Pharmacological Blockade of Serotonin 5-HT7 Receptor Reverses Working Memory Deficits in Rats by Normalizing Cortical Glutamate Neurotransmission

Abstract

The role of 5-HT7 receptor has been demonstrated in various animal models of mood disorders; however its function in cognition remains largely speculative. This study evaluates the effects of SB-269970, a selective 5-HT7 antagonist, in a translational model of working memory deficit and investigates whether it modulates cortical glutamate and/or dopamine neurotransmission in rats. The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist. SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/kg) but augmented the deficit induced by scopolamine (0.06 mg/kg). The ability of SB-269970 to modulate MK-801-induced glutamate and dopamine extracellular levels was separately evaluated using biosensor technology and microdialysis in the prefrontal cortex of freely moving rats. SB-269970 normalized MK-801 -induced glutamate but not dopamine extracellular levels in the prefrontal cortex. Rat plasma and brain concentrations of MK-801 were not affected by co-administration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. These results indicate that 5-HT7 receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission.

Differential effects of α7 nicotinic receptor agonist PHA-543613 on spatial memory performance of rats in two distinct pharmacological dementia models

“…Such importance of the striking differences between the efficacy of memory enhancer treatments in different preclinical pharmacological models is also supported by the study of Bonaventure et al [33], where a 5-HT7 receptor antagonist diminished memory impairment caused by MK-801, but, in the same time, augmented scopolamine induced amnestic symptoms in a delayed non-matching to position task in rats.…”

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

“…The action of SB-269970 on set-shifting and object recognition in ketamine-treated animals also corroborates previous findings demonstrating its effectiveness in other cognitive domains. Accordingly, SB-269970 attenuated the PCP-induced deficits in reversal learning [9] as well as dizocilpine-induced impairment in a delayed non-matching to position task in rats [6]. SB-269970 also reversed memory deficits demonstrated in an autoshaping Pavlovian instrumental learning task in rats after systemic administration of dizocilpine [28] or after intra-PFC infusion of ketamine [29].…”

“…For example, Bonaventure et al [6] demonstrated that the effectiveness of SB-269970 in ameliorating dizocilpine-induced cognitive deficits was accompanied by normalisation of the dizocilpine-evoked enhancement of glutamate efflux in the rat mPFC. It has been suggested that the increased glutamate release in the mPFC, a secondary effect of NMDAR blockade, may be responsible for the NMDAR antagonist-induced cognitive impairment [36].…”

“…Several recent reports have suggested that these receptors may be involved in the control of learning and memory processes. While the involvement of 5-HT7 receptors in modulating cognitive processes under physiological conditions remains poorly understood [4], [5], recent data suggest that 5-HT7 antagonists are effective in overcoming cognitive impairments in an animal model of schizophrenia involving blockade of N-methyl-D-aspartate receptors (NMDARs) [6]–[9]. This issue is of special interest because several atypical antipsychotics, e.g., amisulpride and lurasidone, are characterised by a high affinity for 5-HT7 receptors [10], [11].…”

Development of CNS multi-receptor ligands: Modification of known D2 pharmacophores

“…7, 8 Several recent articles have indicated that the negative symptoms of schizophrenia may be ameliorated by activating the serotonin 5-HT 1A receptor (5-HT 1A R) 9–13 while the cognitive symptoms may be treated by agents that activate the 5-HT 1A R and antagonize the 5-HT 7 receptor (5-HT 7 R). 14–18 Taken together, we hypothesize that a drug that interacts appropriately with these receptors should have improved therapeutic outcomes over several currently marketed drugs for treating schizophrenia. Indeed, one of the most recent drugs introduced on the market, lurasidone, targets multiple receptors including D 2 , 5-HT 2A , 5-HT 7 and 5-HT 1A , and has found clinical utility not only in treating the positive symptoms of schizophrenia but also in producing improvement in cognitive symptoms, and is even prescribed for bipolar depression.…”