Metaplastic Effects of Ketamine and MK-801 on Glutamate Receptors Expression in Rat Medial Prefrontal Cortex and Hippocampus

Abstract

Ketamine and MK-801 by blocking NMDA receptors may induce reinforcing effects as well as schizophrenia-like symptoms. Recent results showed that ketamine can also effectively reverse depressive signs in patients’ refractory to standard therapies. This evidence clearly points to the need of characterization of effects of these NMDARs antagonists on relevant brain areas for mood disorders. The aim of the present study was to investigate the molecular changes occurring at glutamatergic synapses 24 h after ketamine or MK-801 treatment in the rat medial prefrontal cortex (mPFC) and hippocampus (Hipp). In particular, we analyzed the levels of the glutamate transporter-1 (GLT-1), NMDA receptors, AMPA receptors subunits, and related scaffolding proteins. In the homogenate, we found a general decrease of protein levels, whereas their changes in the post-synaptic density were more complex. In fact, ketamine in the mPFC decreased the level of GLT-1 and increased the level of GluN2B, GluA1, GluA2, and scaffolding proteins, likely indicating a pattern of enhanced excitability. On the other hand, MK-801 only induced sparse changes with apparently no correlation to functional modification. Differently from mPFC, in Hipp, both substances reduced or caused no changes of glutamate receptors and scaffolding proteins expression. Ketamine decreased NMDA receptors while increased AMPA receptors subunit ratios, an effect indicative of permissive metaplastic modulation; conversely, MK-801 only decreased the latter, possibly representing a blockade of further synaptic plasticity. Taken together, these findings indicate a fine tuning of glutamatergic synapses by ketamine compared to MK-801 both in the mPFC and Hipp.

CBD Effects on Motor Profile and Neurobiological Indices Related to Glutamatergic Function Induced by Repeated Ketamine Pre-Administration

“…Overall, our data show a repeated KET-induced increase in GluN1, GluN2A, and GluN2B subunits in the PFC and the NAc. Taking into consideration previous studies that support the dampening effects of sub-anesthetic KET on these subunits’ protein expression ( Brakatselos et al, 2021 ; Piva et al, 2021 ), we could postulate that the increase observed in the current study can be related with homeostatic, compensatory mechanisms that function towards the normalization of neurotransmission and neuroplastic processes after sustained KET exposure. In this case, CBD treatment in a crucial time frame before the protein expression read-out, modulates KET-induced changes only in the PFC, thus exhibiting a region-specific homeostatic role.…”

“…Ketamine acts as an uncompetitive inhibitor of NMDA glutamate receptors ( Martin and Lodge, 1985 ). NMDA receptor hypofunction is associated with the neurobiology and symptomatology of schizophrenia, while glutamatergic neurotransmission has been essentially related to cognitive function and neuroplasticity ( Frohlich and Van Horn, 2014 ; Piva et al, 2021 ).…”

“…Post-mortem findings from patients with schizophrenia, as well as preclinical studies link the disease’s biological substrate with impaired expression of glutamate receptors ( Meador-Woodruff and Healy, 2000 ; Mueller et al, 2004 ; Benesh et al, 2020 ), which, in turn, is regarded as an index of neuroplasticity ( El-Gaamouch et al, 2012 ; Brakatselos et al, 2021 ; Piva et al, 2021 ). In parallel, NMDA receptor inhibitors, including KET, have been shown to affect neuroplastic indices in a plethora of experimental models; these neuroplastic effects involve changes in the glutamate receptor status in terms of expression, subunit composition, phosphorylation state, and downstream signaling ( Anver et al, 2011 ; Kamiyama et al, 2011 ; McNally et al, 2011 ; Izumi and Zorumski, 2014 ; Widman and McMahon, 2018 ; Piva et al, 2021 ).…”

“…Post-mortem findings from patients with schizophrenia, as well as preclinical studies link the disease’s biological substrate with impaired expression of glutamate receptors ( Meador-Woodruff and Healy, 2000 ; Mueller et al, 2004 ; Benesh et al, 2020 ), which, in turn, is regarded as an index of neuroplasticity ( El-Gaamouch et al, 2012 ; Brakatselos et al, 2021 ; Piva et al, 2021 ). In parallel, NMDA receptor inhibitors, including KET, have been shown to affect neuroplastic indices in a plethora of experimental models; these neuroplastic effects involve changes in the glutamate receptor status in terms of expression, subunit composition, phosphorylation state, and downstream signaling ( Anver et al, 2011 ; Kamiyama et al, 2011 ; McNally et al, 2011 ; Izumi and Zorumski, 2014 ; Widman and McMahon, 2018 ; Piva et al, 2021 ). In particular, ERK1/2 signaling is involved in NMDA receptors downstream processes, and plays a pivotal role in the integration of neurotransmission events, the regulation of synaptic plasticity, and cognitive functions ( Sun and Nan 2017 ; Albert-Gascó et al, 2020 ), while preclinical and post-mortem studies associate abnormal ERK signaling with schizophrenia manifestation ( Kyosseva 2003 ).…”

“…Furthermore, KET has been shown to affect ERK signaling in brain regions associated with the biological substrate of schizophrenia ( Ahn et al, 2006 ; Bharne et al, 2016 ; Nygard et al, 2017 ; Meng et al, 2020 ). Although there are many studies investigating the effects of acute or repeated KET administration ( Becker et al, 2003 ; Trujillo et al, 2008 ; Nikiforuk and Popik, 2012 ; Sampaio et al, 2018 ), there is no consensus on a specific experimental pattern for approaching schizophrenia and linking symptomatology to neurobiology, while there is limited information concerning the impact of acute or repeated KET administration on neuroplasticity indices ( Luo et al, 2020 ; Brakatselos et al, 2021 ; Piva et al, 2021 ).…”