Translating the N-methyl-d-aspartate receptor antagonist model of schizophrenia to treatments for cognitive impairment in schizophrenia

Abstract

The N-methyl-D-aspartate receptor (NMDAR) antagonists, phencyclidine (PCP), dizocilpine (MK-801), or ketamine, given subchronically (sc) to rodents and primates, produce prolonged deficits in cognitive function, including novel object recognition (NOR), an analog of human declarative memory, one of the cognitive domains impaired in schizophrenia. Atypical antipsychotic drugs (AAPDs) have been reported to improve declarative memory in some patients with schizophrenia, as well as to ameliorate and prevent the NOR deficit in rodents following scNMDAR antagonist treatment. While the efficacy of AAPDs to improve cognitive impairment in schizophrenia (CIS) is limited, at best, and controversial, single doses of all currently available AAPDs so far tested transiently restore NOR in rodents following scNMDAR antagonist treatment. Typical antipsychotic drugs (APDs), e.g. haloperidol and perphenazine, are ineffective in this rodent model, and may be less effective as treatments of some domains of CIS. Serotonergic mechanisms, including, but not limited to serotonin (5-HT)2A and 5-HT7 antagonism, 5-HT(1A), and GABA(A) agonism, contribute to the efficacy of the AAPDs in the scNMDAR antagonist rodent models, which are relevant to the loss of GABA interneuron/hyperglutamate hypothesis of the etiology of CIS. The ability of sub-effective doses of the atypical APDs to ameliorate NOR in the scNMDAR-treated rodents can be restored by the addition of a sub-effective dose of the 5-HT(1A) partial agonist, tandospirone, or the 5-HT7 antagonist, SB269970. The mGluR2/3 agonist, LY379268, which itself is unable to restore NOR in the scNMDAR-treated rodents, can also restore NOR when given with lurasidone, an AAPD. Enhancing cortical and hippocampal dopamine and acetylcholine efflux, or both, may contribute to the restoration of NOR by the atypical APDs. Importantly, co-administration of lurasidone, tandospirone, or SB269970, with PCP, to rodents, at doses 5-10 fold greater than those acutely effective to restore NOR following scNMDAR treatment, prevents the effect of scPCP to produce an enduring deficit in NOR. This difference in dosage may be relevant to utilizing AAPDs to prevent the onset of CIS in individuals at high risk for developing schizophrenia. The scNMDAR paradigm may be useful for identifying possible means to treat and prevent CIS.

Successful treatment with risperidone increases 5‐HT 3A receptor gene expression in patients with paranoid schizophrenia – data from a prospective study

“…Previous studies demonstrated the activation of 5‐HT3A receptor could increase dopamine release (Liu, Thielen, Rodd, & Mcbride, 2006), and the elevation of dopamine might contribute to the improvement of schizophrenic symptoms (Díaz‐Mataix et al., 2005). Furthermore, lines of evidence indicated the ability of 5‐HT3 receptors to modulate the release of acetylcholine and GABA (gama‐amino butyric acid) (Choi et al., 2007), which were thought to be involved in antipsychotics efficiency (Meltzer et al., 2013). Whether risperidone functions though upregulating 5‐HT3A receptor, thus inducing the release of the neurotransmission is worthy of further investigation.…”

Effects of haloperidol, olanzapine, ziprasidone, and PHA‐543613 on spatial learning and memory in the Morris water maze test in naïve and MK‐801‐treated mice

“…The hypofunction of glutamatergic receptors is the pathophysiology of schizophrenia of the glutamatergic hypothesis, and the N-methyl-d-aspartate receptor (NMDAR) antagonists, such as dizocilpine (MK-801), phencyclidine, and ketamine, produce schizophrenia-like behavior and cognitive deficits (Gaspar, Bustamante, Silva, & Aboitiz, 2009;Lobellova et al, 2013;Meltzer et al, 2013). Acute treatment with MK-801 is extensively utilized to establish animal model of cognitive impairment, such as spatial learning and memory.…”

Superior effects of quetiapine compared with aripiprazole and iloperidone on MK-801-induced olfactory memory impairment in female mice

“…Aripiprazole is an atypical antipsychotic with a novel pharmacological profile that acts as a partial agonist of dopamine D 2 and D 3 and serotonin (5-HT) 5-HT 1A receptors, and as an antagonist for 5-HT 2A receptors (17,18). Aripiprazole has moderate affinity for histamine, α-adrenergic, and D 4 receptors, as well as the serotonin transporter; however, it has no appreciable affinity for cholinergic muscarinic receptors (17,18) Different NMDA receptor antagonist-induced experimental models have been investigated to demonstrate the cognitive impairments, and selective ligands for serotonin and adrenoceptors have been examined in these models (22,23). In addition, post-training administration of the specific 5-HT7 receptor antagonists, SB-269970 and DR-4004, improved MK-801-induced memory impairments in rat auto-shaping tasks (22).…”

“…Aripiprazole has moderate affinity for histamine, α-adrenergic, and D 4 receptors, as well as the serotonin transporter; however, it has no appreciable affinity for cholinergic muscarinic receptors (17,18) Different NMDA receptor antagonist-induced experimental models have been investigated to demonstrate the cognitive impairments, and selective ligands for serotonin and adrenoceptors have been examined in these models (22,23). In addition, post-training administration of the specific 5-HT7 receptor antagonists, SB-269970 and DR-4004, improved MK-801-induced memory impairments in rat auto-shaping tasks (22). Quetiapine reversed MK-801-induced deficits in the current study and this may be linked via the interactions between serotonin receptors and adrenoceptors.…”