This research aimed to assess the role of dorsal hippocampal (CA1) NMDA glutamate receptors in the interaction effects of lithium and quetiapine on memory consolidation in the step-through inhibitory avoidance task in male rats.
The present data illustrate that immediately after training (post-training), intraperitoneal (i.p.) administration of higher doses of lithium impaired inhibitory avoidance learning memory consolidation. The most significant response was obtained with the 40 mg/kg dose.
These results are in agreement with our prior study and other studies, which have found that systemic and/or intra-CA1 administration of lithium impairs memory formation by altering information coding and synaptic plasticity, resulting in induction of amnesia in a variety of tasks (Pachet and Wisniewski, 2003, Senturk et al., 2007, Zarrindast et al., 2008, Parsaei et al., 2016, Amiri et al., 2020). Hence, the effects of lithium on the brain may be particularly relevant to hippocampal-dependent cognitive processes.
Furthermore, our recent findings indicated that the phosphorylation levels of CAMKII and CREB in the hippocampus and the prefrontal cortex (PFC) are inhibited in lithium-induced memory impairment, suggesting that the hippocampus and the PFC CAMKII-CREB signaling pathway may be involved in lithium’s effect on memory deficits (Amiri et al., 2020). These findings agree with the results of other studies, which reported that acute and/or chronic lithium treatment diminished CREB phosphorylation in the hippocampus and other brain regions (Rantamäki et al., 2006, Böer et al., 2008).
Despite such findings, some researchers have found that lithium had positive effects on memory consolidation using some behavioral tasks (Tsaltas et al., 2007, Shim et al., 2012), which may be due to variations in the amount of lithium administered, duration of drug exposure, site of lithium injection, and the variables examined in different tasks.
Our results also illustrated that post-training i.p. administration of lower doses of quetiapine (1.25 and 2.5 mg/kg) did not affect memory consolidation, whereas the higher doses of the same drug (5, 10, and 20 mg/kg) improved memory consolidation of inhibitory avoidance learning. In line with such findings, it has been reported that quetiapine enhances memory consolidation and retrieval in a variety of tasks (Kasper and Resinger, 2003, Potvin et al., 2003). Quetiapine treatment at the lower dose (5 mg/kg) reverses contextual fear conditioning deficits but not spatial reversal deficits in rats treated with kainic acid (an agonist of kainate-class ionotropic glutamate receptors) (Martin et al., 2005) and improved objective recognition memory in neurodegenerative animal models (Velligan et al., 2002, Mutlu et al., 2017).
Quetiapine was found to improve the decrease in BDNF-positive cells in the basolateral amygdala and hippocampus of transgenic models of mice with Alzheimer's disease (Tempier et al., 2013) through its modulating effects on neuroprotective factors such as reducing demyelination and increasing BDNF (He et al., 2020).
Moreover, it could up regulate the cerebral levels of B-cell lymphoma 2 (Bcl-2) as a neurotrophic factor in Alzheimer's disease transgenic mice (Ghasemi and Dehpour, 2011, He et al., 2018).
Despite such findings, it has recently been reported that chronic treatment with quetiapine (25 mg/kg/day for 30 or 90 days) leads to time-dependent impairments in novel object recognition (NOR) performance, enhancements in the pro-BDNF/BDNF ratio, and reductions in Akt and CREB phosphorylation in the hippocampus (Poddar et al., 2020).
This discrepancy may be due to drug doses, acute and/or chronic treatment, type of experiment, and less selective activity on diverse neurotransmitter receptors.
Multiple clinical studies have documented that treatment with quetiapine plus lithium is generally well-tolerated in patients with acute bipolar disorder (BPD) and has greater efficacy than quetiapine alone (Bourin et al., 2014). Interestingly, this study illustrated that specific doses of quetiapine can improve lithium-induced memory impairment (40 mg/kg). These results agree with the findings of other researchers who reported that quetiapine treatment ameliorated reference memory impairment induced by the phencyclidine (PCP; an NMDA receptor antagonist) in the radial arm maze task in rats (Denys et al., 2004, He et al., 2006). Furthermore, it has been reported that quetiapine improves PCP-induced cognitive deficits in mice in a dose-dependent manner (Tanibuchi et al., 2009).
It has been well documented that the CA1 NMDA receptor signaling pathways have a crucial role in synaptic plasticity, long-term potentiation (LTP), and memory formation (Warburton et al., 2013, Amiri et al., 2020).
To evaluate whether the CA1 NMDA receptor signaling pathway plays a role in the effects of lithium and quetiapine on memory consolidation, this pathway was activated and/or inhibited by the intra-CA1 administration of NMDA (an NMDA receptor agonist) and MK-801 (a noncompetitive NMDA receptor antagonist), respectively.
Our prior investigations revealed that immediate post-training intra-CA1 microinjection of higher doses of NMDA ameliorate, while MK-801 diminishes memory consolidation using inhibitory avoidance task. However, lower doses of the drugs did not affect memory consolidation (de Lima et al., 2005, Jafari-Sabet, 2006, Jafari-Sabet et al., 2017, Jafari-Sabet et al., 2018).
Multiple experimental studies have shown that the activation of CA1 NMDA receptors is involved in the learning and memory processes in a one-trial inhibitory avoidance task (Jafari-Sabet, 2006, Amiri et al., 2020). Furthermore, activating CA1 NMDA receptors by its agonists leads to the activation of CREB and CaMKII in the CA1 regions of the dorsal hippocampus in rodents using a hippocampal-associated learning task. Although inhibiting CA1 NMDA receptors by its antagonists leads to inhibition of these alterations (Cammarota et al., 2000, Amiri et al., 2020).
In another series of experiments, our findings revealed that intra-CA1 microinjection of the lower doses of NMDA (10− 5 and 10− 4 µg/rat), which did not affect memory consolidation by itself, potentiated the memory amelioration induced by the co-administration of lithium (40 mg/kg) and quetiapine (2.5 mg/kg), indicating a potentiated effect between quetiapine and NMDA.
These results are in agreement with our prior study and those of other researchers who found that post-training intra-CA1 microinjection of low dose of NMDA (10− 4 µg/rat) significantly lessened memory deficit induced by lithium in hippocampal-dependent learning and memory tasks in rodents (Parsaei et al., 2016, Amiri et al., 2020).
Our results also revealed that intra-CA1 microinjection of the lower doses of MK-801 (0.0625 and 0.125 µg/rat), which did not affect memory consolidation by itself, reversed the memory amelioration induced by the co-administration of lithium (40 mg/kg) and quetiapine (10 mg/kg), indicating that CA1 NMDA receptors signaling pathway may be involved in the interplay among lithium and quetiapine on memory consolidation.
Hence, these findings suggest a functional interaction between quetiapine and lithium via CA1 NMDA receptor mechanisms in inhibitory avoidance learning memory consolidation.
The results are consistent with our previous study and other studies, which found that post-training intra-CA1 microinjection of sub-threshold dose of the competitive and noncompetitive NMDA receptor antagonists significantly increases lithium-induced memory deficits using hippocampal-related behavioral tasks (Parsaei et al., 2016, Amiri et al., 2020). In addition, quetiapine has been shown to regulate glutamate receptor activity in the hippocampus and other areas of the brain. The stimulatory effects of quetiapine on monoamines such as norepinephrine, dopamine, and serotonin have been reported to be mediated by NMDA/glutamate receptors (Yamamura et al., 2009). Moreover, quetiapine has been shown to reduce schizophrenia-like behaviors, including memory loss, and attenuate BDNF reduction in mice treated with MK-801 (Fumagalli et al., 2004, He et al., 2020). Hence, it can be said that quetiapine affects NMDA receptor activity and modulates the effect of lithium on these receptors.