , 49 ], although its current application to neurodevelopmental disorders and neuropharmacology is relatively novel.…”

“…There is substantial preclinical evidence that they enhance rodent cognitive performance across a variety of domains and reverse NMDA receptor antagonist-induced deficits in pharmacological models of schizophrenia [ 12 ]. Although previous studies have shown reversal of isolation-induced deficits in visual recognition memory by 5-HT 6 receptor antagonists [ 13 – 15 ] further evaluation against a broader array of cognitive deficits in this non-pharmacological neurodevelopmental model appears justified.…”

Calbindin Deficits May Underlie Dissociable Effects of 5-HT6 and mGlu7 Antagonists on Glutamate and Cognition in a Dual-Hit Neurodevelopmental Model for Schizophrenia

“…A diverse array of compounds, including 5-HT 6 antagonists [42,[110][111][112], an mGlu 2/3 agonist [49], NMDA receptor glycine modulatory site partial agonist [113], α4β2 and α7 nicotinic receptor agonists [114], donepezil [115], risperidone [47], and fluoxetine [116], all reverse "single-hit" isolation-induced NOD deficits. Some of these approaches are associated with clinical benefit in other psychiatric or neurodegenerative disorders but ultimately lack marked clinical benefit in schizophrenia [117][118][119].…”

Multiple dissociation constants of the Intepirdine hydrochloride using regression of multiwavelength spectrophotometric pH-titration data

“…Intepirdine has also has been reported to reverse both experimentally induced and age-related learning deficits in rats [2] [3]. In December 2014, Axovant Sciences acquired the rights to this drug and renamed it RVT-101 [4][5][6]. At AAIC 2015, it was presented [7] a more thorough analysis of prior Phase 2b GSK data that had been analyzed previously based on the intent-to-treat population, and came up with a slightly larger effect size on essentially similar efficacy results.…”